Summary
56%
|
Pharmacokinetic
|
-18% | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Erythromycin | |||||||||||
| Alfentanil | |||||||||||
| Efavirenz | |||||||||||
| Scores | -12% | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
|
QT time prolongation
| |||||||||||
|
Anticholinergic effects
| |||||||||||
|
Serotonergic effects
| |||||||||||
|
Adverse drug events
|
-14% | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Nausea | |||||||||||
| Hypercholesterolemia | |||||||||||
| Vomiting | |||||||||||
Variants ✨
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Intended use
Explanations of the substances for patients
Pharmacokinetics
-18%
| ∑ Exposurea | ery | alf | efa | |
|---|---|---|---|---|
| Erythromycin | 0.79 | n.a. | 0.79 | |
| Alfentanil | 0.23 | 2.66 | 0.2 | |
| Efavirenz | 1.01 [1.01,1.89] 1 | 1.01 | 1 |
Relevant genotypes: 1CYP2B6
Symbol (a): x-fold change in AUC
Legend (n.a.): Information not available
Symbol (a): x-fold change in AUC
Legend (n.a.): Information not available
The changes in exposure mentioned relate to changes in the plasma concentration-time curve [AUC]. Efavirenz exposure increases to 101%, when combined with erythromycin (101%) and alfentanil (100%). The AUC is between 101% and 189% depending on the CYP2B6
Rating:
The pharmacokinetic parameters of the average population are used as the starting point for calculating the individual changes in exposure due to the interactions.
Erythromycin has a low oral bioavailability [ F ] of 24%, which is why the maximum plasma level [Cmax] tends to change strongly with an interaction. The terminal half-life [ t12 ] is rather short at 2.3 hours and constant plasma levels [ Css ] are reached quickly. The protein binding [ Pb ] is moderately strong at 73% and the volume of distribution [ Vd ] is 56 liters, which is why, with a mean hepatic extraction rate of 0.42, both liver blood flow [Q] and a change in protein binding [Pb] are relevant. The metabolism mainly takes place via CYP3A4 and the active transport takes place partly via MRP2 and PGP.
Alfentanil has a mean oral bioavailability [ F ] of 41%, which is why the maximum plasma levels [Cmax] tend to change with an interaction. The terminal half-life [ t12 ] is rather short at 1.1 hours and constant plasma levels [ Css ] are reached quickly. The protein binding [ Pb ] is moderately strong at 90% and the volume of distribution [ Vd ] is 36 liters in the middle range. Since the substance has a low hepatic extraction rate of 0.24, displacement from protein binding [Pb] in the context of an interaction can increase exposure. The metabolism mainly takes place via CYP3A4.
Efavirenz has a mean oral bioavailability [ F ] of 73%, which is why the maximum plasma levels [Cmax] tend to change with an interaction. The terminal half-life [ t12 ] is rather long at 47.5 hours and constant plasma levels [ Css ] are only reached after more than 190 hours. The protein binding [ Pb ] is very strong at 99.6% and the volume of distribution [ Vd ] is very large at 184 liters, The metabolism takes place via CYP1A2, CYP2B6 and CYP3A4, among others and the active transport takes place partly via BCRP and UGT2B7.
Serotonergic effects
-4%
| Scores | ∑ Points | ery | alf | efa |
|---|---|---|---|---|
| Serotonergic Effects a | 1 | Ø | + | Ø |
Symbol (a): Increased risk from 5 points.
Recommendation: As a precautionary measure, symptoms of serotonergic overstimulation should be taken into account, especially after increasing the dose and at doses in the upper therapeutic range.
Rating: Alfentanil has a mild effect on the serotonergic system. The risk of a serotonergic syndrome can be classified as low with this medication if the dosage is in the usual range. According to our knowledge, neither erythromycin nor efavirenz increase serotonergic activity.
Anticholinergic effects
-0%
| Scores | ∑ Points | ery | alf | efa |
|---|---|---|---|---|
| Kiesel b | 0 | Ø | Ø | Ø |
Symbol (b): Increased risk from 3 points.
Rating: According to our findings, neither erythromycin, alfentanil nor efavirenz increase anticholinergic activity.
QT time prolongation
-10%
| Scores | ∑ Points | ery | alf | efa |
|---|---|---|---|---|
| RISK-PATH c | 3.5 | +++ | Ø | ++ |
Symbol (c): Increased risk from 10 points. Questions about risk factors should be answered.
Recommendation:
In order to be able to estimate the individual risk for arrhythmias, we recommend that you answer the following
Rating: In combination, erythromycin and efavirenz can potentially trigger ventricular arrhythmias of the torsades de pointes type. We do not know of any QT-prolonging potential for alfentanil.
General adverse effects
-14%
| Side effects | ∑ frequency | ery | alf | efa |
|---|---|---|---|---|
| Nausea | 33.0 % | + | 28.0↓ | 6.0 |
| Hypercholesterolemia | 31.5 % | n.a. | n.a. | 31.5 |
| Vomiting | 22.5 % | + | 18.0↓ | 4.5 |
| Hypertension | 18.0 % | n.a. | 18.0↓ | n.a. |
| Tachycardia | 12.0 % | n.a. | 12.0↓ | n.a. |
| Rash | 11.6 % | n.a. | n.a. | 11.6 |
| Hypotension | 10.0 % | n.a. | 10.0↓ | n.a. |
| Diarrhea | 9.4 % | + | n.a. | 8.5 |
| Pruritus | 9.0 % | n.a. | n.a. | 9.0 |
| Dizziness | 8.5 % | n.a. | n.a. | 8.5 |
Tabular extract of the most common side effects
Sign (+): side effect described, but frequency not known
Sign (↑/↓): frequency rather higher / lower due to exposure
Sign (+): side effect described, but frequency not known
Sign (↑/↓): frequency rather higher / lower due to exposure
Systemic
Fatigue (7.5%): efavirenz
Respiratory
Apnea (6%): alfentanil
Respiratory depression (2%): alfentanil
Laryngeal spasm: alfentanil
Neurological
Headache (5.7%): efavirenz
Dream disorder: efavirenz
Seizure: erythromycin, alfentanil
Raised intracranial pressure: alfentanil
Mental
Depression (1.6%): efavirenz
Suicidal: efavirenz
Gastrointestinal
Abdominal pain: erythromycin
Loss of appetite: erythromycin
Clostridium difficile diarrhea: erythromycin
Pancreatitis: erythromycin
Hepatic
Elevated ALT: efavirenz
Elevated AST: efavirenz
Elevated GGT: efavirenz
Cholestatic hepatitis: erythromycin
Liver failure: erythromycin, efavirenz
Metabolic
Hypertriglyceridemia: efavirenz
Immunological
Hypersensitivity reaction: alfentanil
Allergic skin reactions like pruritus and rash: erythromycin
Angioedema: erythromycin
Auricular
Hearing loss: erythromycin
Cardiac
Ventricular arrhythmia: erythromycin
Asystole: alfentanil
Bradycardia: alfentanil
Dermatological
Stevens johnson syndrome: erythromycin, efavirenz
Toxic epidermal necrolysis: erythromycin
Erythema multiforme: efavirenz
Renal
Tubulointerstitial nephritis: erythromycin
Limitations
Based on your
References
Authors: Freedman RA Anderson KP Green LS Mason JW
Abstract: No Abstract available
Pubmed Id: 3812231
Abstract: No Abstract available
Authors: Wong CB Windle J
Abstract: Erythromycin is a widely used antibiotic in today's armamentarium of antibiotics. Although erythromycin induced ventricular tachyarrhythmia is rare, this potentially life-threatening reaction should be kept in mind. The relative rarity of 'torsades de pointes' arrhythmia suggests that other predisposing factors contribute to the acquired long QT syndrome. Since more and more macrolide products have been approved by the Food and Drug Administration for use in the United States, the potential problem with 'torsades de pointes' may exist with each of the macrolide antibiotic. Until the exact mechanisms of the arrhythmia are worked out, close monitoring of rhythms and QT intervals of high risk patients who require erythromycin is certainly advisable. Only a heightened awareness among the physicians and medical personnel can the adverse outcome be minimized.
Pubmed Id: 7566254
Abstract: Erythromycin is a widely used antibiotic in today's armamentarium of antibiotics. Although erythromycin induced ventricular tachyarrhythmia is rare, this potentially life-threatening reaction should be kept in mind. The relative rarity of 'torsades de pointes' arrhythmia suggests that other predisposing factors contribute to the acquired long QT syndrome. Since more and more macrolide products have been approved by the Food and Drug Administration for use in the United States, the potential problem with 'torsades de pointes' may exist with each of the macrolide antibiotic. Until the exact mechanisms of the arrhythmia are worked out, close monitoring of rhythms and QT intervals of high risk patients who require erythromycin is certainly advisable. Only a heightened awareness among the physicians and medical personnel can the adverse outcome be minimized.
