Effect of Different Durations of Ketoconazole Dosing on the Single‐Dose Pharmacokinetics of Midazolam: Shortening the Paradigm

Stoch, S. Aubrey; Friedman, Evan; Maes, Andrea; Yee, Ka Lai; Xu, Yang; Larson, Patrick; Fitzgerald, Maria; Chodakewitz, Jeffrey A.; Wagner, John A.

doi:10.1177/0091270008331133

Cited by 40 publications

(55 citation statements)

References 20 publications

(30 reference statements)

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“…For example, a 36% higher midazolam AUC was observed after 5 days of ketoconazole (400 mg QD) treatment, relative to a single dose (Stoch et al, 2009). This time dependence provides an unusual challenge for DDI predictions, because ketoconazole does not accumulate in plasma after multiple doses, and data obtained from human liver microsomes are generally characterized as rapidly reversible and competitive in nature.…”

Section: Discussionmentioning

confidence: 99%

“…A complete search of the literature using the Metabolism and Transport Drug Interaction Database (University of Washington, Seattle, WA) indentified 11 clinical DDI studies and 16 dosage scenarios from 17 published clinical results using midazolam as CYP3A probe (intravenous and oral) and ketoconazole as inhibitor (400 mg QD and 200 mg QD and BID for various durations) as of 2012 (Olkkola et al, 1994;McCrea et al, 1999;Tsunoda et al, 1999;Goh et al, 2002;Lee et al, 2002;Lam et al, 2003;Eap et al, 2004;Chung et al, 2006;Tham et al, 2006;Yong et al, 2008;Krishna et al, 2009;Stoch et al, 2009). The specific treatment regimens of ketoconazole and midazolam used in the literature reports were reproduced in the simulations.…”

Section: Model Validation and Simulationmentioning

confidence: 99%

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Optimization of Drug-Drug Interaction Study Design: Comparison of Minimal Physiologically Based Pharmacokinetic Models on Prediction of CYP3A Inhibition by Ketoconazole

Han

Mao²,

Chien

et al. 2013

Drug Metab Dispos

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Ketoconazole is a potent CYP3A inhibitor used to assess the contribution of CYP3A to drug clearance and quantify the increase in drug exposure due to a strong inhibitor. Physiologically based pharmacokinetic (PBPK) models have been used to evaluate treatment regimens resulting in maximal CYP3A inhibition by ketoconazole but have reached different conclusions. We compare two PBPK models of the ketoconazole-midazolam interaction, model 1 (Chien et al., 2006) and model 2 implemented in Simcyp (version 11), to predict 16 published treatment regimens. With use of model 2, 41% of the study point estimates of area under the curve (AUC) ratio and 71% of the 90% confidence intervals were predicted within 1.5-fold of the observed, but these increased to 82 and 100%, respectively, with model 1. For midazolam, model 2 predicted a maximal midazolam AUC ratio of 8 and a hepatic fraction metabolized by CYP3A (f m ) of 0.97, whereas model 1 predicted 17 and 0.90, respectively, which are more consistent with observed data. On the basis of model 1, ketoconazole (400 mg QD) for at least 3 days and substrate administration within 2 hours is required for maximal CYP3A inhibition. Ketoconazole treatment regimens that use 200 mg BID underestimate the systemic fraction metabolized by CYP3A (0.86 versus 0.90) for midazolam. The systematic underprediction also applies to CYP3A substrates with high bioavailability and long half-lives. The superior predictive performance of model 1 reflects the need for accumulation of ketoconazole at enzyme site and protracted inhibition. Model 2 is not recommended for inferring optimal study design and estimation of fraction metabolized by CYP3A.

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Section: Discussionmentioning

confidence: 99%

Section: Model Validation and Simulationmentioning

confidence: 99%

Optimization of Drug-Drug Interaction Study Design: Comparison of Minimal Physiologically Based Pharmacokinetic Models on Prediction of CYP3A Inhibition by Ketoconazole

Han

Mao²,

Chien

et al. 2013

Drug Metab Dispos

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“…The intended sample size was based on the known variability in the AUC and C max associated with midazolam. Sample size calculations were based on a study by Stoch et al (11), who reported 90% CIs for GMRs of midazolam AUCs based on within-subject AUC variability and midazolam 2-mg oral doses in the presence of ketoconazole. The natural log-scale standard deviations (SD) computed from these CIs were 0.22 for AUC and 0.31 for C max .…”

