QT time prolongation
Adverse drug events
Variants ✨For the computationally intensive evaluation of the variants, please choose the paid standard subscription.
Explanations of the substances for patients
Monitoring of tacrolimus and voriconazole recommended.
Increased tacrolimus concentration and risk of ventricular arrhythmiasMechanism: Additive extension of the QT time. Voriconazole is a strong inhibitor of CYP3A4, which significantly catalyzes the breakdown of tacrolimus.
Effect: The additive prolongation of the QT time increases the likelihood of cardiac adverse effects such as arrhythmias, torsades de pointes or cardiac arrest. In clinical studies, voriconazole increased the Cmax and AUC of tacrolimus (0.1 mg / kg body weight, single dose) by 117% and 221%, respectively. According to the Swiss specialist information for voriconazole, the combination with a QT-prolonging CYP3A4 substrate is formally contraindicated.
Measures: Regular ECG check-ups of the QT time, especially when changing drug therapy. If voriconazole is used with existing tacrolimus therapy, the prescribing information recommends reducing the tacrolimus dose to one third of the starting dose and carefully monitoring whole blood tacrolimus levels. When voriconazole is discontinued, tacrolimus levels should be carefully monitored and the dose increased if necessary.
Monitoring of voriconazole and diazepam recommended.
Elevated diazepam concentrations - increased / prolonged sedationMechanism: Diazepam is hepatically metabolized via the CYP isozymes CYP3A4 and CYP2C19.
Effect: The effect of diazepam can be strengthened and prolonged by inhibiting the breakdown. In a study on 12 healthy volunteers, taking the combination was associated with a 2.2-fold increase in diazepam AUC and a 2-fold increase in the half-life of diazepam. The increased exposure to diazepam can possibly be associated with increased ADRs (e.g. drowsiness, dizziness).
Measures: Clinically monitor tolerability (e.g. increased sedation, dizziness), select a lower diazepam dose if necessary. Alternative benzodiazepines can be lorazepam or oxazepam, which are not metabolized by CYP enzymes.
|Voriconazole||1 [0.74,2.64] 1||1||1|
|Diazepam||2.24 [1.54,2.74] 1||2.24||1|
The reported changes in exposure correspond to the changes in the plasma concentration-time curve [ AUC ]. Tacrolimus exposure increases to 500%, when combined with voriconazole (500%) and diazepam (100%). Due to the narrow therapeutic index, the risk of toxicity is increased. If this therapy cannot be avoided, close therapeutic drug monitoring of tacrolimus must be carried out. Diazepam exposure increases to 224%, when combined with voriconazole (224%) and tacrolimus (100%). The AUC is between 154% and 274% depending on the CYP2C19
The pharmacokinetic parameters of the average population are used as the starting point for calculating the individual changes in exposure due to the interactions.
Voriconazole has a high oral bioavailability [ F ] of 88%, which is why the maximum plasma level [Cmax] tends to change little during an interaction. The terminal half-life [ t12 ] is rather short at 6 hours and constant plasma levels [ Css ] are reached quickly. The protein binding [ Pb ] is rather weak at 58% and the volume of distribution [ Vd ] is very large at 90 liters, Since the substance has a low hepatic extraction rate of 0.11, displacement from protein binding [Pb] in the context of an interaction can lead to increased exposure. The metabolism takes place via CYP2C19, CYP2C9 and CYP3A4, among others.
Diazepam has a mean oral bioavailability [ F ] of 76%, which is why the maximum plasma levels [Cmax] tend to change with an interaction. The terminal half-life [ t12 ] is rather long at 36 hours and constant plasma levels [ Css ] are only reached after more than 144 hours. The protein binding [ Pb ] is 97% strong and the volume of distribution [ Vd ] is very large at 83 liters. Since the substance has a low hepatic extraction rate of 0.03, displacement from protein binding [Pb] in the context of an interaction can lead to increased exposure. The metabolism takes place via CYP2B6, CYP2C19 and CYP3A4, among others.
Tacrolimus has a low oral bioavailability [ F ] of 18%, which is why the maximum plasma level [Cmax] tends to change strongly with an interaction. The terminal half-life [ t12 ] is rather long at 40 hours and constant plasma levels [ Css ] are only reached after more than 160 hours. The therapeutic window is narrow and the safety margin is therefore small. Even small changes in exposure can increase the risk of toxicity. The protein binding [ Pb ] is very strong at 98.9% and the volume of distribution [ Vd ] is very large at 116 liters, Since the substance has a low hepatic extraction rate of 0.05, displacement from protein binding [Pb] in the context of an interaction can lead to increased exposure. The metabolism mainly takes place via CYP3A4 and the active transport takes place partly via MRP2 and PGP.
|Serotonergic Effects a||0||Ø||Ø||Ø|
Rating: According to our knowledge, neither voriconazole, diazepam nor tacrolimus increase serotonergic activity.
|Kiesel & Durán b||1||Ø||+||Ø|
Recommendation: As a precaution, attention should be paid to anticholinergic symptoms, especially after increasing the dose and at doses in the upper therapeutic range.
Rating: Diazepam only has a mild effect on the anticholinergic system. The risk of anticholinergic syndrome with this medication is rather low if the dosage is in the usual range. According to our knowledge, neither voriconazole nor tacrolimus increase anticholinergic activity.
QT time prolongation
Rating: In combination, voriconazole and tacrolimus can potentially trigger ventricular arrhythmias of the torsades de pointes type. We do not know of any QT-prolonging potential for diazepam.
General adverse effects
|Side effects||∑ frequency||vor||dia||tac|
|Blurred vision||26.0 %||26.0||n.a.||n.a.|
|Peripheral edema||22.5 %||1.9||n.a.||21.0↑|
Elevated serum creatinine (16%): tacrolimus
Renal failure: voriconazole, tacrolimus
Hemolytic uremic syndrome: tacrolimus
Hyperglycemia (15%): tacrolimus
Atrial fibrillation (14.9%): tacrolimus
Cardiac arrest (14.9%): tacrolimus
Myocardial infarction (14.9%): tacrolimus
Heart failure: tacrolimus
Acute respiratory distress syndrome (14.9%): tacrolimus
Dyspnea (10%): voriconazole
Respiratory depression: diazepam
Insomnia (14%): tacrolimus
Paresthesia (10%): tacrolimus
Seizure: diazepam, tacrolimus
Abdominal pain (12%): voriconazole
Nausea (6.3%): voriconazole, tacrolimus
Vomiting (5.4%): voriconazole, tacrolimus
Diarrhea (2.9%): voriconazole, tacrolimus
Hypokalemia (11%): voriconazole
Hallucinations (9.5%): voriconazole
Rebound effect: diazepam
Photophobia (6%): voriconazole
Optic neuritis: voriconazole
Fever (5.7%): voriconazole
Cholestatic hepatitis (4.9%): voriconazole
Hepatotoxicity (1.9%): voriconazole, tacrolimus
Jaundice (1.9%): voriconazole
Liver failure (1.9%): voriconazole
Erythema multiforme (1.9%): voriconazole
Malignant melanoma (1.9%): voriconazole
Squamous cell carcinoma (1.9%): voriconazole
Stevens johnson syndrome (1.9%): voriconazole
Toxic epidermal necrolysis (1.9%): voriconazole
Prolonged bleeding time: tacrolimus
Diabetes mellitus: tacrolimus
Hypersensitivity reaction: tacrolimus
Based on your answers and scientific information, we assess the individual risk of undesirable side effects. These recommendations are intended to advise professionals and are not a substitute for consultation with a doctor. In the restricted test version (alpha), the risk of all substances has not yet been conclusively assessed.