Authors: Somogyi AA Bochner F Hetzel D Williams DB
Abstract: To determine the role of acid hydrolysis on the gastrointestinal absorption of erythromycin, six healthy subjects received erythromycin as a 240 mg intravenous dose, a 250 mg oral solution administered via endoscope directly into the duodenum and bypassing the stomach, and an enteric-coated 250 mg capsule. Blood samples were collected for 6 hours and serum erythromycin quantified by a microbiological method. The time to achieve maximum serum concentrations for the solution was 0.25 +/- 0.08 (mean +/- SD) hours and for the capsule was 2.92 +/- 0.55 hours. The absolute bioavailability of erythromycin from the capsule was 32 +/- 7% and for the duodenal solution 43 +/- 14%. The ratio of the areas under the serum erythromycin concentration-time curve of capsule to solution was 80 +/- 28% (range 38 to 110%). There is substantial loss of erythromycin apart from gastric acid hydrolysis, which cannot be accounted for by hepatic first-pass metabolism. Attempts to further improve the oral bioavailability of erythromycin beyond 50% by manipulation of formulation are likely to be futile.
Pubmed Id: 7724478
Abstract: To determine the role of acid hydrolysis on the gastrointestinal absorption of erythromycin, six healthy subjects received erythromycin as a 240 mg intravenous dose, a 250 mg oral solution administered via endoscope directly into the duodenum and bypassing the stomach, and an enteric-coated 250 mg capsule. Blood samples were collected for 6 hours and serum erythromycin quantified by a microbiological method. The time to achieve maximum serum concentrations for the solution was 0.25 +/- 0.08 (mean +/- SD) hours and for the capsule was 2.92 +/- 0.55 hours. The absolute bioavailability of erythromycin from the capsule was 32 +/- 7% and for the duodenal solution 43 +/- 14%. The ratio of the areas under the serum erythromycin concentration-time curve of capsule to solution was 80 +/- 28% (range 38 to 110%). There is substantial loss of erythromycin apart from gastric acid hydrolysis, which cannot be accounted for by hepatic first-pass metabolism. Attempts to further improve the oral bioavailability of erythromycin beyond 50% by manipulation of formulation are likely to be futile.
Authors: Adkins JC Noble S
Abstract: Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) which shows good inhibitory activity against HIV-1. Reduced susceptibility to efavirenz has been reported with HIV-1 variants containing single and multiple mutations to the reverse transcriptase enzyme. In vitro and in vivo data suggest that the resistance profile of efavirenz overlaps with that of the NNRTIs nevirapine and delavirdine. Clinically significant drug interactions have been reported with efavirenz and indinavir and saquinavir. An increase in dosage of indinavir from 800 to 1000 mg 3 times daily is recommended during coadministration with efavirenz. Use of efavirenz in combination with saquinavir as the sole protease inhibitor is not recommended. Once-daily efavirenz in combination with zidovudine plus lamivudine or indinavir or nelfinavir increased CD4+ cell counts and reduced HIV RNA plasma levels to below quantifiable levels (< 400 copies/ml) in HIV-infected patients. A sustained reduction in viral load was maintained for at least 72 weeks in 1 study. Nervous system symptoms (including headache, dizziness, insomnia and fatigue) and dermatological effects (including maculopapular rash) appear to be the most common adverse events reported with efavirenz-containing antiretroviral regimens.
Pubmed Id: 9878993
Abstract: Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) which shows good inhibitory activity against HIV-1. Reduced susceptibility to efavirenz has been reported with HIV-1 variants containing single and multiple mutations to the reverse transcriptase enzyme. In vitro and in vivo data suggest that the resistance profile of efavirenz overlaps with that of the NNRTIs nevirapine and delavirdine. Clinically significant drug interactions have been reported with efavirenz and indinavir and saquinavir. An increase in dosage of indinavir from 800 to 1000 mg 3 times daily is recommended during coadministration with efavirenz. Use of efavirenz in combination with saquinavir as the sole protease inhibitor is not recommended. Once-daily efavirenz in combination with zidovudine plus lamivudine or indinavir or nelfinavir increased CD4+ cell counts and reduced HIV RNA plasma levels to below quantifiable levels (< 400 copies/ml) in HIV-infected patients. A sustained reduction in viral load was maintained for at least 72 weeks in 1 study. Nervous system symptoms (including headache, dizziness, insomnia and fatigue) and dermatological effects (including maculopapular rash) appear to be the most common adverse events reported with efavirenz-containing antiretroviral regimens.
Authors: Castillo R Pedalino RP El-Sherif N Turitto G
Abstract: OBJECTIVE: To report a case of acquired long QT syndrome that, after exclusion of all other possible causes, was probably related to therapy with efavirenz, a novel nonnucleoside reverse transcriptase inhibitor. CASE SUMMARY: This patient presented with recurrent syncope and polymorphic ventricular tachycardia, which was treated with overdrive ventricular pacing and was eliminated by discontinuation of the offending drug. DISCUSSION: This is the first reported case of QT prolongation and severe ventricular arrhythmia associated with the use of efavirenz. The temporal relationship between the initiation of treatment and the onset of electrocardiographic abnormalities, the absence of other apparent precipitating factors, as well as the normalization of QT interval and the resolution of the arrhythmia after discontinuation of the drug, strongly suggest a causal relationship between efavirenz and this adverse clinical event. CONCLUSIONS: Our case shows that any new pharmaceutical compound introduced in clinical practice may potentially result in QT prolongation and life-threatening arrhythmia.
Pubmed Id: 12022902
Abstract: OBJECTIVE: To report a case of acquired long QT syndrome that, after exclusion of all other possible causes, was probably related to therapy with efavirenz, a novel nonnucleoside reverse transcriptase inhibitor. CASE SUMMARY: This patient presented with recurrent syncope and polymorphic ventricular tachycardia, which was treated with overdrive ventricular pacing and was eliminated by discontinuation of the offending drug. DISCUSSION: This is the first reported case of QT prolongation and severe ventricular arrhythmia associated with the use of efavirenz. The temporal relationship between the initiation of treatment and the onset of electrocardiographic abnormalities, the absence of other apparent precipitating factors, as well as the normalization of QT interval and the resolution of the arrhythmia after discontinuation of the drug, strongly suggest a causal relationship between efavirenz and this adverse clinical event. CONCLUSIONS: Our case shows that any new pharmaceutical compound introduced in clinical practice may potentially result in QT prolongation and life-threatening arrhythmia.
Authors: Csajka C Marzolini C Fattinger K Décosterd LA Fellay J Telenti A Biollaz J Buclin T
Abstract: OBJECTIVE: The reverse transcriptase inhibitor efavirenz is currently used at a fixed dose of 600 mg/d. However, dosage individualization based on plasma concentration monitoring might be indicated. This study aimed to assess the efavirenz pharmacokinetic profile and interpatient versus intrapatient variability in patients who are positive for human immunodeficiency virus, to explore the relationship between drug exposure, efficacy, and central nervous system toxicity and to build up a Bayesian approach for dosage adaptation. METHODS: The population pharmacokinetic analysis was performed by use of NONMEM based on plasma samples from a cohort of unselected patients receiving efavirenz. With the use of a 1-compartment model with first-order absorption, the influence of demographic and clinical characteristics on oral clearance and oral volume of distribution was examined. The average drug exposure during 1 dosing interval was estimated for each patient and correlated with markers of efficacy and toxicity. The population kinetic parameters and the variabilities were integrated into a Bayesian equation for dosage adaptation based on a single plasma sample. RESULTS: Data from 235 patients with a total of 719 efavirenz concentrations were collected. Oral clearance was 9.4 L/h, oral volume of distribution was 252 L, and the absorption rate constant was 0.3 h(-1). Neither the demographic covariates evaluated nor the comedications showed a clinically significant influence on efavirenz pharmacokinetics. A large interpatient variability was found to affect efavirenz relative bioavailability (coefficient of variation, 54.6%), whereas the intrapatient variability was small (coefficient of variation, 26%). An inverse correlation between average drug exposure and viral load and a trend with central nervous system toxicity were detected. This enabled the derivation of a dosing adaptation strategy suitable to bring the average concentration into a therapeutic target from 1000 to 4000 microg/L to optimize viral load suppression and to minimize central nervous system toxicity. CONCLUSIONS: The high interpatient and low intrapatient variability values, as well as the potential relationship with markers of efficacy and toxicity, support the therapeutic drug monitoring of efavirenz. However, further evaluation is needed before individualization of an efavirenz dosage regimen based on routine drug level monitoring should be recommended for optimal patient management.
Pubmed Id: 12545140
Abstract: OBJECTIVE: The reverse transcriptase inhibitor efavirenz is currently used at a fixed dose of 600 mg/d. However, dosage individualization based on plasma concentration monitoring might be indicated. This study aimed to assess the efavirenz pharmacokinetic profile and interpatient versus intrapatient variability in patients who are positive for human immunodeficiency virus, to explore the relationship between drug exposure, efficacy, and central nervous system toxicity and to build up a Bayesian approach for dosage adaptation. METHODS: The population pharmacokinetic analysis was performed by use of NONMEM based on plasma samples from a cohort of unselected patients receiving efavirenz. With the use of a 1-compartment model with first-order absorption, the influence of demographic and clinical characteristics on oral clearance and oral volume of distribution was examined. The average drug exposure during 1 dosing interval was estimated for each patient and correlated with markers of efficacy and toxicity. The population kinetic parameters and the variabilities were integrated into a Bayesian equation for dosage adaptation based on a single plasma sample. RESULTS: Data from 235 patients with a total of 719 efavirenz concentrations were collected. Oral clearance was 9.4 L/h, oral volume of distribution was 252 L, and the absorption rate constant was 0.3 h(-1). Neither the demographic covariates evaluated nor the comedications showed a clinically significant influence on efavirenz pharmacokinetics. A large interpatient variability was found to affect efavirenz relative bioavailability (coefficient of variation, 54.6%), whereas the intrapatient variability was small (coefficient of variation, 26%). An inverse correlation between average drug exposure and viral load and a trend with central nervous system toxicity were detected. This enabled the derivation of a dosing adaptation strategy suitable to bring the average concentration into a therapeutic target from 1000 to 4000 microg/L to optimize viral load suppression and to minimize central nervous system toxicity. CONCLUSIONS: The high interpatient and low intrapatient variability values, as well as the potential relationship with markers of efficacy and toxicity, support the therapeutic drug monitoring of efavirenz. However, further evaluation is needed before individualization of an efavirenz dosage regimen based on routine drug level monitoring should be recommended for optimal patient management.
