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Pharmacological advice for alprazolam, cimetidine and itraconazole

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Version 6.0.32 (Beta Preview)

Summary Summary info 69%

Pharmacokinetic -2%
Alprazolam
Cimetidine
Itraconazole
Scores -8%
QT time prolongation
Anticholinergic effects
Serotonergic effects
Adverse drug events -21%
Somnolence
Sedation
Fatigue

Variants ✨

For the computationally intensive evaluation of the variants, please choose the paid standard subscription.

medication Intended use

Explanations of the substances for patients

undefined Pharmacokinetics info -2%

∑ Exposureaalpcimitr
Alprazolam 1.77 1.18 1.74
Cimetidine n.a.n.a.n.a.
Itraconazole 1.06 1 1.06
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]. Alprazolam exposure increases to 177%, when combined with cimetidine (118%) and itraconazole (174%). This can lead to increased side effects. We did not detect any change in exposure to cimetidine. We cannot currently estimate the influence of alprazolam and itraconazole. Itraconazole exposure increases to 106%, when combined with alprazolam (100%) and cimetidine (106%).

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.
Alprazolam has a high oral bioavailability [ F ] of 88%, which is why the maximum plasma levels [Cmax] tend to change little during an interaction. The terminal half-life [ t12 ] is 11.7 hours and constant plasma levels [ Css ] are reached after approximately 46.8 hours. The protein binding [ Pb ] is moderately strong at 70.2% and the volume of distribution [ Vd ] is 50 liters in the middle range, Since the substance has a low hepatic extraction rate of 0.04, displacement from protein binding [Pb] in the context of an interaction can increase exposure. The metabolism mainly takes place via CYP3A4.
Cimetidine has a mean oral bioavailability [ F ] of 65%, which is why the maximum plasma levels [Cmax] tend to change with an interaction. The terminal half-life [ t12 ] is rather short at 1.6333333 hours and constant plasma levels [ Css ] are reached quickly. The protein binding [ Pb ] is very weak at 19% and the volume of distribution [ Vd ] is very large at 91 liters. The metabolism does not take place via the common cytochromes and the active transport takes place partly via BCRP and PGP.
Itraconazole has a mean oral bioavailability [ F ] of 55%, which is why the maximum plasma levels [Cmax] tend to change with an interaction. The terminal half-life [ t12 ] is 21 hours and constant plasma levels [ Css ] are reached after approximately 84 hours. The protein binding [ Pb ] is very strong at 99.8% and the volume of distribution [ Vd ] is very large at 796 liters, which is why, with a mean hepatic extraction rate of 0.44, 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 in particular via PGP.

transmitter Serotonergic effects info -0%

Scores ∑ Points alpcimitr
Serotonergic Effects a 0 Ø Ø Ø
Symbol (a): Increased risk from 5 points.

Rating: According to our knowledge, neither alprazolam, cimetidine nor itraconazole increase serotonergic activity.

transmitter Anticholinergic effects info -7%

Scores ∑ Points alpcimitr
Kiesel b 3+++Ø
Symbol (b): Increased risk from 3 points.

Recommendation: The risk of anticholinergic side effects such as blurred vision, confusion and tremor is increased with this therapy. If possible, the therapy should be switched or the patient should be closely monitored for other symptoms Constipation, mydriasis and reduced vigilance are monitored.

Rating: Together, cimetidine (moderate) and alprazolam (mild) increase anticholinergic activity. According to our findings, itraconazole does not increase anticholinergic activity.

electrocardiogram QT time prolongation info -1%

Scores ∑ Points alpcimitr
RISK-PATH c 0.5Ø++
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 in full.

Rating: In combination, cimetidine and itraconazole can potentially trigger ventricular arrhythmias of the torsades de pointes type. We do not know of any QT-prolonging potential for alprazolam.