Abstract: The effects of steady state dosing with omeprazole and cimetidine on plasma diazepam levels have been studied in 12 healthy males. Single doses of diazepam (0.1 mg.kg-1 i.v.) were administered after one week of treatment with omeprazole 20 mg once daily, cimetidine 400 mg b.d. or placebo, and the treatment was continued for a further 5 days. Blood was collected for 120 h after the dose of diazepam for the measurement of diazepam and its major metabolite desmethyl diazepam. The mean clearance of diazepam was decreased by 27% and 38% and its half-life was increased by 36% and 39% after omeprazole and cimetidine, respectively. Neither drug had any apparent effect on the volume of distribution of diazepam. Desmethyldiazepam appeared more slowly after both omeprazole and cimetidine. It is concluded that the decrease in diazepam clearance was associated with inhibition of hepatic metabolism both by omeprazole and cimetidine. However, since diazepam has a wide therapeutic range, it is unlikely that concomitant treatment with therapeutically recommended doses of either omeprazole or cimetidine will result in a clinically significant interaction with diazepam.
Abstract: Healthy volunteers received single doses of three benzodiazepines (diazepam, 10 mg i.v.; alprazolam, 1.0 mg orally; lorazepam, 2 mg i.v.) on two occasions in random sequence. One trial was a control; for the other, subjects ingested propoxyphene, 65 mg every 6 h, for the duration of the benzodiazepine study. The kinetics of each benzodiazepine were determined from multiple plasma concentrations measured following each dose. For diazepam, propoxyphene produced a small and statistically insignificant prolongation of elimination half-life (43 vs 38 h) and reduction of total clearance (0.41 vs 0.47 ml min-1 kg-1). Propoxyphene significantly prolonged alprazolam half-life (18 vs 12 h, P less than 0.005) and reduced total clearance (0.8 vs 1.3 ml min-1 kg-1, P less than 0.005). Propoxyphene had no apparent influence on lorazepam half-life (13.4 vs 13.5 h) or clearance (1.5 vs 1.4 ml min-1 kg-1). Thus propoxyphene significantly impairs the clearance of alprazolam, biotransformed mainly by the oxidative reaction of aliphatic hydroxylation. Propoxyphene has far less effect on the oxidation of diazepam by N-demethylation, and has no apparent influence on lorazepam conjugation.
Abstract: 1 The absorption of single doses of diazepam in six adult epileptic subjects following intravenous, oral and rectal administration were studied in order to evaluate the usefulness of the latter in emergency situations in the adult. 2 Diazepam tablets (Valium, Roche) and rectal solution (Valium solution for intravenous administration) produced similar peak serum concentrations after delays of 15-90 min. 3 Two suppository formulations showed statistically significant differences in absorption characteristics. 4 Serum diazepam levels above 400 ng ml-1 (suggested to be necessary for a satisfactory anticonvulsant effect) were reached in only a few subjects after rectal doses of 10-20 mg of solution, and then usually after a delay of over 2 h.
Abstract: Metabolism of diazepam (DZP) was studied in vitro to clarify the involvement of different forms of hepatic cytochrome P450 (CYP) in rats, and humans of Japanese and Caucasian origin. Microsomal 3-hydroxylation was the major pathway of DZP metabolism in rats and was inhibited by anti-CYP3A antibodies. Purified CYP3As and CYP2C11 catalysed 3-hydroxylation and N-demethylation, respectively, in the reconstituted systems. The rates of both reactions in human liver microsomes depended on the substrate concentration: the rate of 3-hydroxylation was 3-4 times higher than N-demethylation at 0.2 mM; the two activities were essentially the same at a lower substrate concentration (0.02 mM). Inhibitions of the N-demethylation by anti-CYP2C antibody and S-mephenytoin also depended on the substrate concentration and was detectable only at a low substrate concentration. Kinetic studies revealed the presence of two distinct catalytic activities for the N-demethylation; low Km and low Vmax, and high Km and high Vmax. The former activity seems to be mediated by a CYP2C P450 form. On the other hand, DZP 3-hydroxylation was rather selectively catalysed by a CYP3A P450 at the low and high substrate concentrations. These results were consistent with the observation in vivo that DZP N-demethylation and S-mephenytoin 4'-hydroxylation are closely correlated in humans. These results also suggest that the apparent discrepancy on the role of CYP forms in DZP metabolism in vitro and in vivo may reside in the difference in substrate concentration.
Abstract: The effects of pretreatment with a seven day course of ciprofloxacin on pharmacokinetics and pharmacodynamics of an intravenous (5 mg) dose of diazepam were investigated in a group of 12 healthy volunteers in a double-blind placebo-controlled crossover study. Ciprofloxacin pretreatment significantly reduced diazepam CL (without ciprofloxacin: 19.5 ml.h-1 kg-1; with ciprofloxacin: 12.3 ml.h-1 kg-1). Diazepam t1/2 was also prolonged (without ciprofloxacin: 36.7 h; with ciprofloxacin: 71.1 h), but volume of distribution was unaltered (without ciprofloxacin: 1.1 l.kg-1; with ciprofloxacin: 1.1 l.kg-1). However, no significant changes were detected in psychometric tests of digit symbol substitution, tapping rate and short memory, as well as levels of concentration, vigilance and tension measured by visual analogue scales.
Abstract: The purpose of this open-label, prospective study was to compare steady state concentrations and clearances of intravenously administered cyclosporine or tacrolimus with and without concomitant high-dose (400 mg/day) fluconazole in allogeneic BMT patients. Twenty-one patients were evaluable. The mean steady state cyclosporine and tacrolimus concentrations without fluconazole were 320.3 and 18.2 ng/ml and increased to 389.2 and 21.2 ng/ml, respectively, after the addition of fluconazole, corresponding to a 21% (P=0.031) and 16% (P=0.125) increase. The mean steady state clearance of cyclosporine and tacrolimus without fluconazole was 6.82 and 1.28 ml/min/kg, which decreased to 5.57 and 1.10 ml/min/kg with fluconazole, corresponding to a 21% (P=0.031) and 16% (P=0.125) decrease, respectively. The 21% difference in the cyclosporine concentration and clearance was not thought to be clinically significant. These results suggest that fluconazole's interaction with cyclosporine or tacrolimus may be a result of fluconazole's inhibition of gut metabolism, resulting in a greater extent of absorption.