Authors: Prime KP Woolfson RG Pakianathan MR
Abstract: There are few data on the use of highly active antiretroviral therapy in HIV-positive patients with end-stage renal disease. We describe the tolerability, safety and efficacy of an efavirenz-containing regimen in one such patient on continuous ambulatory peritoneal dialysis.
Pubmed Id: 12869233
Abstract: There are few data on the use of highly active antiretroviral therapy in HIV-positive patients with end-stage renal disease. We describe the tolerability, safety and efficacy of an efavirenz-containing regimen in one such patient on continuous ambulatory peritoneal dialysis.
Authors: Klees TM Sheffels P Dale O Kharasch ED
Abstract: The synthetic opioid alfentanil is an analgesic and an in vivo probe for hepatic and first-pass CYP3A activity. Alfentanil is a particularly useful CYP3A probe because pupil diameter change is a surrogate for plasma concentrations, thereby affording noninvasive assessment of CYP3A. Alfentanil undergoes extensive CYP3A4 metabolism via two major pathways, forming noralfentanil and N-phenylpropionamide. This investigation evaluated alfentanil metabolism in vitro to noralfentanil and N-phenylpropionamide, by expressed CYP3A5 and CYP3A7 in addition to CYP3A4, with and without coexpressed or exogenous cytochrome b(5). Effects of the CYP3A inhibitors troleandomycin and ketoconazole were also determined. Rates of noralfentanil and N-phenylpropionamide formation by CYP3A4 and 3A5 in the absence of b(5) were generally equivalent, although the metabolite formation ratio differed, whereas those by CYP3A7 were substantially less. CYP3A4 and 3A5 were equipotently inhibited by troleandomycin, whereas ketoconazole was an order of magnitude more potent toward CYP3A4. Cytochrome b(5) qualitatively and quantitatively altered alfentanil metabolism, with b(5) coexpression having a greater effect than exogenous addition. Addition or coexpression of b(5) markedly stimulated the formation of both metabolites and changed the formation of noralfentanil but not N-phenylpropionamide from apparent single-site to multisite Michaelis-Menten kinetics. These results demonstrate that alfentanil is a substrate for CYP3A5 in addition to CYP3A4, and the effects of the CYP3A inhibitors troleandomycin and ketoconazole are CYP3A enzyme-selective. Alfentanil is one of the few CYP3A substrates that is metabolized in vitro as avidly by both CYP3A4 and 3A5. Polymorphic CYP3A5 expression may contribute to inter-individual variability in alfentanil metabolism.
Pubmed Id: 15557344
Abstract: The synthetic opioid alfentanil is an analgesic and an in vivo probe for hepatic and first-pass CYP3A activity. Alfentanil is a particularly useful CYP3A probe because pupil diameter change is a surrogate for plasma concentrations, thereby affording noninvasive assessment of CYP3A. Alfentanil undergoes extensive CYP3A4 metabolism via two major pathways, forming noralfentanil and N-phenylpropionamide. This investigation evaluated alfentanil metabolism in vitro to noralfentanil and N-phenylpropionamide, by expressed CYP3A5 and CYP3A7 in addition to CYP3A4, with and without coexpressed or exogenous cytochrome b(5). Effects of the CYP3A inhibitors troleandomycin and ketoconazole were also determined. Rates of noralfentanil and N-phenylpropionamide formation by CYP3A4 and 3A5 in the absence of b(5) were generally equivalent, although the metabolite formation ratio differed, whereas those by CYP3A7 were substantially less. CYP3A4 and 3A5 were equipotently inhibited by troleandomycin, whereas ketoconazole was an order of magnitude more potent toward CYP3A4. Cytochrome b(5) qualitatively and quantitatively altered alfentanil metabolism, with b(5) coexpression having a greater effect than exogenous addition. Addition or coexpression of b(5) markedly stimulated the formation of both metabolites and changed the formation of noralfentanil but not N-phenylpropionamide from apparent single-site to multisite Michaelis-Menten kinetics. These results demonstrate that alfentanil is a substrate for CYP3A5 in addition to CYP3A4, and the effects of the CYP3A inhibitors troleandomycin and ketoconazole are CYP3A enzyme-selective. Alfentanil is one of the few CYP3A substrates that is metabolized in vitro as avidly by both CYP3A4 and 3A5. Polymorphic CYP3A5 expression may contribute to inter-individual variability in alfentanil metabolism.
Authors: Kharasch ED Walker A Hoffer C Sheffels P
Abstract: This investigation determined the ability of alfentanil miosis and single-point concentrations to detect various degrees of CYP3A inhibition. Results were compared with those for midazolam, an alternative CYP3A probe. Twelve volunteers were studied in a randomized 4-way crossover, targeting 12%, 25%, and 50% inhibition of hepatic CYP3A. They received 0, 100, 200, or 400 mg oral fluconazole, followed 1 hour later by 1 mg intravenous midazolam and then 15 microg/kg intravenous alfentanil 1 hour later. The next day, they received fluconazole, followed by 3 mg oral midazolam and 40 microg/kg oral alfentanil. Dark-adapted pupil diameters were measured coincident with blood sampling. Area under the plasma concentration-time curve (AUC) ratios (fluconazole/control) after 100, 200, and 400 mg fluconazole were (geometric mean) 1.3*, 1.4*, and 2.0* for intravenous midazolam and 1.2*, 1.6*, and 2.2* for intravenous alfentanil (*significantly different from control), indicating 16% to 21%, 31% to 36%, and 43% to 53% inhibition of hepatic CYP3A. Single-point concentration ratios were 1.5*, 1.8*, and 2.4* for intravenous midazolam (at 5 hours) and 1.2*, 1.6*, and 2.2* for intravenous alfentanil (at 4 hours). Pupil miosis AUC ratios were 0.9, 1.0, and 1.2*. After oral dosing, plasma AUC ratios were 2.3*, 3.6*, and 5.3* for midazolam and 1.8*, 2.9*, and 4.9* for alfentanil; plasma single-point ratios were 2.4*, 4.5*, and 6.9* for midazolam and 1.8*, 2.9*, and 4.9* for alfentanil, and alfentanil miosis ratios were 1.1, 1.9*, and 2.7*. Plasma concentration AUC ratios of alfentanil and midazolam were equivalent for detecting hepatic and first-pass CYP3A inhibition. Single-point concentrations were an acceptable surrogate for formal AUC determinations and as sensitive as AUCs for detecting CYP3A inhibition. Alfentanil miosis could detect 50% to 70% inhibition of CYP3A activity, but was less sensitive than plasma AUCs. Further refinements are needed to increase the sensitivity of alfentanil miosis for detecting small CYP3A changes.
Pubmed Id: 16172184
Abstract: This investigation determined the ability of alfentanil miosis and single-point concentrations to detect various degrees of CYP3A inhibition. Results were compared with those for midazolam, an alternative CYP3A probe. Twelve volunteers were studied in a randomized 4-way crossover, targeting 12%, 25%, and 50% inhibition of hepatic CYP3A. They received 0, 100, 200, or 400 mg oral fluconazole, followed 1 hour later by 1 mg intravenous midazolam and then 15 microg/kg intravenous alfentanil 1 hour later. The next day, they received fluconazole, followed by 3 mg oral midazolam and 40 microg/kg oral alfentanil. Dark-adapted pupil diameters were measured coincident with blood sampling. Area under the plasma concentration-time curve (AUC) ratios (fluconazole/control) after 100, 200, and 400 mg fluconazole were (geometric mean) 1.3*, 1.4*, and 2.0* for intravenous midazolam and 1.2*, 1.6*, and 2.2* for intravenous alfentanil (*significantly different from control), indicating 16% to 21%, 31% to 36%, and 43% to 53% inhibition of hepatic CYP3A. Single-point concentration ratios were 1.5*, 1.8*, and 2.4* for intravenous midazolam (at 5 hours) and 1.2*, 1.6*, and 2.2* for intravenous alfentanil (at 4 hours). Pupil miosis AUC ratios were 0.9, 1.0, and 1.2*. After oral dosing, plasma AUC ratios were 2.3*, 3.6*, and 5.3* for midazolam and 1.8*, 2.9*, and 4.9* for alfentanil; plasma single-point ratios were 2.4*, 4.5*, and 6.9* for midazolam and 1.8*, 2.9*, and 4.9* for alfentanil, and alfentanil miosis ratios were 1.1, 1.9*, and 2.7*. Plasma concentration AUC ratios of alfentanil and midazolam were equivalent for detecting hepatic and first-pass CYP3A inhibition. Single-point concentrations were an acceptable surrogate for formal AUC determinations and as sensitive as AUCs for detecting CYP3A inhibition. Alfentanil miosis could detect 50% to 70% inhibition of CYP3A activity, but was less sensitive than plasma AUCs. Further refinements are needed to increase the sensitivity of alfentanil miosis for detecting small CYP3A changes.