Other side effects General adverse effects info -21%

Side effects ∑ frequency alpcimitr
Somnolence49.9 %49.9n.a.n.a.
Sedation45.2 %45.2n.a.n.a.
Fatigue32.8 %31.3n.a.2.3
Coordination problem24.8 %24.8n.a.n.a.
Memory impairment24.3 %24.3n.a.n.a.
Dizziness22.9 %20.8n.a.2.6
Increased appetite19.9 %19.9n.a.n.a.
Constipation17.1 %17.1n.a.n.a.
Dysarthria17.1 %17.1n.a.n.a.
Weight gain14.9 %14.9n.a.n.a.
Tabular extract of the most common side effects
Sign (+): side effect described, but frequency not known
Sign (↑/↓): frequency rather higher / lower due to exposure

Gastrointestinal
Xerostomia (12.4%): alprazolam
Nausea (7%): itraconazole
Vomiting (5%): itraconazole
Abdominal pain (2.9%): itraconazole
Diarrhea (2.9%): itraconazole
Pancreatitis: cimetidine, itraconazole

Mental
Depression (11.7%): alprazolam
Irritability: alprazolam
Rebound effect: alprazolam
Addiction: alprazolam
Psychosis: cimetidine

Reproductive system
Reduced libido (10.2%): alprazolam

Respiratory
Nasopharyngitis (9%): itraconazole
Upper respiratory infection (8%): itraconazole
Sinusitis (4.5%): itraconazole
Pulmonary edema: itraconazole

Neurological
Headache (6.1%): itraconazole
Confusion (6%): alprazolam

Dermatological
Rash (6%): itraconazole
Pruritus (4%): itraconazole
Stevens johnson syndrome: alprazolam

Metabolic
Gynecomastia (4%): cimetidine

Cardiac
Peripheral edema (4%): itraconazole
Hypertension (3%): itraconazole
Heart failure: itraconazole

Systemic
Fever (2.5%): itraconazole

Electrolytes
Hypokalemia: itraconazole
Hyperkalemia: itraconazole

Hepatic
Liver failure: alprazolam
Hepatotoxicity: itraconazole

Auricular
Hearing loss: itraconazole

Immunological
Hypersensitivity reaction: itraconazole

Limitations Limitations

Based on your and scientific information, we assess the individual risk of undesirable side effects. The orange filled bars signal the basic potential of the drugs to cause this side effect. 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.