Abstract: Tacrolimus, a novel macrocyclic lactone with potent immunosuppressive properties, is currently available as an intravenous formulation and as a capsule for oral use, although other formulations are under investigation. Tacrolimus concentrations in biological fluids have been measured using a number of methods, which are reviewed and compared in the present article. The development of a simple, specific and sensitive assay method for measuring concentrations of tacrolimus is limited by the low absorptivity of the drug, low plasma and blood concentrations, and the presence of metabolites and other drugs which may interfere with the determination of tacrolimus concentrations. Currently, most of the pharmacokinetic data available for tacrolimus are based on an enzyme-linked immunosorbent assay method, which does not distinguish tacrolimus from its metabolites. The rate of absorption of tacrolimus is variable with peak blood or plasma concentrations being reached in 0.5 to 6 hours; approximately 25% of the oral dose is bioavailable. Tacrolimus is extensively bound to red blood cells, with a mean blood to plasma ratio of about 15; albumin and alpha 1-acid glycoprotein appear to primarily bind tacrolimus in plasma. Tacrolimus is completely metabolised prior to elimination. The mean disposition half-life is 12 hours and the total body clearance based on blood concentration is approximately 0.06 L/h/kg. The elimination of tacrolimus is decreased in the presence of liver impairment and in the presence of several drugs. Various factors that contribute to the large inter- and interindividual variability in the pharmacokinetics of tacrolimus are reviewed here. Because of this variability, the narrow therapeutic index of tacrolimus, and the potential for several drug interactions, monitoring of tacrolimus blood concentrations is useful for optimisation of therapy and dosage regimen design.
Abstract: 1. We have examined the metabolism of diazepam by ten human cytochrome P450 forms (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4 and 3A5) expressed in HepG2 cells using a recombinant vaccinia virus system. 2. Among the P450 forms tested, diazepam was significantly demethylated by CYP2B6, 2C9, 2C19, 3A4 and 3A5, with 2C19 exhibiting the highest rate at concentrations < 0.1 mM, and hydroxylated only by the latter three enzymes, with 3A5 being the most active. The N-demethylation activity of diazepam by 2C19 at a concentration of 20 microM was six times of that by 3A4. However, that by 2C9 was detected at only a trace level. 3. CYP2C19, 3A4 and 3A5 of the ten human P450s catalysed the 3-hydroxylation of nordiazepam, and 2B6, the 2C subfamily and the 3A subfamily catalysed the N-demethylation of temazepam. CYP3A4 exhibited the highest activity of nordiazepam 3-hydroxylation and temazepam N-demethylation. 4. Diazepam N-demethylation by human liver microsomes correlated with diazepam 3-hydroxylation, but not S-mephenytoin 4'-hydroxylation. 5. Our results suggest that in the human liver, the metabolism of diazepam to nordiazepam is mediated by CYP3A4, which has been reported as the most abundant P450 form in human liver as well as 2C19, which has been reported as a polymorphic enzyme.
Abstract: No Abstract available
Abstract: Tacrolimus is a marketed immunosuppressant used in liver and kidney transplantation. It is subject to extensive metabolism by CYP3A4 and is a substrate for P-glycoprotein-mediated transport. A pharmacokinetic interaction with rifampin, an antituberculosis agent and potent inducer of CYP3A4 and P-glycoprotein, and tacrolimus was evaluated in six healthy male volunteers. Tacrolimus was administered at doses of 0.1 mg/kg orally and 0.025 mg/kg/4 hours intravenously. The pharmacokinetics of tacrolimus were obtained from serial blood samples collected over 96 hours, after single oral and intravenous administration prior to and during an 18-day concomitant rifampin dosing phase. Coadministration of rifampin significantly increased tacrolimus clearance (36.0 +/- 8.1 ml/hr/kg vs. 52.8 +/- 9.6 ml/hr/kg; p = 0.03) and decreased tacrolimus bioavailability (14.4% +/- 5.7% vs. 7.0% +/- 2.7%; p = 0.03). Rifampin appears to induce both intestinal and hepatic metabolism of tacrolimus, most likely through induction of CYP3A and P-glycoprotein in the liver and small bowel.
Abstract: Tacrolimus is a macrolide lactone with potent immunosuppressive properties. It has been shown in clinical studies to prevent allograft rejection. The pharmacokinetics of tacrolimus in healthy subjects and transplant patients has been described in earlier studies using immunoassay methods; however, detailed information on the absorption, distribution, metabolism, and excretion of tacrolimus using a radiolabeled drug is lacking. The objective of the present study was to characterize the disposition of tacrolimus after single i.v. (0.01 mg/kg) and oral (0.05 mg/kg) administration of 14C-labeled drug in six healthy subjects. Tacrolimus was absorbed rapidly after oral dosing with a mean Cmax and Tmax of 42 ng/ml and 1 h, respectively. The oral bioavailability was about 20%. After i.v. and oral dosing, most of the administered dose was recovered in feces, suggesting that bile is the principal route of elimination. Urinary excretion accounted for less than 3% of total administered dose. In systemic circulation, unchanged parent compound accounted for nearly all the radioactivity; however, less than 0.5% of unchanged drug was detectable in feces and urine. The excretion of the metabolites was formation-rate-limited. The mean total body clearance at 37.5 ml/min was equivalent to about 3% of the liver blood flow. Renal clearance was less than 1% of the total body clearance. The mean elimination half-life was 44 h.
Abstract: (R,S)-Oxazepam is a 1,4-benzodiazepine anxiolytic drug that is metabolized primarily by hepatic glucuronidation. In previous studies, S-oxazepam (but not R-oxazepam) was shown to be polymorphically glucuronidated in humans. The aim of the present study was to identify UDP-glucuronosyltransferase (UGT) isoforms mediating R- and S-oxazepam glucuronidation in human liver, with the long term objective of elucidating the molecular genetic basis for this drug metabolism polymorphism. All available recombinant UGT isoforms were screened for R- and S-oxazepam glucuronidation activities. Enzyme kinetic parameters were then determined in representative human liver microsomes (HLMs) and in UGTs that showed significant activity. Of 12 different UGTs evaluated, only UGT2B15 showed significant S-oxazepam glucuronidation. Furthermore, the apparent K(m) for UGT2B15 (29-35 microM) was similar to values determined for HLMs (43-60 microM). In contrast, R-oxazepam was glucuronidated by UGT1A9 and UGT2B7. Although apparent K(m) values for HLMs (256-303 microM) were most similar to UGT2B7 (333 microM) rather than UGT1A9 (12 microM), intrinsic clearance values for UGT1A9 were 10 times higher than for UGT2B7. A common genetic variation results in aspartate (UGT2B15*1) or tyrosine (UGT2B15*2) at position 85 of the UGT2B15 protein. Microsomes from human embryonic kidney (HEK)-293 cells overexpressing UGT2B15*1 showed 5 times higher S-oxazepam glucuronidation activity than did UGT2B15*2 microsomes. Similar results were obtained for other substrates, including eugenol, naringenin, 4-methylumbelliferone, and androstane-3alpha-diol. In conclusion, S-oxazepam is stereoselectively glucuronidated by UGT2B15, whereas R-oxazepam is glucuronidated by multiple UGT isoforms. Allelic variation associated with the UGT2B15 gene may explain polymorphic S-oxazepam glucuronidation in humans.