Authors: Saari TI Laine K Leino K Valtonen M Neuvonen PJ Olkkola KT
Abstract: OBJECTIVE: Alfentanil is a short-acting synthetic opioid analgesic, which is extensively metabolized, mainly by hepatic cytochrome P450 (CYP) 3A enzymes. Concomitant administration of alfentanil and CYP3A inhibitors may lead to clinically important drug interactions. We investigated the possible interactions between alfentanil and orally administered voriconazole and terbinafine. METHODS: A randomized crossover study design in 3 phases was used. Twelve healthy volunteers were given 20 microg/kg intravenous alfentanil without pretreatment (control), after oral voriconazole administration (400 mg twice on the first day and 200 mg twice on the second day), or after oral terbinafine administration (250 mg once daily for 3 days). Plasma concentrations of alfentanil were measured for 10 hours, and the pharmacokinetic parameters were calculated by use of noncompartmental methods. RESULTS: Voriconazole decreased the mean plasma clearance of intravenous alfentanil by 85%, from the control value of 4.4+/-2.4 mL.min-1.kg-1 to 0.67+/-0.27 mL.min-1.kg-1 (P<.001), and prolonged its elimination half-life from 1.5+/-0.49 hours to 6.6+/-1.8 hours (P<.001). The area under the alfentanil plasma concentration-time curve was increased by 6-fold by voriconazole (P<.001). Terbinafine had no statistically significant effect on the pharmacokinetics of alfentanil. Alfentanil administration caused nausea in 5 volunteers and vomiting in 2. These side effects all occurred in volunteers in the voriconazole phase. CONCLUSION: Oral voriconazole, but not terbinafine, markedly inhibited the metabolism of alfentanil. Caution should be exercised when alfentanil is given to patients receiving voriconazole. It is reasonable to assume that patients receiving voriconazole require 70% to 90% less alfentanil for the maintenance of analgesia than patients who are not receiving concomitant CYP3A inhibitors.
Pubmed Id: 17112806
Abstract: OBJECTIVE: Alfentanil is a short-acting synthetic opioid analgesic, which is extensively metabolized, mainly by hepatic cytochrome P450 (CYP) 3A enzymes. Concomitant administration of alfentanil and CYP3A inhibitors may lead to clinically important drug interactions. We investigated the possible interactions between alfentanil and orally administered voriconazole and terbinafine. METHODS: A randomized crossover study design in 3 phases was used. Twelve healthy volunteers were given 20 microg/kg intravenous alfentanil without pretreatment (control), after oral voriconazole administration (400 mg twice on the first day and 200 mg twice on the second day), or after oral terbinafine administration (250 mg once daily for 3 days). Plasma concentrations of alfentanil were measured for 10 hours, and the pharmacokinetic parameters were calculated by use of noncompartmental methods. RESULTS: Voriconazole decreased the mean plasma clearance of intravenous alfentanil by 85%, from the control value of 4.4+/-2.4 mL.min-1.kg-1 to 0.67+/-0.27 mL.min-1.kg-1 (P<.001), and prolonged its elimination half-life from 1.5+/-0.49 hours to 6.6+/-1.8 hours (P<.001). The area under the alfentanil plasma concentration-time curve was increased by 6-fold by voriconazole (P<.001). Terbinafine had no statistically significant effect on the pharmacokinetics of alfentanil. Alfentanil administration caused nausea in 5 volunteers and vomiting in 2. These side effects all occurred in volunteers in the voriconazole phase. CONCLUSION: Oral voriconazole, but not terbinafine, markedly inhibited the metabolism of alfentanil. Caution should be exercised when alfentanil is given to patients receiving voriconazole. It is reasonable to assume that patients receiving voriconazole require 70% to 90% less alfentanil for the maintenance of analgesia than patients who are not receiving concomitant CYP3A inhibitors.
Authors: Kharasch ED Walker A Isoherranen N Hoffer C Sheffels P Thummel K Whittington D Ensign D
Abstract: The hepatic and first-pass cytochrome P4503A (CYP3A) probe alfentanil (ALF) is also metabolized in vitro by CYP3A5. Human hepatic microsomal ALF metabolism is higher in livers with at least one CYP3A5*1 allele and higher CYP3A5 protein content, compared with CYP3A5*3 homozygotes with little CYP3A5. The influence of CYP3A5 genotype on ALF pharmacokinetics and pharmacodynamics was studied, and compared to midazolam (MDZ), another CYP3A probe. Healthy volunteers (58 men, 41 women) were genotyped for CYP3A5 *1, *3, *6, and *7 alleles. They received intravenous MDZ then ALF, and oral MDZ and ALF the next day. Plasma MDZ and ALF concentrations were determined by mass spectrometry. Dark-adapted pupil diameters were determined coincident with blood sampling. In CYP3A5(*)3/(*)3 (n=62), (*)1/(*)3 (n=28), and (*)1/(*)1 (n=8) genotypes, systemic clearances of ALF were 4.6+/-1.8, 4.8+/-1.7, and 3.9+/-1.7 ml/kg/min and those of MDZ were 7.8+/-2.3, 7.7+/-2.3, and 6.0+/-1.4 ml/kg/min, respectively (not significant), and apparent oral clearances were 11.8+/-7.2, 13.3+/-6.1, and 12.6+/-8.2 ml/kg/min for ALF and 35.2+/-19.0, 36.4+/-15.7, and 29.4+/-9.3 ml/kg/min for MDZ (not significant). Clearances were not different between African Americans (n=25) and Whites (n=68), or between CYP3A5 genotypes within African Americans. ALF pharmacodynamics was not different between CYP3A5 genotypes. There was consistent concordance between ALF and MDZ, in clearances and extraction ratios. Thus, in a relatively large cohort of healthy subjects with constitutive CYP3A activity, CYP3A5 genotype had no effect on the systemic or apparent oral clearances, or pharmacodynamics, of the CYP3A probes ALF and MDZ, despite affecting their hepatic microsomal metabolism.
Pubmed Id: 17554244
Abstract: The hepatic and first-pass cytochrome P4503A (CYP3A) probe alfentanil (ALF) is also metabolized in vitro by CYP3A5. Human hepatic microsomal ALF metabolism is higher in livers with at least one CYP3A5*1 allele and higher CYP3A5 protein content, compared with CYP3A5*3 homozygotes with little CYP3A5. The influence of CYP3A5 genotype on ALF pharmacokinetics and pharmacodynamics was studied, and compared to midazolam (MDZ), another CYP3A probe. Healthy volunteers (58 men, 41 women) were genotyped for CYP3A5 *1, *3, *6, and *7 alleles. They received intravenous MDZ then ALF, and oral MDZ and ALF the next day. Plasma MDZ and ALF concentrations were determined by mass spectrometry. Dark-adapted pupil diameters were determined coincident with blood sampling. In CYP3A5(*)3/(*)3 (n=62), (*)1/(*)3 (n=28), and (*)1/(*)1 (n=8) genotypes, systemic clearances of ALF were 4.6+/-1.8, 4.8+/-1.7, and 3.9+/-1.7 ml/kg/min and those of MDZ were 7.8+/-2.3, 7.7+/-2.3, and 6.0+/-1.4 ml/kg/min, respectively (not significant), and apparent oral clearances were 11.8+/-7.2, 13.3+/-6.1, and 12.6+/-8.2 ml/kg/min for ALF and 35.2+/-19.0, 36.4+/-15.7, and 29.4+/-9.3 ml/kg/min for MDZ (not significant). Clearances were not different between African Americans (n=25) and Whites (n=68), or between CYP3A5 genotypes within African Americans. ALF pharmacodynamics was not different between CYP3A5 genotypes. There was consistent concordance between ALF and MDZ, in clearances and extraction ratios. Thus, in a relatively large cohort of healthy subjects with constitutive CYP3A activity, CYP3A5 genotype had no effect on the systemic or apparent oral clearances, or pharmacodynamics, of the CYP3A probes ALF and MDZ, despite affecting their hepatic microsomal metabolism.
Authors: Murtagh FE Chai MO Donohoe P Edmonds PM Higginson IJ
Abstract: The numbers of patients dying with end-stage renal disease (ESRD), particularly those managed conservatively (without dialysis) or withdrawing from dialysis is increasing rapidly in developed countries. There is growing awareness of the extensive symptom control needs of these patients. Pain is a common problem, and has been both under-recognized and under-treated. It is challenging to manage, largely because of the constraints very poor renal function places on use of medication. Although pharmacological reviews of opioid use in renal failure have been published, there is a need for clinical recommendations to aid palliative and renal specialists in providing effective pain control. This review describes the pharmacological evidence for and against the use of the different opioid medications, and translates this into clinical recommendations for ESRD patients managed conservatively, not for those on dialysis for whom there are different pharmacological considerations. Acetaminophen (paracetamol) is recommended at Step 1 of the World Health Organization ladder. Of the Step 2 analgesics, tramadol is the least problematic, although dose reduction and increased dosing interval are required, and caution should be exercised. Of the Step 3 analgesics, fentanyl, alfentanil and methadone are recommended. There is limited evidence for buprenorphine, although theoretical reasons why it may be a good choice for these patients. Hydromorphone and oxycodone cannot be recommended because of extremely limited evidence, although each is likely a better choice than morphine or diamorphine. Morphine and diamorphine themselves are not recommended because of known accumulation of potentially toxic metabolites.