literature References

1. Fraser AD et al. Urinary screening for alprazolam and its major metabolites by the Abbott ADx and TDx analyzers with confirmation by GC/MS. Journal of analytical toxicology.
Authors: Fraser AD Bryan W Isner AF
Abstract: Alprazolam is a short-acting triazolobenzodiazepine with anxiolytic and antidepressant properties. It has a half-life of 10-15 hours after multiple oral doses. Approximately 20% of an oral dose is excreted unchanged in the urine. The major urinary metabolites are alpha-OH alprazolam glucuronide and 3-HMB benzophenone glucuronide. The objective of this study was to characterize the reactivity of alprazolam and three metabolites in the Abbott ADx and TDx urinary benzodiazepine assays compared with the EMIT d.a.u. benzodiazepine assay. Alprazolam (at 300 ng/mL) gave an equivalent response as the 300 ng/mL low control (nordiazepam). alpha-OH alprazolam gave an equivalent response to this control between 300-500 ng/mL and 4-OH alprazolam between 500-1000 ng/mL. The 3-HMB benzophenone was not positive even at 10,000 ng/mL. The ADx screening assay was positive in 26 of 31 urine specimens collected from alprazolam-treated patients. All 31 of these specimens were confirmed positive for alpha-OH alprazolam by GC/MS after enzymatic hydrolysis and formation of a TMS derivative. For the TDx, 27 of 31 specimens were positive for benzodiazepines and all 31 were confirmed by GC/MS. All 5 of the negative ADx specimens and 4 of 5 TDx specimens contained 150-400 ng/mL of alpha-OH alprazolam. In conclusion, both the ADx and TDx urine benzodiazepine assays are acceptable screening assays for alprazolam use when the alpha-OH alprazolam concentration is greater than 400 ng/mL.
Pubmed Id: 2046338
2. Fawcett JA et al. Alprazolam: pharmacokinetics, clinical efficacy, and mechanism of action. Pharmacotherapy.
Authors: Fawcett JA Kravitz HM
Abstract: Alprazolam, a triazolobenzodiazepine, is the first of this new class of benzodiazepine drugs to be marketed in the United States and Canada. It achieves peak serum levels in 0.7 to 2.1 hours and has a serum half-life of 12 to 15 hours. When given in the recommended daily dosage of 0.5 to 4.0 mg, it is as effective as diazepam and chlordiazepoxide as an anxiolytic agent. Its currently approved indication is for the treatment of anxiety disorders and symptoms of anxiety, including anxiety associated with depression. Although currently not approved for the treatment of depressive disorders, studies published to date have demonstrated that alprazolam compares favorably with standard tricyclic antidepressants. Also undergoing investigation is the potential role of alprazolam in the treatment of panic disorders. Alprazolam has been used in elderly patients with beneficial results and a low frequency of adverse reactions. Its primary side effect, drowsiness, is less than that produced by diazepam at comparable doses. Data on toxicity, tolerance, and withdrawal profile are limited, but alprazolam seems to be at least comparable to other benzodiazepines. Drug interaction data are also limited, and care should be exercised when prescribing alprazolam for patients taking other psychotropic drugs because of potential additive depressant effects.
Pubmed Id: 6133268
3. Smith RB et al. Pharmacokinetics and pharmacodynamics of alprazolam after oral and IV administration. Psychopharmacology. 1984
Authors: Smith RB Kroboth PD Vanderlugt JT Phillips JP Juhl RP
Abstract: Six fasting male subjects (20-32 years of age) received an oral tablet and an IV 1.0-mg dose of alprazolam in a crossover-design study. Alprazolam plasma concentration in multiple samples during 36 h after dosing was determined by electron-capture gas-liquid chromatography. Psychomotor performance tests, digit-symbol substitution (DSS), and perceptual speed (PS) were administered at 0, 1.25, 2.25, 5.0, and 12.5 h. Sedation was assessed by the subjects and by an observer using the Stanford Sleepiness Scale and a Nurse Rating Sedation Scale (NRSS), respectively. Mean kinetic parameters after IV and oral alprazolam were as follows: volume of distribution (Vd) 0.72 and 0.84 l/kg; elimination half-life (t1/2) 11.7 and 11.8 h; clearance (Cl) 0.74 and 0.89 ml/min/kg. There were no significant differences between IV and oral alprazolam