Abstract: No Abstract available
Abstract: The binding of drugs to plasma proteins is important to consider when concentrations in whole blood (eg, in forensic toxicology) are compared with therapeutic and toxic concentrations based on the analysis of plasma or serum. The plasma to whole blood distribution of diazepam (D) and its major metabolite nordiazepam (ND) was investigated under in vitro and ex vivo conditions. Studies in vitro were done by spiking whole blood with D and ND to give concentrations ranging from 0.1 to 1.0 microg/g. Venous blood was also obtained from hospital blood donors (n = 66) after informed consent. The hematocrit, hemoglobin, and water content of blood specimens were determined by routine procedures before D and ND were added to produce target concentrations of approximately 0.5 microg/g for each substance. The ex vivo work was done with blood specimens from hospital outpatients who were being medicated with D. Concentrations of D and ND were determined in body fluids by capillary column gas chromatography after adding prazepam as internal standard and solvent extraction with butyl acetate. The method limit of quantitation was 0.03 microg/g for both D and ND. The concentrations of D and ND were highest in plasma and lowest in erythrocytes. The plasma/blood (P/B) distribution ratios did not depend on drug concentration between 0.1 and 1.0 microg/g. The mean P/B ratios were 1.79:1 for D and 1.69:1 for ND when hematocrit was 45%. Furthermore, the P/B ratio for D (y) was positively correlated with blood hematocrit (x) and the regression equation was y = 0.636 + 0.025x (r = 0.86, P < 0.001). A similar strong association was found between the P/B ratio and hematocrit for ND (r = 0.79). P/B ratios of D and ND, blood hematocrit, hemoglobin, and the water content differed between sexes (P < 0.001). The overall mean P/B ratios for D and ND were 1.69 +/- 0.097 (+/- SD) and 1.62 +/- 0.08 (P < 0.001, n = 66) respectively when the mean hematocrit was 42.9 +/- 3.4 (+/- SD). For forensic purposes, it would be better to forgo making any conversion of a drug concentration measured in whole blood to that expected in plasma or serum; instead, therapeutic and toxic concentrations should be established for the actual specimens received.
Abstract: The metabolic activities of six psychotropic drugs, diazepam, clotiazepam, tofisopam, etizolam, tandospirone, and imipramine, were determined for 14 isoforms of recombinant human hepatic cytochrome P450s (CYPs) and human liver microsomes by measuring the disappearance rate of parent compounds. In vitro kinetic studies revealed that Vmax/Km values in human liver microsomes were the highest for tofisopam, followed by tandospirone>clotiazepam>imipramine, diazepam, and etizolam. Among the recombinant CYPs, CYP3A4 exhibited the highest metabolic activities of all compounds except for clotiazepam and imipramine. The metabolism of clotiazepam was catalyzed by CYP2B6, CYP3A4, CYP2C18, and CYP2C19, and imipramine was metabolized by CYP2D6 most efficiently. In addition, the metabolic activities of diazepam, clotiazepam, and etizolam in human liver microsomes were inhibited by 2.5 microM ketoconazole, a CYP3A4 inhibitor, by 97.5%, 65.1%, and 83.5%, respectively, and the imipramine metabolism was not detected after the addition of 1 or 10 microM quinidine, a CYP2D6 inhibitor. These results suggest that the psychotropic drugs investigated are metabolized predominantly by CYP3A4, except that CYP2D6 catalyzes the metabolism of imipramine. In addition, this approach based on the disappearance rate appears to be useful for the identification of the responsible CYP isoform(s) of older drugs, for which metabolic profiles have not been reported.
Abstract: The effects of five antifungal drugs, fluconazole, itraconazole, micafungin, miconazole, and voriconazole, on cytochrome P450 (CYP) 2C9-mediated tolbutamide hydroxylation, CYP2C19-mediated S-mephenytoin 4'-hydroxylation, and CYP3A4-mediated nifedipine oxidation activities in human liver microsomes were compared. In addition, the effects of preincubation were estimated to investigate the mechanism-based inhibition. The IC50 value against tolbutamide hydroxylation was the lowest for miconazole (2.0 microM), followed by voriconazole (8.4 microM) and fluconazole (30.3 microM). Similarly, the IC50 value against S-mephenytoin 4'-hydroxylation was the lowest for miconazole (0.33 microM), followed by voriconazole (8.7 microM) and fluconazole (12.3 microM). On the other hand, micafungin at a concentration of 10 or 25 microM neither inhibited nor stimulated tolbutamide hydroxylation and S-mephenytoin 4'-hydroxylation, and the IC50 values for itraconazole against these were greater than 10 microM. These results suggest that miconazole is the strongest inhibitor of CYP2C9 and CYP2C19, followed by voriconazole and fluconazole, whereas micafungin would not cause clinically significant interactions with other drugs that are metabolized by CYP2C9 or CYP2C19 via the inhibition of metabolism. The IC50 value of voriconazole against nifedipine oxidation was comparable with that of fluconazole and micafungin and higher than that of itraconazole and miconazole. The stimulation of the inhibition of CYP2C9-, CYP2C19-, or CYP3A4-mediated reactions by 15-min preincubation was not observed for any of the antifungal drugs, suggesting that these drugs are not mechanism-based inhibitors.
Abstract: This review presents the published clinical pharmacokinetic data for the antifungal agent voriconazole. Aspects regarding absorption, tissue distribution, elimination and kinetic interactions are also discussed.
Abstract: Voriconazole is the first available second-generation triazole with potent activity against a broad spectrum of clinically significant fungal pathogens, including Aspergillus,Candida, Cryptococcus neoformans, and some less common moulds. Voriconazole is rapidly absorbed within 2 hours after oral administration and the oral bioavailability is over 90%, thus allowing switching between oral and intravenous formulations when clinically appropriate. Voriconazole shows nonlinear pharmacokinetics due to its capacity-limited elimination, and its pharmacokinetics are therefore dependent upon the administered dose. With increasing dose, voriconazole shows a superproportional increase in area under the plasma concentration-time curve (AUC). In doses used in children (age < 12 years) voriconazole pharmacokinetics appear to be linear. Steady-state plasma concentrations are reached approximately 5 days after both intravenous and oral administration; however, steady state is reached within 24 hours with voriconazole administered as an intravenous loading dose. The volume of distribution of voriconazole is 2-4.6 L/kg, suggesting extensive distribution into extracellular and intracellular compartments. Voriconazole was measured in tissue samples of brain, liver, kidney, heart, lung as well as cerebrospinal fluid. The plasma protein binding is about 60% and independent of dose or plasma concentrations. Clearance is hepatic via N-oxidation by the hepatic cytochrome P450 (CYP) isoenzymes, CYP2C19, CYP2C9 and CYP3A4. The elimination half-life of voriconazole is approximately 6 hours, and approximately 80% of the total dose is recovered in the urine, almost completely as metabolites. As with other azole drugs, the potential for drug interactions is considerable. Voriconazole shows time-dependent fungistatic activity against Candida species and time-dependent slow fungicidal activity against Aspergillus species. A short post-antifungal effect of voriconazole is evident only for Aspergillus species. The predictive pharmacokinetic/pharmacodynamic parameter for voriconazole treatment efficacy in Candida infections is the free drug AUC from 0 to 24 hour : minimum inhibitory concentration ratio.
Abstract: Anticholinergic Drug Scale (ADS) scores were previously associated with serum anticholinergic activity (SAA) in a pilot study. To replicate these results, the association between ADS scores and SAA was determined using simple linear regression in subjects from a study of delirium in 201 long-term care facility residents who were not included in the pilot study. Simple and multiple linear regression models were then used to determine whether the ADS could be modified to more effectively predict SAA in all 297 subjects. In the replication analysis, ADS scores were significantly associated with SAA (R2 = .0947, P < .0001). In the modification analysis, each model significantly predicted SAA, including ADS scores (R2 = .0741, P < .0001). The modifications examined did not appear useful in optimizing the ADS. This study replicated findings on the association of the ADS with SAA. Future work will determine whether the ADS is clinically useful for preventing anticholinergic adverse effects.