Pubmed Id: 17844723
Abstract: The numbers of patients dying with end-stage renal disease (ESRD), particularly those managed conservatively (without dialysis) or withdrawing from dialysis is increasing rapidly in developed countries. There is growing awareness of the extensive symptom control needs of these patients. Pain is a common problem, and has been both under-recognized and under-treated. It is challenging to manage, largely because of the constraints very poor renal function places on use of medication. Although pharmacological reviews of opioid use in renal failure have been published, there is a need for clinical recommendations to aid palliative and renal specialists in providing effective pain control. This review describes the pharmacological evidence for and against the use of the different opioid medications, and translates this into clinical recommendations for ESRD patients managed conservatively, not for those on dialysis for whom there are different pharmacological considerations. Acetaminophen (paracetamol) is recommended at Step 1 of the World Health Organization ladder. Of the Step 2 analgesics, tramadol is the least problematic, although dose reduction and increased dosing interval are required, and caution should be exercised. Of the Step 3 analgesics, fentanyl, alfentanil and methadone are recommended. There is limited evidence for buprenorphine, although theoretical reasons why it may be a good choice for these patients. Hydromorphone and oxycodone cannot be recommended because of extremely limited evidence, although each is likely a better choice than morphine or diamorphine. Morphine and diamorphine themselves are not recommended because of known accumulation of potentially toxic metabolites.
Authors: Kharasch ED Hoffer C Whittington D Walker A Bedynek PS
Abstract: BACKGROUND: Methadone clearance is highly variable, and drug interactions are problematic. Both have been attributed to CYP3A, but actual mechanisms are unknown. Drug interactions can provide such mechanistic information. Ritonavir/indinavir, one of the earliest protease inhibitor combinations, may inhibit CYP3A. We assessed ritonavir/indinavir effects on methadone pharmacokinetics and pharmacodynamics, intestinal and hepatic CYP3A activity, and intestinal transporters (P-glycoprotein) activity. CYP3A and transporters were assessed with alfentanil and fexofenadine, respectively. METHODS: Twelve healthy human immunodeficiency virus-negative volunteers underwent a sequential three-part crossover. On three consecutive days, they received oral alfentanil/fexofenadine, intravenous alfentanil, and intravenous plus oral (deuterium-labeled) methadone, repeated after acute (3 days) and steady-state (2 weeks) ritonavir/indinavir. Plasma and urine analytes were measured by mass spectrometry. Opioid effects were assessed by miosis. RESULTS: Alfentanil apparent oral clearance was inhibited more than 97% by both acute and steady-state ritonavir/indinavir, and systemic clearance was inhibited more than 90% due to diminished hepatic and intestinal extraction. Ritonavir/indinavir increased fexofenadine area under the plasma concentration-time curve four- to five-fold, suggesting significant inhibition of gastrointestinal P-glycoprotein. Ritonavir/indinavir slightly increased methadone N-demethylation, but it had no significant effects on methadone plasma concentrations or on systemic or apparent oral clearance, renal clearance, hepatic extraction or clearance, or bioavailability. Ritonavir/indinavir had no significant effects on methadone plasma concentration-effect relationships. CONCLUSIONS: Inhibition of both hepatic and intestinal CYP3A activity is responsible for ritonavir/indinavir drug interactions. Methadone disposition was unchanged, despite profound inhibition of CYP3A activity, suggesting little or no role for CYP3A in clinical methadone metabolism and clearance. Methadone bioavailability was unchanged, despite inhibition of gastrointestinal P-glycoprotein activity, suggesting that this transporter does not limit methadone intestinal absorption.
Pubmed Id: 19225389
Abstract: BACKGROUND: Methadone clearance is highly variable, and drug interactions are problematic. Both have been attributed to CYP3A, but actual mechanisms are unknown. Drug interactions can provide such mechanistic information. Ritonavir/indinavir, one of the earliest protease inhibitor combinations, may inhibit CYP3A. We assessed ritonavir/indinavir effects on methadone pharmacokinetics and pharmacodynamics, intestinal and hepatic CYP3A activity, and intestinal transporters (P-glycoprotein) activity. CYP3A and transporters were assessed with alfentanil and fexofenadine, respectively. METHODS: Twelve healthy human immunodeficiency virus-negative volunteers underwent a sequential three-part crossover. On three consecutive days, they received oral alfentanil/fexofenadine, intravenous alfentanil, and intravenous plus oral (deuterium-labeled) methadone, repeated after acute (3 days) and steady-state (2 weeks) ritonavir/indinavir. Plasma and urine analytes were measured by mass spectrometry. Opioid effects were assessed by miosis. RESULTS: Alfentanil apparent oral clearance was inhibited more than 97% by both acute and steady-state ritonavir/indinavir, and systemic clearance was inhibited more than 90% due to diminished hepatic and intestinal extraction. Ritonavir/indinavir increased fexofenadine area under the plasma concentration-time curve four- to five-fold, suggesting significant inhibition of gastrointestinal P-glycoprotein. Ritonavir/indinavir slightly increased methadone N-demethylation, but it had no significant effects on methadone plasma concentrations or on systemic or apparent oral clearance, renal clearance, hepatic extraction or clearance, or bioavailability. Ritonavir/indinavir had no significant effects on methadone plasma concentration-effect relationships. CONCLUSIONS: Inhibition of both hepatic and intestinal CYP3A activity is responsible for ritonavir/indinavir drug interactions. Methadone disposition was unchanged, despite profound inhibition of CYP3A activity, suggesting little or no role for CYP3A in clinical methadone metabolism and clearance. Methadone bioavailability was unchanged, despite inhibition of gastrointestinal P-glycoprotein activity, suggesting that this transporter does not limit methadone intestinal absorption.
Authors: Kharasch ED Walker A Whittington D Hoffer C Bedynek PS
Abstract: BACKGROUND: Methadone plasma concentrations are decreased by nelfinavir. Methadone clearance and the drug interactions have been attributed to CYP3A4, but actual mechanisms of methadone clearance and the nelfinavir interaction are unknown. We assessed nelfinavir effects on methadone pharmacokinetics and pharmacodynamics, intestinal and hepatic CYP3A4/5 activity, and intestinal P-glycoprotein transport activity. CYP3A4/5 and transporters were assessed using alfentanil and fexofenadine, respectively. METHODS: Twelve healthy HIV-negative volunteers underwent a sequential crossover. On three consecutive days they received oral alfentanil plus fexofenadine, intravenous alfentanil, and intravenous plus oral methadone. This was repeated after nelfinavir. Plasma and urine analytes were measured by mass spectrometry. Opioid effects were measured by pupil diameter change (miosis). RESULTS: Nelfinavir decreased intravenous and oral methadone plasma concentrations 40-50%. Systemic clearance, hepatic clearance, and hepatic extraction all increased 1.6- and 2-fold, respectively, for R- and S-methadone; apparent oral clearance increased 1.7- and 1.9-fold. Nelfinavir stereoselectively increased (S>R) methadone metabolism and metabolite formation clearance, and methadone renal clearance. Methadone bioavailability and P-glycoprotein activity were minimally affected. Nelfinavir decreased alfentanil systemic and apparent oral clearances 50 and 76%, respectively. Nelfinavir appeared to shift the methadone plasma concentration-effect (miosis) curve leftward and upward. CONCLUSIONS: Nelfinavir induced methadone clearance by increasing renal clearance, and more so by stereoselectively increasing hepatic metabolism, extraction and clearance. Induction occurred despite 50% inhibition of hepatic CYP3A4/5 activity and more than 75% inhibition of first-pass CYP3A4/5 activity, suggesting little or no role for CYP3A in clinical methadone disposition. Nelfinavir may alter methadone pharmacodynamics, increasing clinical effects.
Pubmed Id: 19232844
Abstract: BACKGROUND: Methadone plasma concentrations are decreased by nelfinavir. Methadone clearance and the drug interactions have been attributed to CYP3A4, but actual mechanisms of methadone clearance and the nelfinavir interaction are unknown. We assessed nelfinavir effects on methadone pharmacokinetics and pharmacodynamics, intestinal and hepatic CYP3A4/5 activity, and intestinal P-glycoprotein transport activity. CYP3A4/5 and transporters were assessed using alfentanil and fexofenadine, respectively. METHODS: Twelve healthy HIV-negative volunteers underwent a sequential crossover. On three consecutive days they received oral alfentanil plus fexofenadine, intravenous alfentanil, and intravenous plus oral methadone. This was repeated after nelfinavir. Plasma and urine analytes were measured by mass spectrometry. Opioid effects were measured by pupil diameter change (miosis). RESULTS: Nelfinavir decreased intravenous and oral methadone plasma concentrations 40-50%. Systemic clearance, hepatic clearance, and hepatic extraction all increased 1.6- and 2-fold, respectively, for R- and S-methadone; apparent oral clearance increased 1.7- and 1.9-fold. Nelfinavir stereoselectively increased (S>R) methadone metabolism and metabolite formation clearance, and methadone renal clearance. Methadone bioavailability and P-glycoprotein activity were minimally affected. Nelfinavir decreased alfentanil systemic and apparent oral clearances 50 and 76%, respectively. Nelfinavir appeared to shift the methadone plasma concentration-effect (miosis) curve leftward and upward. CONCLUSIONS: Nelfinavir induced methadone clearance by increasing renal clearance, and more so by stereoselectively increasing hepatic metabolism, extraction and clearance. Induction occurred despite 50% inhibition of hepatic CYP3A4/5 activity and more than 75% inhibition of first-pass CYP3A4/5 activity, suggesting little or no role for CYP3A in clinical methadone disposition. Nelfinavir may alter methadone pharmacodynamics, increasing clinical effects.