in Vd, t1/2, or area under the curve. The mean fraction absorbed after oral administration was 0.92. Performance on PS and DSS tests was impaired at 1.25 and 2.5 h, but had returned to baseline at 5.0 h for both treatments. Onset of sedation was rapid after IV administration and the average time of peak sedation was 0.48 h. Sedation scores were significantly lower during hour 1 after oral administration than after IV, but were not significantly different at later times. Alprazolam is fully available after oral administration and kinetic parameters are not affected by route of administration. With the exception of rapidity of onset, the pharmacodynamic profiles of IV and oral alprazolam are very similar after a 1.0-mg dose.
Pubmed Id: 6152055
4. Herings RM et al. Public health problems and the rapid estimation of the size of the population at risk. Torsades de pointes and the use of terfenadine and astemizole in The Netherlands. Pharmacy world & science : PWS. 1993
Authors: Herings RM Stricker BH Leufkens HG Bakker A Sturmans F Urquhart J
Abstract: Recently, the use of astemizole and terfenadine, both non-sedating H1-antihistamines, caused considerable concern. Several case reports suggested an association of both drugs with an increased risk of torsades de pointes, a special form of ventricular tachycardia. The increased risk of both H1-antihistamines was associated with exposure to supratherapeutic doses; for terfenadine the risk was also associated with concomitant exposure to the cytochrome P-450 inhibitors ketoconazole, erythromycin and cimetidine. To predict the size of the population that runs the risk of developing this potentially fatal adverse reaction in the Netherlands, the prevalence of prescribing supratherapeutic doses and the concomitant exposure to terfenadine and cytochrome P-450 inhibitors was studied. Data were obtained from the PHARMO data base in 1990, a pharmacy-based record linkage system encompassing a catchment population of 300,000 individuals. The results of the study showed that the prescribing of supratherapeutic doses and the concomitant exposure to terfenadine and cytochrome P-450 inhibitors was low. Furthermore, the results of a sensitivity analysis showed that the risk of fatal torsades de pointes has to be as high as 1 in 10,000 to cause one death in the Netherlands in one year.
Pubmed Id: 8257958
5. Pohjola-Sintonen S et al. Torsades de pointes after terfenadine-itraconazole interaction. BMJ (Clinical research ed.). 1993
Authors: Pohjola-Sintonen S Viitasalo M Toivonene L Neuvonen P
Abstract: No Abstract available
Pubmed Id: 8382980
6. Ikeda S et al. Astemizole-induced torsades de pointes in a patient with vasospastic angina. Japanese circulation journal. 1998
Authors: Ikeda S Oka H Matunaga K Kubo S Asai S Miyahara Y Osaka A Kohno S
Abstract: Astemizole (Hismanal), an antihistamine agent, has been reported to be associated with ventricular arrhythmias. In this paper we present a case of QT prolongation and torsades de pointes (TdP) in a 77-year-old woman who had been taking astemizole (10 mg/day) for 6 months because of allergic skin disease. At the time of admission, the serum concentration of astemizole and its metabolites was markedly elevated at 15.85 ng/ml, approximately 3 times the normal level. The patient was also taking cimetidine, a known inhibitor of cytochrome P-450 enzymatic activity, and during her admission was diagnosed as having vasospastic angina. To the best of our knowledge, this is the first report of astemizole-induced QT prolongation and TdP in Japan.
Pubmed Id: 9583453
7. Isoherranen N et al. Role of itraconazole metabolites in CYP3A4 inhibition. Drug metabolism and disposition: the biological fate of chemicals. 2004
Authors: Isoherranen N Kunze KL Allen KE Nelson WL Thummel KE