Abstract: We describe 2 patients who developed prolonged QTc interval on electrocardiogram while being treated with voriconazole. The first patient had undergone induction chemotherapy for acute myelogenous leukemia, and her course had been complicated by invasive aspergillosis and an acute cardiomyopathy. She developed torsades de pointes 3 weeks after starting voriconazole therapy. She was re-challenged with voriconazole without recurrent QTc prolongation or cardiac dysfunction. The second patient had a significantly prolonged QTc interval while on voriconazole therapy. We recommend careful monitoring for QTc prolongation and arrhythmia in patients who are receiving voriconazole, particularly those who have significant electrolyte disturbances, are on concomitant QT prolonging medications, have heart failure such as from a dilated cardiomyopathy, or have recently received anthracycline-based chemotherapy. The potential for synergistic cardiotoxicity must be carefully considered.
Abstract: OBJECTIVE: We assessed the effect of voriconazole and fluconazole on the pharmacokinetics and pharmacodynamics of diazepam. METHODS: Twelve healthy volunteers took 5 mg of oral diazepam in a randomised order on three study sessions: without pretreatment, after oral voriconazole 400 mg twice daily on the first day and 200 mg twice daily on the second day, or after oral fluconazole 400 mg on the first day and 200 mg on the second day. Plasma concentrations of diazepam and N-desmethyldiazepam were determined for up to 48 h. Pharmacodynamic variables were measured for 12 h. RESULTS: In the voriconazole phase, the area under the plasma concentration time curve (AUC 0-infinity) of diazepam was increased (geometric mean ratio) 2.2-fold (p < 0.05; 90% confidence interval [CI] 1.56 to 2.82). This was associated with the prolongation of the mean elimination half-life (t(1/2)) from 31 h to 61 h (p < 0.01) after voriconazole. In the fluconazole phase, the AUC 0-infinity of diazepam was increased 2.5-fold (p < 0.01; 90% CI 1.94 to 3.40), and the t(1/2) was prolonged from 31 h to 73 h (p < 0.001). The peak plasma concentration of diazepam was practically unchanged by voriconazole and fluconazole. The pharmacodynamics of diazepam were changed only modestly. CONCLUSION: Both voriconazole and fluconazole considerably increase the exposure to diazepam. Recurrent administration of diazepam increases the risk of clinically significant interactions during voriconazole or fluconazole treatment, because the elimination of diazepam is impaired significantly.
Abstract: The objective of this study was to measure the anticholinergic activity (AA) of medications commonly used by older adults. A radioreceptor assay was used to investigate the AA of 107 medications. Six clinically relevant concentrations were assessed for each medication. Rodent forebrain and striatum homogenate was used with tritiated quinuclidinyl benzilate. Drug-free serum was added to medication and atropine standard-curve samples. For medications that showed detectable AA, average steady-state peak plasma and serum concentrations (C(max)) in older adults were used to estimate relationships between in vitro dose and AA. All results are reported in pmol/mL of atropine equivalents. At typical doses administered to older adults, amitriptyline, atropine, clozapine, dicyclomine, doxepin, L-hyoscyamine, thioridazine, and tolterodine demonstrated AA exceeding 15 pmol/mL. Chlorpromazine, diphenhydramine, nortriptyline, olanzapine, oxybutynin, and paroxetine had AA values of 5 to 15 pmol/mL. Citalopram, escitalopram, fluoxetine, lithium, mirtazapine, quetiapine, ranitidine, and temazepam had values less than 5 pmol/mL. Amoxicillin, celecoxib, cephalexin, diazepam, digoxin, diphenoxylate, donepezil, duloxetine, fentanyl, furosemide, hydrocodone, lansoprazole, levofloxacin, metformin, phenytoin, propoxyphene, and topiramate demonstrated AA only at the highest concentrations tested (patients with above-average C(max) values, who receive higher doses, or are frail may show AA). The remainder of the medications investigated did not demonstrate any AA at the concentrations examined. Psychotropic medications were particularly likely to demonstrate AA. Each of the drug classifications investigated (e.g., antipsychotic, cardiovascular) had at least one medication that demonstrated AA at therapeutic doses. Clinicians can use this information when choosing between equally efficacious medications, as well as in assessing overall anticholinergic burden.
Abstract: Voriconazole is an effective antifungal drug, but adverse drug-drug interactions associated with its use are of major clinical concern. To identify the mechanisms of these interactions, we tested the inhibitory potency of voriconazole with eight human cytochrome P450 (CYP) enzymes. Isoform-specific probes were incubated with human liver microsomes (HLMs) (or expressed CYPs) and cofactors in the absence and the presence of voriconazole. Preincubation experiments were performed to test mechanism-based inactivation. In pilot experiments, voriconazole showed inhibition of CYP2B6, CYP2C9, CYP2C19, and CYP3A (half-maximal [50%] inhibitory concentrations, <6 microM); its effect on CYP1A2, CYP2A6, CYP2C8, and CYP2D6 was marginal (<25% inhibition at 100 microM voriconazole). Further detailed experiments with HLMs showed that voriconazole is a potent competitive inhibitor of CYP2B6 (K(i) < 0.5), CYP2C9 (K(i) = 2.79 microM), and CYP2C19 (K(i) = 5.1 microM). The inhibition of CYP3A by voriconazole was explained by noncompetitive (K(i) = 2.97 microM) and competitive (K(i) = 0.66 microM) modes of inhibition. Prediction of the in vivo interaction of voriconazole from these in vitro data suggests that voriconazole would substantially increase the exposure of drugs metabolized by CYP2B6, CYP2C9, CYP2C19, and CYP3A. Clinicians should be aware of these interactions and monitor patients for adverse effects or failure of therapy.
Abstract: BACKGROUND: Cognitive decline is common in Parkinson's disease (PD). Although some of the aetiological factors are known, it is not yet known whether drugs with anticholinergic activity (AA) contribute to this cognitive decline. Such knowledge would provide opportunities to prevent acceleration of cognitive decline in PD. OBJECTIVE: To study whether the use of agents with anticholinergic properties is an independent risk factor for cognitive decline in patients with PD. METHODS: A community-based cohort of patients with PD (n=235) were included and assessed at baseline. They were reassessed 4 and 8 years later. Cognition was assessed using the Mini-Mental State Examination (MMSE). A detailed assessment of the AA of all drugs prescribed was made, and AA was classified according to a standardised scale. Relationships between cognitive decline and AA load and duration of treatment were assessed using bivariate and multivariate statistical analyses. RESULTS: More than 40% used drugs with AA at baseline. During the 8-year follow-up, the cognitive decline was higher in those who had been taking AA drugs (median decline on MMSE 6.5 points) compared with those who had not taken such drugs (median decline 1 point; p=0.025). In linear regression analyses adjusting for age, baseline cognition and depression, significant associations with decline on MMSE were found for total AA load (standardised beta=0.229, p=0.04) as well as the duration of using AA drugs (standardised beta 0.231, p=0.032). CONCLUSION: Our findings suggest that there is an association between anticholinergic drug use and cognitive decline in PD. This may provide an important opportunity for clinicians to avoid increasing progression of cognitive decline by avoiding drugs with AA. Increased awareness by clinicians is required about the classes of drugs that have anticholinergic properties.