Authors: Sun H Frassetto LA Huang Y Benet LZ
Abstract: Nonrenal clearance of drugs can be significantly lower in patients with end-stage renal disease (ESRD) than in those with normal renal function. Using erythromycin (ER) as a probe compound, we investigated whether this decrease in nonrenal clearance is due to reduced hepatic clearance (CL(H)) and/or gut metabolism. We also examined the potential effects of the uremic toxins 3-carboxy-4-methyl-5-propyl-2-furan propanoic acid (CMPF) and indoxyl sulfate (Indox) on ER disposition. Route-randomized, two-way crossover pharmacokinetic studies of ER were conducted in 12 ESRD patients and 12 healthy controls after oral (250 mg) and intravenous (125 mg) dosing with ER. In patients with ESRD, CL(H) decreased 31% relative to baseline values (0.35 +/- 0.14 l/h/kg vs. 0.51 +/- 0.13 l/h/kg, P = 0.01), with no change in steady-state volume of distribution. With oral dosing, the bioavailability of ER increased 36% in patients with ESRD, and this increase was not related to changes in gut availability. As expected, plasma levels of CMPF and Indox were significantly higher in the patients than in the healthy controls. However, no correlation was observed between CL(H) of ER and the levels of uremic toxins.
Pubmed Id: 20090676
Abstract: Nonrenal clearance of drugs can be significantly lower in patients with end-stage renal disease (ESRD) than in those with normal renal function. Using erythromycin (ER) as a probe compound, we investigated whether this decrease in nonrenal clearance is due to reduced hepatic clearance (CL(H)) and/or gut metabolism. We also examined the potential effects of the uremic toxins 3-carboxy-4-methyl-5-propyl-2-furan propanoic acid (CMPF) and indoxyl sulfate (Indox) on ER disposition. Route-randomized, two-way crossover pharmacokinetic studies of ER were conducted in 12 ESRD patients and 12 healthy controls after oral (250 mg) and intravenous (125 mg) dosing with ER. In patients with ESRD, CL(H) decreased 31% relative to baseline values (0.35 +/- 0.14 l/h/kg vs. 0.51 +/- 0.13 l/h/kg, P = 0.01), with no change in steady-state volume of distribution. With oral dosing, the bioavailability of ER increased 36% in patients with ESRD, and this increase was not related to changes in gut availability. As expected, plasma levels of CMPF and Indox were significantly higher in the patients than in the healthy controls. However, no correlation was observed between CL(H) of ER and the levels of uremic toxins.
Authors: Franke RM Lancaster CS Peer CJ Gibson AA Kosloske AM Orwick SJ Mathijssen RH Figg WD Baker SD Sparreboom A
Abstract: The macrolide antiobiotic erythromycin undergoes extensive hepatic metabolism and is commonly used as a probe for cytochrome P450 (CYP) 3A4 activity. By means of a transporter screen, erythromycin was identified as a substrate for the transporter ABCC2 (MRP2) and its murine ortholog, Abcc2. Because these proteins are highly expressed on the biliary surface of hepatocytes, we hypothesized that impaired Abcc2 function may influence the rate of hepatobiliary excretion and thereby enhance erythromycin metabolism. Using Abcc2 knockout mice, we found that Abcc2 deficiency was associated with a significant increase in erythromycin metabolism, whereas murine Cyp3a protein expression and microsomal Cyp3a activity were not affected. Next, in a cohort of 108 human subjects, we observed that homozygosity for a common reduced-function variant in ABCC2 (rs717620) was also linked to an increase in erythromycin metabolism but was not correlated with the clearance of midazolam. These results suggest that impaired ABCC2 function can alter erythromycin metabolism, independent of changes in CYP3A4 activity.
Pubmed Id: 21451505
Abstract: The macrolide antiobiotic erythromycin undergoes extensive hepatic metabolism and is commonly used as a probe for cytochrome P450 (CYP) 3A4 activity. By means of a transporter screen, erythromycin was identified as a substrate for the transporter ABCC2 (MRP2) and its murine ortholog, Abcc2. Because these proteins are highly expressed on the biliary surface of hepatocytes, we hypothesized that impaired Abcc2 function may influence the rate of hepatobiliary excretion and thereby enhance erythromycin metabolism. Using Abcc2 knockout mice, we found that Abcc2 deficiency was associated with a significant increase in erythromycin metabolism, whereas murine Cyp3a protein expression and microsomal Cyp3a activity were not affected. Next, in a cohort of 108 human subjects, we observed that homozygosity for a common reduced-function variant in ABCC2 (rs717620) was also linked to an increase in erythromycin metabolism but was not correlated with the clearance of midazolam. These results suggest that impaired ABCC2 function can alter erythromycin metabolism, independent of changes in CYP3A4 activity.
Authors: King S Forbes K Hanks GW Ferro CJ Chambers EJ
Abstract: BACKGROUND: Opioid use in patients with renal impairment can lead to increased adverse effects. Opioids differ in their effect in renal impairment in both efficacy and tolerability. This systematic literature review forms the basis of guidelines for opioid use in renal impairment and cancer pain as part of the European Palliative Care Research Collaborative's opioid guidelines project. OBJECTIVE: The objective of this study was to identify and assess the quality of evidence for the safe and effective use of opioids for the relief of cancer pain in patients with renal impairment and to produce guidelines. SEARCH STRATEGY: The Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, MedLine, EMBASE and CINAHL were systematically searched in addition to hand searching of relevant journals. SELECTION CRITERIA: Studies were included if they reported a clinical outcome relevant to the use of selected opioids in cancer-related pain and renal impairment. The selected opioids were morphine, diamorphine, codeine, dextropropoxyphene, dihydrocodeine, oxycodone, hydromorphone, buprenorphine, tramadol, alfentanil, fentanyl, sufentanil, remifentanil, pethidine and methadone. No direct comparator was required for inclusion. Studies assessing the long-term efficacy of opioids during dialysis were excluded. DATA COLLECTION AND ANALYSIS: This is a narrative systematic review and no meta-analysis was performed. The Grading of RECOMMENDATIONS Assessment, Development and Evaluation (GRADE) approach was used to assess the quality of the studies and to formulate guidelines. MAIN RESULTS: Fifteen original articles were identified. Eight prospective and seven retrospective clinical studies were identified but no randomized controlled trials. No results were found for diamorphine, codeine, dihydrocodeine, buprenorphine, tramadol, dextropropoxyphene, methadone or remifentanil. CONCLUSIONS: All of the studies identified have a significant risk of bias inherent in the study methodology and there is additional significant risk of publication bias. Overall evidence is of very low quality. The direct clinical evidence in cancer-related pain and renal impairment is insufficient to allow formulation of guidelines but is suggestive of significant differences in risk between opioids. RECOMMENDATIONS: RECOMMENDATIONS regarding opioid use in renal impairment and cancer pain are made on the basis of pharmacokinetic data, extrapolation from non-cancer pain studies and from clinical experience. The risk of opioid use in renal impairment is stratified according to the activity of opioid metabolites, potential for accumulation and reports of successful or harmful use. Fentanyl, alfentanil and methadone are identified, with caveats, as the least likely to cause harm when used appropriately. Morphine may be associated with toxicity in patients with renal impairment. Unwanted side effects with morphine may be satisfactorily dealt with by either increasing the dosing interval or reducing the 24 hour dose or by switching to an alternative opioid.