Abstract: Itraconazole (ITZ) is a potent inhibitor of CYP3A in vivo. However, unbound plasma concentrations of ITZ are much lower than its reported in vitro Ki, and no clinically significant interactions would be expected based on a reversible mechanism of inhibition. The purpose of this study was to evaluate the reasons for the in vitro-in vivo discrepancy. The metabolism of ITZ by CYP3A4 was studied. Three metabolites were detected: hydroxy-itraconazole (OH-ITZ), a known in vivo metabolite of ITZ, and two new metabolites: keto-itraconazole (keto-ITZ) and N-desalkyl-itraconazole (ND-ITZ). OHITZ and keto-ITZ were also substrates of CYP3A4. Using a substrate depletion kinetic approach for parameter determination, ITZ exhibited an unbound K(m) of 3.9 nM and an intrinsic clearance (CLint) of 69.3 ml.min(-1).nmol CYP3A4(-1). The respective unbound Km values for OH-ITZ and keto-ITZ were 27 nM and 1.4 nM and the CLint values were 19.8 and 62.5 ml.min(-1).nmol CYP3A4(-1). Inhibition of CYP3A4 by ITZ, OH-ITZ, keto-ITZ, and ND-ITZ was evaluated using hydroxylation of midazolam as a probe reaction. Both ITZ and OH-ITZ were competitive inhibitors of CYP3A4, with unbound Ki (1.3 nM for ITZ and 14.4 nM for OH-ITZ) close to their respective Km. ITZ, OH-ITZ, keto-ITZ and ND-ITZ exhibited unbound IC50 values of 6.1 nM, 4.6 nM, 7.0 nM, and 0.4 nM, respectively, when coincubated with human liver microsomes and midazolam (substrate concentration < Km). These findings demonstrate that ITZ metabolites are as potent as or more potent CYP3A4 inhibitors than ITZ itself, and thus may contribute to the inhibition of CYP3A4 observed in vivo after ITZ dosing.
Pubmed Id: 15242978
8. Karyekar CS et al. Renal interaction between itraconazole and cimetidine. Journal of clinical pharmacology. 2004
Authors: Karyekar CS Eddington ND Briglia A Gubbins PO Dowling TC
Abstract: Renal drug interactions can result from competitive inhibition between drugs that undergo extensive renal tubular secretion by transporters such as P-glycoprotein (P-gp). The purpose of this study was to evaluate the effect of itraconazole, a known P-gp inhibitor, on the renal tubular secretion of cimetidine in healthy volunteers who received intravenous cimetidine alone and following 3 days of oral itraconazole (400 mg/day) administration. Glomerular filtration rate (GFR) was measured continuously during each study visit using iothalamate clearance. Iothalamate, cimetidine, and itraconazole concentrations in plasma and urine were determined using high-performance liquid chromatography/ultraviolet (HPLC/UV) methods. Renal tubular secretion (CL(sec)) of cimetidine was calculated as the difference between renal clearance (CL(r)) and GFR (CL(ioth)) on days 1 and 5. Cimetidine pharmacokinetic estimates were obtained for total clearance (CL(T)), volume of distribution (Vd), elimination rate constant (K(el)), area under the plasma concentration-time curve (AUC(0-240 min)), and average plasma concentration (Cp(ave)) before and after itraconazole administration. Plasma itraconazole concentrations following oral dosing ranged from 0.41 to 0.92 microg/mL. The cimetidine AUC(0-240 min) increased by 25% (p < 0.01) following itraconazole administration. The GFR and Vd remained unchanged, but significant reductions in CL(T) (655 vs. 486 mL/min, p < 0.001) and CL(sec) (410 vs. 311 mL/min, p = 0.001) were observed. The increased systemic exposure of cimetidine during coadministration with itraconazole was likely due to inhibition of P-gp-mediated renal tubular secretion. Further evaluation of renal P-gp-modulating drugs such as itraconazole that may alter the renal excretion of coadministered drugs is warranted.
Pubmed Id: 15286096
9. Park JY et al. Effect of CYP3A5*3 genotype on the pharmacokinetics and pharmacodynamics of alprazolam in healthy subjects. Clinical pharmacology and therapeutics. 2006
Authors: Park JY Kim KA Park PW Lee OJ Kang DK Shon JH Liu KH Shin JG
Abstract: OBJECTIVE: Our objective was to evaluate the effect of the CYP3A5 genotype on the pharmacokinetics and pharmacodynamics of alprazolam in healthy volunteers. METHODS: Nineteen healthy male volunteers were divided into 3 groups on the basis of the genetic polymorphism of CYP3A5. The groups comprised subjects with CYP3A5*1/*1 (n=5), CYP3A5*1/*3 (n=7), or CYP3A5*3/*3 (n=7). After a single oral 1-mg dose of alprazolam, plasma concentrations of alprazolam were measured up to 72 hours, together with assessment of psychomotor function by use of the Digit Symbol Substitution Test, according to CYP3A5 genotype. RESULTS: The area under the plasma concentration-time curve for alprazolam was significantly greater in subjects with CYP3A5*3/*3 (830.5+/-160.4 ng . h/mL [mean+/-SD]) than in those with CYP3A5*1/*1 (599.9+/-141.0 ng . h/mL) (P=.030). The oral clearance of alprazolam was also significantly different between the CYP3A5*1/*1 group (3.5+/-0.8 L/h) and CYP3A5*3/*3 group (2.5+/-0.5 L/h) (P=.036). Although a trend was noted for the area under the Digit Symbol Substitution Test score change-time curve (area under the effect curve) to be greater in subjects with CYP3A5*3/*3 (177.2+/-84.6) than in those with CYP3A5*1/*1 (107.5+/-44), the difference did not reach statistical significance (P=.148). CONCLUSIONS: The CYP3A5*3 genotype affects the disposition of alprazolam and thus influences the plasma levels of alprazolam.