Abstract: The objective of this study was to evaluate the pharmacokinetics of voriconazole and the potential correlations between pharmacokinetic parameters and patient variables in liver transplant patients on a fixed-dose prophylactic regimen. Multiple blood samples were collected within one dosing interval from 15 patients who were initiated on a prophylactic regimen of voriconazole at 200 mg enterally (tablets) twice daily starting immediately posttransplant. Voriconazole plasma concentrations were measured using high-pressure liquid chromatography (HPLC). Noncompartmental pharmacokinetic analysis was performed to estimate pharmacokinetic parameters. The mean apparent systemic clearance over bioavailability (CL/F), apparent steady-state volume of distribution over bioavailability (Vss/F), and half-life (t1/2) were 5.8+/-5.5 liters/h, 94.5+/-54.9 liters, and 15.7+/-7.0 h, respectively. There was a good correlation between the area under the concentration-time curve from 0 h to infinity (AUC0-infinity) and trough voriconazole plasma concentrations. t1/2, maximum drug concentration in plasma (Cmax), trough level, AUC0-infinity, area under the first moment of the concentration-time curve from 0 h to infinity (AUMC0-infinity), and mean residence time from 0 h to infinity (MRT0-infinity) were significantly correlated with postoperative time. t1/2, lambda, AUC0-infinity, and CL/F were significantly correlated with indices of liver function (aspartate transaminase [AST], total bilirubin, and international normalized ratio [INR]). The Cmax, last concentration in plasma at 12 h (Clast), AUMC0-infinity, and MRT0-infinity were significantly lower in the presence of deficient CYP2C19*2 alleles. Donor characteristics had no significant correlation with any of the pharmacokinetic parameters estimated. A fixed dosing regimen of voriconazole results in a highly variable exposure of voriconazole in liver transplant patients. Given that trough voriconazole concentration is a good measure of drug exposure (AUC), the voriconazole dose can be individualized based on trough concentration measurements in liver transplant patients.
Abstract: The three hydroxybenzodiazepines oxazepam, temazepam, and lorazepam used for their anxiolytic, sedative, and anticonvulsant properties are metabolized by glucuronidation, which is the predominant pathway in the clearance mechanism of exogenous and endogenous substances during phase II metabolism. The aim of this study was the synthesis of benzodiazepine-O-glucuronides as analytical reference substances. All benzodiazepines are prescribed clinically as racemic formulations. The resulting conjugates from the coupling reactions with glucuronic acid are epimeric pairs of glucuronides. Due to the importance of stereochemical factors in drug disposition it is necessary to separate the diastereomeric forms after synthesis. An enzyme-assisted synthesis was developed and optimized by using microsomal UGT from fresh swine liver to receive multimilligram amounts of the benzodiazepine glucuronides, which were not accessible by standard synthetic procedures, like the Koenigs-Knorr- and Williamson-ether-synthesis. Swine liver microsomes were prepared by homogenization and differential centrifugation of liver tissue. In the presence of liver microsomes the benzodiazepines and cofactor UDPGA were incubated for 24h. After incubation the microsomes were removed by protein precipitation and the residual benzodiazepines by liquid-liquid extraction (dichloromethane). The epimeric pairs of benzodiazepine glucuronides were separated by preparative high performance liquid chromatography (HPLC) followed by solid phase extraction (SPE) to obtain the pure benzodiazepine glucuronide epimers. The synthesis products were characterized by mass spectroscopy and nuclear magnetic resonance (NMR) spectroscopy.
Abstract: No Abstract available
Abstract: BACKGROUND/AIMS: The nature and extent of adverse cognitive effects due to the prescription of anticholinergic drugs in older people with and without dementia is unclear. METHODS: We calculated the anticholinergic load (ACL) of medications taken by participants of the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing, a cohort of 211 Alzheimer's disease (AD) patients, 133 mild cognitive impairment (MCI) patients and 768 healthy controls (HC) all aged over 60 years. The association between ACL and cognitive function was examined for each diagnostic group (HC, MCI, AD). RESULTS: A high ACL within the HC group was associated with significantly slower response speeds for the Stroop color and incongruent trials. No other significant relationships between ACL and cognition were noted. CONCLUSION: In this large cohort, prescribed anticholinergic drugs appeared to have modest effects upon psychomotor speed and executive function, but not on other areas of cognition in healthy older adults.
Abstract: UNLABELLED: The hepatitis C virus protease inhibitor telaprevir is an inhibitor of the enzyme cytochrome P450 3A, responsible for the metabolism of both cyclosporine and tacrolimus. This Phase I, open-label, nonrandomized, single-sequence study assessed the effect of telaprevir coadministration on the pharmacokinetics of a single dose of either cyclosporine or tacrolimus in two separate panels of 10 healthy volunteers each. In Part A, cyclosporine was administered alone as a single 100-mg oral dose, followed by a minimum 8-day washout period, and subsequent coadministration of a single 10-mg oral dose of cyclosporine with either a single dose of telaprevir (750 mg) or with steady-state telaprevir (750 mg every 8 hours [q8h]). In Part B, tacrolimus was administered alone as a single 2-mg oral dose, followed by a minimum 14-day washout period, and subsequent coadministration of a single 0.5-mg dose of tacrolimus with steady-state telaprevir (750 mg q8h). Coadministration with steady-state telaprevir increased cyclosporine dose-normalized (DN) exposure (DN_AUC(0-∞)) by approximately 4.6-fold and increased tacrolimus DN_AUC(0-∞) by approximately 70-fold. Coadministration with telaprevir increased the terminal elimination half-life (t(½)) of cyclosporine from a mean (standard deviation [SD]) of 12 (1.67) hours to 42.1 (11.3) hours and t(½) of tacrolimus from a mean (SD) of 40.7 (5.85) hours to 196 (159) hours. CONCLUSION: In this study, telaprevir increased the blood concentrations of both cyclosporine and tacrolimus significantly, which could lead to serious or life-threatening adverse events. Telaprevir has not been studied in organ transplant patients; its use in these patients is not recommended because the required studies have not been completed to understand appropriate dose adjustments needed for safe coadministration of telaprevir with cyclosporine or tacrolimus, and regulatory approval has not been obtained.