Pubmed Id: 21708859
Abstract: BACKGROUND: Opioid use in patients with renal impairment can lead to increased adverse effects. Opioids differ in their effect in renal impairment in both efficacy and tolerability. This systematic literature review forms the basis of guidelines for opioid use in renal impairment and cancer pain as part of the European Palliative Care Research Collaborative's opioid guidelines project. OBJECTIVE: The objective of this study was to identify and assess the quality of evidence for the safe and effective use of opioids for the relief of cancer pain in patients with renal impairment and to produce guidelines. SEARCH STRATEGY: The Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, MedLine, EMBASE and CINAHL were systematically searched in addition to hand searching of relevant journals. SELECTION CRITERIA: Studies were included if they reported a clinical outcome relevant to the use of selected opioids in cancer-related pain and renal impairment. The selected opioids were morphine, diamorphine, codeine, dextropropoxyphene, dihydrocodeine, oxycodone, hydromorphone, buprenorphine, tramadol, alfentanil, fentanyl, sufentanil, remifentanil, pethidine and methadone. No direct comparator was required for inclusion. Studies assessing the long-term efficacy of opioids during dialysis were excluded. DATA COLLECTION AND ANALYSIS: This is a narrative systematic review and no meta-analysis was performed. The Grading of RECOMMENDATIONS Assessment, Development and Evaluation (GRADE) approach was used to assess the quality of the studies and to formulate guidelines. MAIN RESULTS: Fifteen original articles were identified. Eight prospective and seven retrospective clinical studies were identified but no randomized controlled trials. No results were found for diamorphine, codeine, dihydrocodeine, buprenorphine, tramadol, dextropropoxyphene, methadone or remifentanil. CONCLUSIONS: All of the studies identified have a significant risk of bias inherent in the study methodology and there is additional significant risk of publication bias. Overall evidence is of very low quality. The direct clinical evidence in cancer-related pain and renal impairment is insufficient to allow formulation of guidelines but is suggestive of significant differences in risk between opioids. RECOMMENDATIONS: RECOMMENDATIONS regarding opioid use in renal impairment and cancer pain are made on the basis of pharmacokinetic data, extrapolation from non-cancer pain studies and from clinical experience. The risk of opioid use in renal impairment is stratified according to the activity of opioid metabolites, potential for accumulation and reports of successful or harmful use. Fentanyl, alfentanil and methadone are identified, with caveats, as the least likely to cause harm when used appropriately. Morphine may be associated with toxicity in patients with renal impairment. Unwanted side effects with morphine may be satisfactorily dealt with by either increasing the dosing interval or reducing the 24 hour dose or by switching to an alternative opioid.
Authors: Michaud V Ogburn E Thong N Aregbe AO Quigg TC Flockhart DA Desta Z
Abstract: Drug-drug interactions involving efavirenz are of major concern in clinical practice. We evaluated the effects of multiple doses of efavirenz on omeprazole 5-hydroxylation (CYP2C19) and sulfoxidation (CYP3A). Healthy volunteers (n = 57) were administered a single 20 mg oral dose of racemic omeprazole either with a single 600 mg oral dose of efavirenz or after 17 days of administration of 600 mg/day of efavirenz. The concentrations of racemic omeprazole, 5-hydroxyomeoprazole (and their enantiomers), and omeprazole sulfone in plasma were measured using a chiral liquid chromatography-tandem mass spectrometry method. Relative to single-dose treatment, multiple doses of efavirenz significantly decreased (P < 0.0001) the area under the plasma concentration-time curve from 0 to infinity (AUC(0-∞)) of racemic-, R- and S-omeprazole (2.01- to 2.15-fold) and the corresponding AUC(0-∞) metabolic ratio (MR) for 5-hydroxyomeprazole (1.36- to 1.44-fold) as well as the MR for omeprazole sulfone (∼2.0) (P < 0.0001). The significant reduction in the AUC of 5-hydroxyomeprazole after repeated efavirenz dosing suggests induction of sequential metabolism and mixed inductive/inhibitory effects of efavirenz on CYP2C19. In conclusion, efavirenz enhances omeprazole metabolism in a nonstereoselective manner through induction of CYP3A and CYP2C19 activity.
Pubmed Id: 22318618
Abstract: Drug-drug interactions involving efavirenz are of major concern in clinical practice. We evaluated the effects of multiple doses of efavirenz on omeprazole 5-hydroxylation (CYP2C19) and sulfoxidation (CYP3A). Healthy volunteers (n = 57) were administered a single 20 mg oral dose of racemic omeprazole either with a single 600 mg oral dose of efavirenz or after 17 days of administration of 600 mg/day of efavirenz. The concentrations of racemic omeprazole, 5-hydroxyomeoprazole (and their enantiomers), and omeprazole sulfone in plasma were measured using a chiral liquid chromatography-tandem mass spectrometry method. Relative to single-dose treatment, multiple doses of efavirenz significantly decreased (P < 0.0001) the area under the plasma concentration-time curve from 0 to infinity (AUC(0-∞)) of racemic-, R- and S-omeprazole (2.01- to 2.15-fold) and the corresponding AUC(0-∞) metabolic ratio (MR) for 5-hydroxyomeprazole (1.36- to 1.44-fold) as well as the MR for omeprazole sulfone (∼2.0) (P < 0.0001). The significant reduction in the AUC of 5-hydroxyomeprazole after repeated efavirenz dosing suggests induction of sequential metabolism and mixed inductive/inhibitory effects of efavirenz on CYP2C19. In conclusion, efavirenz enhances omeprazole metabolism in a nonstereoselective manner through induction of CYP3A and CYP2C19 activity.
Authors: Kharasch ED Whittington D Ensign D Hoffer C Bedynek PS Campbell S Stubbert K Crafford A London A Kim T
Abstract: Mechanisms by which efavirenz diminishes methadone plasma concentrations are unknown. This investigation determined efavirenz influence on clinical methadone disposition and miosis, intravenous and oral alfentanil clearance (hepatic and intestinal cytochrome P450 3A4/5 (CYP3A4/5) activity), fexofenadine disposition (intestinal transporters activity), and efavirenz clearance and 8-hydroxylation (CYP2B6 activity), and human hepatocyte effects. Efavirenz induced systemic and oral alfentanil clearances two- to fivefold and induced efavirenz 8-hydroxylation. Efavirenz stereoselectively decreased methadone plasma concentrations 50-70%. Methadone systemic and oral clearances, hepatic clearance and extraction ratio, N-demethylation, and metabolite formation clearance were stereoselectively increased two- to threefold. Bioavailability decreased. Efavirenz shifted methadone concentration-miosis curves leftward and upward. Efavirenz induced hepatocyte CYP2B6 and CYP3A4 expression, activity, and methadone N-demethylation. Results show that efavirenz coinduced hepatic CYP2B6 and CYP3A4/5, coinduced hepatic and intestinal CYP3A4/5, and coinduced gastrointestinal CYP3A4/5 and efflux transporters. Methadone disposition was most consistent with efavirenz induction of hepatic CYP2B6-mediated methadone N-demethylation. Efavirenz may alter methadone pharmacodynamics.
Pubmed Id: 22398970
Abstract: Mechanisms by which efavirenz diminishes methadone plasma concentrations are unknown. This investigation determined efavirenz influence on clinical methadone disposition and miosis, intravenous and oral alfentanil clearance (hepatic and intestinal cytochrome P450 3A4/5 (CYP3A4/5) activity), fexofenadine disposition (intestinal transporters activity), and efavirenz clearance and 8-hydroxylation (CYP2B6 activity), and human hepatocyte effects. Efavirenz induced systemic and oral alfentanil clearances two- to fivefold and induced efavirenz 8-hydroxylation. Efavirenz stereoselectively decreased methadone plasma concentrations 50-70%. Methadone systemic and oral clearances, hepatic clearance and extraction ratio, N-demethylation, and metabolite formation clearance were stereoselectively increased two- to threefold. Bioavailability decreased. Efavirenz shifted methadone concentration-miosis curves leftward and upward. Efavirenz induced hepatocyte CYP2B6 and CYP3A4 expression, activity, and methadone N-demethylation. Results show that efavirenz coinduced hepatic CYP2B6 and CYP3A4/5, coinduced hepatic and intestinal CYP3A4/5, and coinduced gastrointestinal CYP3A4/5 and efflux transporters. Methadone disposition was most consistent with efavirenz induction of hepatic CYP2B6-mediated methadone N-demethylation. Efavirenz may alter methadone pharmacodynamics.
Authors: Ke A Barter Z Rowland-Yeo K Almond L
Abstract: In this study, we present efavirenz physiologically based pharmacokinetic (PBPK) model development as an example of our best practice approach that uses a stepwise approach to verify the different components of the model. First, a PBPK model for efavirenz incorporating in vitro and clinical pharmacokinetic (PK) data was developed to predict exposure following multiple dosing (600 mg q.d.). Alfentanil i.v. and p.o. drug-drug interaction (DDI) studies were utilized to evaluate and refine the CYP3A4 induction component in the liver and gut. Next, independent DDI studies with substrates of CYP3A4 (maraviroc, atazanavir, and clarithromycin) and CYP2B6 (bupropion) verified the induction components of the model (area under the curve [AUC] ratios within 1.0-1.7-fold of observed). Finally, the model was refined to incorporate the fractional contribution of enzymes, including CYP2B6, propagating autoinduction into the model (Racc 1.7 vs. 1.7 observed). This validated mechanistic model can now be applied in clinical pharmacology studies to prospectively assess both the victim and perpetrator DDI potential of efavirenz.
Pubmed Id: 27435752
Abstract: In this study, we present efavirenz physiologically based pharmacokinetic (PBPK) model development as an example of our best practice approach that uses a stepwise approach to verify the different components of the model. First, a PBPK model for efavirenz incorporating in vitro and clinical pharmacokinetic (PK) data was developed to predict exposure following multiple dosing (600 mg q.d.). Alfentanil i.v. and p.o. drug-drug interaction (DDI) studies were utilized to evaluate and refine the CYP3A4 induction component in the liver and gut. Next, independent DDI studies with substrates of CYP3A4 (maraviroc, atazanavir, and clarithromycin) and CYP2B6 (bupropion) verified the induction components of the model (area under the curve [AUC] ratios within 1.0-1.7-fold of observed). Finally, the model was refined to incorporate the fractional contribution of enzymes, including CYP2B6, propagating autoinduction into the model (Racc 1.7 vs. 1.7 observed). This validated mechanistic model can now be applied in clinical pharmacology studies to prospectively assess both the victim and perpetrator DDI potential of efavirenz.