Pubmed Id: 16765147
10. Templeton IE et al. Contribution of itraconazole metabolites to inhibition of CYP3A4 in vivo. Clinical pharmacology and therapeutics. 2008
Authors: Templeton IE Thummel KE Kharasch ED Kunze KL Hoffer C Nelson WL Isoherranen N
Abstract: Itraconazole (ITZ) is metabolized in vitro to three inhibitory metabolites: hydroxy-itraconazole (OH-ITZ), keto-itraconazole (keto-ITZ), and N-desalkyl-itraconazole (ND-ITZ). The goal of this study was to determine the contribution of these metabolites to drug-drug interactions caused by ITZ. Six healthy volunteers received 100 mg ITZ orally for 7 days, and pharmacokinetic analysis was conducted at days 1 and 7 of the study. The extent of CYP3A4 inhibition by ITZ and its metabolites was predicted using this data. ITZ, OH-ITZ, keto-ITZ, and ND-ITZ were detected in plasma samples of all volunteers. A 3.9-fold decrease in the hepatic intrinsic clearance of a CYP3A4 substrate was predicted using the average unbound steady-state concentrations (C(ss,ave,u)) and liver microsomal inhibition constants for ITZ, OH-ITZ, keto-ITZ, and ND-ITZ. Accounting for circulating metabolites of ITZ significantly improved the in vitro to in vivo extrapolation of CYP3A4 inhibition compared to a consideration of ITZ exposure alone.
Pubmed Id: 17495874
11. Kato M et al. The quantitative prediction of CYP-mediated drug interaction by physiologically based pharmacokinetic modeling. Pharmaceutical research. 2008
Authors: Kato M Shitara Y Sato H Yoshisue K Hirano M Ikeda T Sugiyama Y
Abstract: PURPOSE: The objective is to confirm if the prediction of the drug-drug interaction using a physiologically based pharmacokinetic (PBPK) model is more accurate. In vivo Ki values were estimated using PBPK model to confirm whether in vitro Ki values are suitable. METHOD: The plasma concentration-time profiles for the substrate with coadministration of an inhibitor were collected from the literature and were fitted to the PBPK model to estimate the in vivo Ki values. The AUC ratios predicted by the PBPK model using in vivo Ki values were compared with those by the conventional method assuming constant inhibitor concentration. RESULTS: The in vivo Ki values of 11 inhibitors were estimated. When the in vivo Ki values became relatively lower, the in vitro Ki values were overestimated. This discrepancy between in vitro and in vivo Ki values became larger with an increase in lipophilicity. The prediction from the PBPK model involving the time profile of the inhibitor concentration was more accurate than the prediction by the conventional methods. CONCLUSION: A discrepancy between the in vivo and in vitro Ki values was observed. The prediction using in vivo Ki values and the PBPK model was more accurate than the conventional methods.
Pubmed Id: 18483837
12. Ivanyuk A et al. Renal Drug Transporters and Drug Interactions. Clinical pharmacokinetics. 2017
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
13. Yoshida K et al. Accurate Estimation of In Vivo Inhibition Constants of Inhibitors and Fraction Metabolized of Substrates with Physiologically Based Pharmacokinetic Drug-Drug Interaction Models Incorporating Parent Drugs and Metabolites of Substrates with Cluster Newton Method. Drug metabolism and disposition: the biological fate of chemicals. 2018
Authors: Yoshida K Maeda K Konagaya A Kusuhara H
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.
Pubmed Id: 30135241
14. Kiesel EK et al. An anticholinergic burden score for German prescribers: score development. BMC geriatrics. 2018
Authors: Kiesel EK Hopf YM Drey M
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.
Pubmed Id: 30305048

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