Abstract: No Abstract available
Abstract: UNLABELLED: The hepatitis C virus protease inhibitor boceprevir is a strong inhibitor of cytochrome P450 3A4 and 3A5 (CYP3A4/5). Cyclosporine and tacrolimus are calcineurin inhibitor immunosuppressants used to prevent organ rejection after liver transplantation; both are substrates of CYP3A4. This two-part pharmacokinetic interaction study evaluated boceprevir with cyclosporine (part 1) and tacrolimus (part 2). In part 1, 10 subjects received single-dose cyclosporine (100 mg) on day 1, single-dose boceprevir (800 mg) on day 3, and concomitant cyclosporine/boceprevir on day 4. After washout, subjects received boceprevir (800 mg three times a day) for 7 days plus single-dose cyclosporine (100 mg) on day 6. In part 2A, 12 subjects received single-dose tacrolimus (0.5 mg). After washout, they received boceprevir (800 mg three times a day) for 11 days plus single-dose tacrolimus (0.5 mg) on day 6. In part 2B, 10 subjects received single-dose boceprevir (800 mg) and 24 hours later received boceprevir (800 mg) plus tacrolimus (0.5 mg). Coadministration of boceprevir with cyclosporine/tacrolimus was well tolerated. Concomitant boceprevir increased the area under the concentration-time curve from time 0 to infinity after single dosing (AUC(inf) ) and maximum observed plasma (or blood) concentration (C(max) ) of cyclosporine with geometric mean ratios (GMRs) (90% confidence interval [CI]) of 2.7 (2.4-3.1) and 2.0 (1.7-2.4), respectively. Concomitant boceprevir increased the AUC(inf) and C(max) of tacrolimus with GMRs (90% CI) of 17 (14-21) and 9.9 (8.0-12), respectively. Neither cyclosporine nor tacrolimus coadministration had a meaningful effect on boceprevir pharmacokinetics. CONCLUSION: Dose adjustments of cyclosporine should be anticipated when administered with boceprevir, guided by close monitoring of cyclosporine blood concentrations and frequent assessments of renal function and cyclosporine-related side effects. Administration of boceprevir plus tacrolimus requires significant dose reduction and prolongation of the dosing interval for tacrolimus, with close monitoring of tacrolimus blood concentrations and frequent assessments of renal function and tacrolimus-related side effects.
Abstract: Organic anion transporting polypeptide (OATP) family transporters accept a number of drugs and are increasingly being recognized as important factors in governing drug and metabolite pharmacokinetics. OATP1B1 and OATP1B3 play an important role in hepatic drug uptake while OATP2B1 and OATP1A2 might be key players in intestinal absorption and transport across blood-brain barrier of drugs, respectively. To understand the importance of OATPs in the hepatic clearance of drugs, the rate-determining process for elimination should be considered; for some drugs, hepatic uptake clearance rather than metabolic intrinsic clearance is the more important determinant of hepatic clearances. The importance of the unbound concentration ratio (liver/blood), K(p,uu) , of drugs, which is partly governed by OATPs, is exemplified in interpreting the difference in the IC(50) of statins between the hepatocyte and microsome systems for the inhibition of HMG-CoA reductase activity. The intrinsic activity and/or expression level of OATPs are affected by genetic polymorphisms and drug-drug interactions. Their effects on the elimination rate or intestinal absorption rate of drugs may sometimes depend on the substrate drug. This is partly because of the different contribution of OATP isoforms to clearance or intestinal absorption. When the contribution of the OATP-mediated pathway is substantial, the pharmacokinetics of substrate drugs should be greatly affected. This review describes the estimation of the contribution of OATP1B1 to the total hepatic uptake of drugs from the data of fold-increases in the plasma concentration of substrate drugs by the genetic polymorphism of this transporter. To understand the importance of the OATP family transporters, modeling and simulation with a physiologically based pharmacokinetic model are helpful.
Abstract: The objective of this study was to evaluate the effect of the CYP3A5*3 allele on the pharmacokinetics of tacrolimus and amlodipine, and drug-drug interactions between them in healthy subjects. Pharmacokinetic drug interactions between tacrolimus and amlodipine were evaluated in a randomized, 3-period, 6-sequence crossover study in healthy Chinese volunteers according to CYP3A5 genotype. A single-dose and multiple-dose study were designed. A 96-h pharmacokinetic study followed either tacrolimus or amlodipine dose, and the washout periods between the study phases were 14 days. In the single-dose study, apparent oral clearance (CL/F) of tacrolimus (5 mg) in CYP3A5 expressers was 3.8-fold (p = 0.008) higher than that in CYP3A5 non-expressers. Amlodipine decreased mean tacrolimus CL/F in CYP3A5 expressers by 2.2-fold (p = 0.005), while it had no effect on that in CYP3A5 non-expressers. The CL/F of amlodipine in CYP3A5 non-expressers was 2.0-fold (p = 0.001) higher than that in CYP3A5 expressers. Tacrolimus increased mean amlodipine CL/F in CYP3A5 expressers by 1.4-fold (p = 0.016) while it had no effect on that in CYP3A5 non-expressers. Tacrolimus slightly reduced the AUC₀-∞ of amlodipine in both CYP3A5 expressers and non-expressers. Dose adjustment of tacrolimus should be considered according to CYP3A5*3 genetic polymorphism when tacrolimus is coadministered with amlodipine.
Abstract: BACKGROUND AND OBJECTIVE: Tacrolimus is an immunosuppressive drug used for the prevention of the allograft rejection in kidney transplant recipients. It exhibits a narrow therapeutic index and large pharmacokinetic variability. Tacrolimus is mainly metabolized by cytochrome P450 (CYP) 3A4 and 3A5 and effluxed via ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp), encoded by ABCB1 gene. The influence of CYP3A5*3 on the pharmacokinetics of tacrolimus has been well characterized. On the other hand, the contribution of polymorphisms in other genes is controversial. In addition, the involvement of other efflux transporters than P-gp in tacrolimus disposition is uncertain. The present study was designed to investigate the effects of genetic polymorphisms of CYP3As and efflux transporters on the pharmacokinetics of tacrolimus. SUBJECTS AND METHODS: A total of 500 blood concentrations of tacrolimus from 102 adult stable kidney transplant recipients were included in the analyses. Genetic polymorphisms in CYP3A4 and CYP3A5 genes were determined. In addition, the genes of efflux transporters including P-gp (ABCB1), multidrug resistance-associated protein (MRP2/ABCC2) and breast cancer resistance protein (BCRP/ABCG2) were genotyped. For ABCC2 gene, haplotypes were determined as follows: H1 (wild type), H2 (1249G>A), H9 (3972C>T) and H12 (-24C>T and 3972C>T). Population pharmacokinetic analysis was performed using nonlinear mixed effects modeling. RESULTS: Analyses revealed that the CYP3A5 expressers (CYP3A5*1 carriers) and MRP2 high-activity group (ABCC2 H2/H2 and H1/H2) showed a decreased dose-normalized trough concentration of tacrolimus by 2.3-fold (p < 0.001) and 1.5-fold (p = 0.007), respectively. The pharmacokinetics of tacrolimus were best described using a two-compartment model with first order absorption and an absorption lag time. In the population pharmacokinetic analysis, CYP3A5 expressers and MRP2 high-activity groups were identified as the significant covariates for tacrolimus apparent clearance expressed as 20.7 × (age/50)(-0.78) × 2.03 (CYP3A5 expressers) × 1.40 (MRP2 high-activity group). No other CYP3A4, ABCB1 or ABCG2 polymorphisms were associated with the apparent clearance of tacrolimus. CONCLUSIONS: This is the first report showing that MRP2/ABCC2 has a crucial impact on the pharmacokinetics of tacrolimus in a haplotype-specific manner. Determination of the ABCC2 as well as CYP3A5 genotype may be useful for more accurate tacrolimus dosage adjustment.