Authors: Marzolini C Rajoli R Battegay M Elzi L Back D Siccardi M
Abstract: BACKGROUND: Antiretroviral drugs are among the therapeutic agents with the highest potential for drug-drug interactions (DDIs). In the absence of clinical data, DDIs are mainly predicted based on preclinical data and knowledge of the disposition of individual drugs. Predictions can be challenging, especially when antiretroviral drugs induce and inhibit multiple cytochrome P450 (CYP) isoenzymes simultaneously. METHODS: This study predicted the magnitude of the DDI between efavirenz, an inducer of CYP3A4 and inhibitor of CYP2C8, and dual CYP3A4/CYP2C8 substrates (repaglinide, montelukast, pioglitazone, paclitaxel) using a physiologically based pharmacokinetic (PBPK) modeling approach integrating concurrent effects on CYPs. In vitro data describing the physicochemical properties, absorption, distribution, metabolism, and elimination of efavirenz and CYP3A4/CYP2C8 substrates as well as the CYP-inducing and -inhibitory potential of efavirenz were obtained from published literature. The data were integrated in a PBPK model developed using mathematical descriptions of molecular, physiological, and anatomical processes defining pharmacokinetics. Plasma drug-concentration profiles were simulated at steady state in virtual individuals for each drug given alone or in combination with efavirenz. The simulated pharmacokinetic parameters of drugs given alone were compared against existing clinical data. The effect of efavirenz on CYP was compared with published DDI data. RESULTS: The predictions indicate that the overall effect of efavirenz on dual CYP3A4/CYP2C8 substrates is induction of metabolism. The magnitude of induction tends to be less pronounced for dual CYP3A4/CYP2C8 substrates with predominant CYP2C8 metabolism. CONCLUSION: PBPK modeling constitutes a useful mechanistic approach for the quantitative prediction of DDI involving simultaneous inducing or inhibitory effects on multiple CYPs as often encountered with antiretroviral drugs.
Pubmed Id: 27599706
Abstract: BACKGROUND: Antiretroviral drugs are among the therapeutic agents with the highest potential for drug-drug interactions (DDIs). In the absence of clinical data, DDIs are mainly predicted based on preclinical data and knowledge of the disposition of individual drugs. Predictions can be challenging, especially when antiretroviral drugs induce and inhibit multiple cytochrome P450 (CYP) isoenzymes simultaneously. METHODS: This study predicted the magnitude of the DDI between efavirenz, an inducer of CYP3A4 and inhibitor of CYP2C8, and dual CYP3A4/CYP2C8 substrates (repaglinide, montelukast, pioglitazone, paclitaxel) using a physiologically based pharmacokinetic (PBPK) modeling approach integrating concurrent effects on CYPs. In vitro data describing the physicochemical properties, absorption, distribution, metabolism, and elimination of efavirenz and CYP3A4/CYP2C8 substrates as well as the CYP-inducing and -inhibitory potential of efavirenz were obtained from published literature. The data were integrated in a PBPK model developed using mathematical descriptions of molecular, physiological, and anatomical processes defining pharmacokinetics. Plasma drug-concentration profiles were simulated at steady state in virtual individuals for each drug given alone or in combination with efavirenz. The simulated pharmacokinetic parameters of drugs given alone were compared against existing clinical data. The effect of efavirenz on CYP was compared with published DDI data. RESULTS: The predictions indicate that the overall effect of efavirenz on dual CYP3A4/CYP2C8 substrates is induction of metabolism. The magnitude of induction tends to be less pronounced for dual CYP3A4/CYP2C8 substrates with predominant CYP2C8 metabolism. CONCLUSION: PBPK modeling constitutes a useful mechanistic approach for the quantitative prediction of DDI involving simultaneous inducing or inhibitory effects on multiple CYPs as often encountered with antiretroviral drugs.
Authors: Ivanyuk A Livio F Biollaz J Buclin T
Abstract: Transporters in proximal renal tubules contribute to the disposition of numerous drugs. Furthermore, the molecular mechanisms of tubular secretion have been progressively elucidated during the past decades. Organic anions tend to be secreted by the transport proteins OAT1, OAT3 and OATP4C1 on the basolateral side of tubular cells, and multidrug resistance protein (MRP) 2, MRP4, OATP1A2 and breast cancer resistance protein (BCRP) on the apical side. Organic cations are secreted by organic cation transporter (OCT) 2 on the basolateral side, and multidrug and toxic compound extrusion (MATE) proteins MATE1, MATE2/2-K, P-glycoprotein, organic cation and carnitine transporter (OCTN) 1 and OCTN2 on the apical side. Significant drug-drug interactions (DDIs) may affect any of these transporters, altering the clearance and, consequently, the efficacy and/or toxicity of substrate drugs. Interactions at the level of basolateral transporters typically decrease the clearance of the victim drug, causing higher systemic exposure. Interactions at the apical level can also lower drug clearance, but may be associated with higher renal toxicity, due to intracellular accumulation. Whereas the importance of glomerular filtration in drug disposition is largely appreciated among clinicians, DDIs involving renal transporters are less well recognized. This review summarizes current knowledge on the roles, quantitative importance and clinical relevance of these transporters in drug therapy. It proposes an approach based on substrate-inhibitor associations for predicting potential tubular-based DDIs and preventing their adverse consequences. We provide a comprehensive list of known drug interactions with renally-expressed transporters. While many of these interactions have limited clinical consequences, some involving high-risk drugs (e.g. methotrexate) definitely deserve the attention of prescribers.
Pubmed Id: 28210973
Abstract: Transporters in proximal renal tubules contribute to the disposition of numerous drugs. Furthermore, the molecular mechanisms of tubular secretion have been progressively elucidated during the past decades. Organic anions tend to be secreted by the transport proteins OAT1, OAT3 and OATP4C1 on the basolateral side of tubular cells, and multidrug resistance protein (MRP) 2, MRP4, OATP1A2 and breast cancer resistance protein (BCRP) on the apical side. Organic cations are secreted by organic cation transporter (OCT) 2 on the basolateral side, and multidrug and toxic compound extrusion (MATE) proteins MATE1, MATE2/2-K, P-glycoprotein, organic cation and carnitine transporter (OCTN) 1 and OCTN2 on the apical side. Significant drug-drug interactions (DDIs) may affect any of these transporters, altering the clearance and, consequently, the efficacy and/or toxicity of substrate drugs. Interactions at the level of basolateral transporters typically decrease the clearance of the victim drug, causing higher systemic exposure. Interactions at the apical level can also lower drug clearance, but may be associated with higher renal toxicity, due to intracellular accumulation. Whereas the importance of glomerular filtration in drug disposition is largely appreciated among clinicians, DDIs involving renal transporters are less well recognized. This review summarizes current knowledge on the roles, quantitative importance and clinical relevance of these transporters in drug therapy. It proposes an approach based on substrate-inhibitor associations for predicting potential tubular-based DDIs and preventing their adverse consequences. We provide a comprehensive list of known drug interactions with renally-expressed transporters. While many of these interactions have limited clinical consequences, some involving high-risk drugs (e.g. methotrexate) definitely deserve the attention of prescribers.
Authors: Hanke N Frechen S Moj D Britz H Eissing T Wendl T Lehr T
Abstract: According to current US Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidance documents, physiologically based pharmacokinetic (PBPK) modeling is a powerful tool to explore and quantitatively predict drug-drug interactions (DDIs) and may offer an alternative to dedicated clinical trials. This study provides whole-body PBPK models of rifampicin, itraconazole, clarithromycin, midazolam, alfentanil, and digoxin within the Open Systems Pharmacology (OSP) Suite. All models were built independently, coupled using reported interaction parameters, and mutually evaluated to verify their predictive performance by simulating published clinical DDI studies. In total, 112 studies were used for model development and 57 studies for DDI prediction. 93% of the predicted area under the plasma concentration-time curve (AUC) ratios and 94% of the peak plasma concentration (C) ratios are within twofold of the observed values. This study lays a cornerstone for the qualification of the OSP platform with regard to reliable PBPK predictions of enzyme-mediated and transporter-mediated DDIs during model-informed drug development. All presented models are provided open-source and transparently documented.
Pubmed Id: 30091221
Abstract: According to current US Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidance documents, physiologically based pharmacokinetic (PBPK) modeling is a powerful tool to explore and quantitatively predict drug-drug interactions (DDIs) and may offer an alternative to dedicated clinical trials. This study provides whole-body PBPK models of rifampicin, itraconazole, clarithromycin, midazolam, alfentanil, and digoxin within the Open Systems Pharmacology (OSP) Suite. All models were built independently, coupled using reported interaction parameters, and mutually evaluated to verify their predictive performance by simulating published clinical DDI studies. In total, 112 studies were used for model development and 57 studies for DDI prediction. 93% of the predicted area under the plasma concentration-time curve (AUC) ratios and 94% of the peak plasma concentration (C) ratios are within twofold of the observed values. This study lays a cornerstone for the qualification of the OSP platform with regard to reliable PBPK predictions of enzyme-mediated and transporter-mediated DDIs during model-informed drug development. All presented models are provided open-source and transparently documented.