Abstract: This article reviews in vitro metabolic and in vivo pharmacokinetic drug-drug interactions of nine antifungal agents: six azoles (fluconazole, itraconazole, ketoconazole, miconazole, posaconazole, and voriconazole) and three echinocandins (anidulafungin, caspofungin, and micafungin). In in vitro interaction studies, itraconazole, ketoconazole, and miconazole were found to have higher inhibitory effects on cytochrome P450 (P450 or CYP) 3A4 and 3A5 activities than the other azoles or echinocandins did. Fluconazole, itraconazole, and voriconazole were relatively less potent inhibitors of CYP3A5 than of CYP3A4. The inhibitory effects of fluconazole, itraconazole, ketoconazole, and voriconazole against CYP3A4 and CYP3A5 seemed to be correlated with their dissociation constants for CYP51 (lanosterol 14α-demethylase) from Candida albicans. In in vivo pharmacokinetic studies, itraconazole was found to be a potent clinically important inhibitor of CYP3A4/5 substrates, and fluconazole and voriconazole increased the blood/plasma concentrations of not only CYP3A4/5 substrates but also CYP2C9 substrates. Miconazole was a potent inhibitor of all P450s investigated in vitro, although there are few detailed studies on the clinical significance of this except for CYP2C9. For the echinocandins, no marked inhibition of P450 activities, except for some inhibition of CYP3A4/5 activity, was observed in vitro. The blood/plasma concentrations of concomitant drugs were not markedly affected by coadministration of echinocandins in vivo, suggesting that echinocandins do not cause clinically significant interactions with drugs that are metabolized by P450s via the inhibition of metabolism. The differential effects of these antifungal agents on P450 activities must be considered when clinicians select antifungal agents for patients also receiving other drugs.
Abstract: BACKGROUND AND OBJECTIVE: Chronic hepatitis C virus (HCV) infection is a major cause of liver transplantation. Drug-drug interactions (DDIs) with cyclosporine and tacrolimus hindered the use of first-generation protease inhibitors in transplant recipients. The current study investigated DDIs between daclatasvir-a pan-genotypic HCV NS5A inhibitor with clinical efficacy in multiple regimens (including all-oral)-and cyclosporine or tacrolimus in healthy subjects. METHODS: Healthy fasted subjects (aged 18-49 years; body mass index 18-32 kg/m(2)) received single oral doses of cyclosporine 400 mg on days 1 and 9, and daclatasvir 60 mg once daily on days 4-11 (group 1, n = 14), or a single oral dose of tacrolimus 5 mg on days 1 and 13, and daclatasvir 60 mg once daily on days 8-19 (group 2, n = 14). Blood samples for pharmacokinetic analysis [by liquid chromatography with tandem mass spectrometry (LC-MS/MS)] were collected on days 1 and 9 for cyclosporine (72 h), on days 1 and 13 for tacrolimus (168 h) and on days 8 and 9 (group 1) or on days 12 and 13 (group 2) for daclatasvir (24 h). Plasma concentrations were determined by validated LC-MS/MS methods. RESULTS: Daclatasvir did not affect the pharmacokinetic parameters of cyclosporine or tacrolimus, and tacrolimus did not affect the pharmacokinetic parameters of daclatasvir. Co-administration of cyclosporine resulted in a 40 % increase in the area under the concentration-time curve of daclatasvir but did not affect its maximum observed concentration. CONCLUSION: On the basis of these observations in healthy subjects, no clinically relevant DDIs between daclatasvir and cyclosporine or tacrolimus are anticipated in liver transplant recipients infected with HCV; dose adjustments during co-administration are unlikely to be required.
Abstract: This report summarizes phase 1 studies that evaluated pharmacokinetic interactions between the novel triazole antifungal agent isavuconazole and the immunosuppressants cyclosporine, mycophenolic acid, prednisolone, sirolimus, and tacrolimus in healthy adults. Healthy subjects received single oral doses of cyclosporine (300 mg; n = 24), mycophenolate mofetil (1000 mg; n = 24), prednisone (20 mg; n = 21), sirolimus (2 mg; n = 22), and tacrolimus (5 mg; n = 24) in the presence and absence of clinical doses of oral isavuconazole (200 mg 3 times daily for 2 days; 200 mg once daily thereafter). Coadministration with isavuconazole increased the area under the concentration-time curves (AUC) of tacrolimus, sirolimus, and cyclosporine by 125%, 84%, and 29%, respectively, and the AUCs of mycophenolic acid and prednisolone by 35% and 8%, respectively. Maximum concentrations (C) of tacrolimus, sirolimus, and cyclosporine were 42%, 65%, and 6% higher, respectively; Cof mycophenolic acid and prednisolone were 11% and 4% lower, respectively. Isavuconazole pharmacokinetics were mostly unaffected by the immunosuppressants. Two subjects experienced elevated creatinine levels in the cyclosporine study; most adverse events were not considered to be of clinical concern. These results indicate that isavuconazole is an inhibitor of cyclosporine, mycophenolic acid, sirolimus, and tacrolimus metabolism.
Abstract: The accurate estimation of "in vivo" inhibition constants () of inhibitors and fraction metabolized () of substrates is highly important for drug-drug interaction (DDI) prediction based on physiologically based pharmacokinetic (PBPK) models. We hypothesized that analysis of the pharmacokinetic alterations of substrate metabolites in addition to the parent drug would enable accurate estimation of in vivoandTwenty-four pharmacokinetic DDIs caused by P450 inhibition were analyzed with PBPK models using an emerging parameter estimation method, the cluster Newton method, which enables efficient estimation of a large number of parameters to describe the pharmacokinetics of parent and metabolized drugs. For each DDI, two analyses were conducted (with or without substrate metabolite data), and the parameter estimates were compared with each other. In 17 out of 24 cases, inclusion of substrate metabolite information in PBPK analysis improved the reliability of bothandImportantly, the estimatedfor the same inhibitor from different DDI studies was generally consistent, suggesting that the estimatedfrom one study can be reliably used for the prediction of untested DDI cases with different victim drugs. Furthermore, a large discrepancy was observed between the reported in vitroand the in vitro estimates for some inhibitors, and the current in vivoestimates might be used as reference values when optimizing in vitro-in vivo extrapolation strategies. These results demonstrated that better use of substrate metabolite information in PBPK analysis of clinical DDI data can improve reliability of top-down parameter estimation and prediction of untested DDIs.
Abstract: BACKGROUND: Anticholinergic drugs put elderly patients at a higher risk for falls, cognitive decline, and delirium as well as peripheral adverse reactions like dry mouth or constipation. Prescribers are often unaware of the drug-based anticholinergic burden (ACB) of their patients. This study aimed to develop an anticholinergic burden score for drugs licensed in Germany to be used by clinicians at prescribing level. METHODS: A systematic literature search in pubmed assessed previously published ACB tools. Quantitative grading scores were extracted, reduced to drugs available in Germany, and reevaluated by expert discussion. Drugs were scored as having no, weak, moderate, or strong anticholinergic effects. Further drugs were identified in clinical routine and included as well. RESULTS: The literature search identified 692 different drugs, with 548 drugs available in Germany. After exclusion of drugs due to no systemic effect or scoring of drug combinations (n = 67) and evaluation of 26 additional identified drugs in clinical routine, 504 drugs were scored. Of those, 356 drugs were categorised as having no, 104 drugs were scored as weak, 18 as moderate and 29 as having strong anticholinergic effects. CONCLUSIONS: The newly created ACB score for drugs authorized in Germany can be used in daily clinical practice to reduce potentially inappropriate medications for elderly patients. Further clinical studies investigating its effect on reducing anticholinergic side effects are necessary for validation.