Section: Methodsmentioning

confidence: 99%

Evaluation of Pharmacokinetic Interaction between PA-824 and Midazolam in Healthy Adult Subjects

Winter

Egizi

Erondu

et al. 2013

Antimicrob Agents Chemother

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This study assessed the safety, tolerability, and pharmacokinetic interaction between PA-824, a novel antitubercular nitroimidazo-oxazine, and midazolam, a CYP3A4 substrate, in 14 healthy adult male and female subjects. The study followed up on observations in vitro that PA-824 caused weak and time-dependent inhibition of CYP3A4. Subjects received a single oral dose of midazolam (2 mg), followed by a 2-day washout. After the washout, all subjects received PA-824 (400 mg) once daily for 14 consecutive days. On day 14, all subjects received the final PA-824 dose coadministered with a 2-mg oral dose of midazolam. The pharmacokinetic endpoints AUC 0 -t , AUC 0 -ؕ , and C max for midazolam and 1-hydroxy midazolam were compared between midazolam administered alone versus midazolam coadministered with PA-824. Statistical analysis demonstrated that the mean midazolam values of C max , AUC 0 -t , and AUC 0 -ؕ parameters were reduced by ca. 16, 15, and 15%, respectively, when PA-824 was coadministered with midazolam. The total exposure (AUC) of 1-hydroxy midazolam was 13 to 14% greater when coadministered with PA-824 compared to midazolam administered alone. The C max of 1-hydroxy midazolam was similar between treatments. Based on these results, PA-824 does not inhibit or induce CYP3A4 to a clinically meaningful extent and is not likely to markedly affect the pharmacokinetics of CYP3A4 metabolized drugs. PA-824 is an antitubercular nitroimidazo-oxazine that possesses significant activity against replicating and nonreplicating/persistent Mycobacterium tuberculosis via a complex mechanism of action distinct from that of any currently marketed drugs for the treatment of tuberculosis (1, 2). Its mechanism of action is believed similar to that of Delamanid, a drug currently under review for market approval by the regulatory authorities (3). PA-824 interferes with M. tuberculosis cell wall biosynthesis by inhibiting the oxidation of hydroxymycolate to ketomycolate. A deazaflavin (F420)-dependent nitroreductase has also been identified whose activity in M. tuberculosis cells is involved in PA-824 activation and activity (2). Reduction of PA-824 to its des-nitroimidazole metabolite by this nitroreductase is associated with generation of reactive nitrogen species, including nitric oxide. PA-824 is active against M. tuberculosis isolates resistant to single or multiple antituberculous drugs and has proven effective in shortening treatment time of drug-sensitive M. tuberculosis in a murine model of tuberculosis (TB) as part of novel drug regimens (4). Moreover, PA-824 was highly active as monotherapy in a 14-day dose ranging early bactericidal activity (EBA) study in humans where similar efficacy profiles were observed across all doses assessed (200 to 1,200 mg/day) (5). In EBA studies, the rate of change over time in the number of M. tuberculosis CFU per ml of sputum in an overnight sputum collection is used to compare different dosing and treatment regimens. In a follow up study exploring a lower dose range (50 to 200 mg/day), a d...

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“…On day 5, either 30 mg tolvaptan or placebo was co-administered with the ketoconazole. Previously it was determined that 1 day of pre-exposure to ketoconazole was sufficient to produce a maximal inhibition of midazolam pharmacokinetics [10]. Ketoconazole dosing was continued on day 6 to ensure inhibition was sustained through out the tolvaptan washout period.…”

Section: Trial Designsmentioning

confidence: 99%

Effects of CYP3A4 inhibition and induction on the pharmacokinetics and pharmacodynamics of tolvaptan, a non‐peptide AVP antagonist in healthy subjects

Shoaf

Bricmont

Mallikaarjun

2012

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Before these trials were done, the effects of CYP3A4 inhibition and induction on the pharmacokinetics (PK) and pharmacodynamics (PD) of tolvaptan in healthy subjects were unknown. As tolvaptan is a CYP3A4 substrate, knowing the effects of inhibition and induction on CYP3A4-mediated metabolism was important for dosing recommendations. WHAT THIS STUDY ADDS• This paper describes the changes in tolvaptan PK and PD following inhibition or induction of CYP3A4 and explores the mechanisms behind the disparity seen between tolvaptan PK and effects on urine output. It also discusses the concentrations at which tolvaptan produces its maximal response on urine output and the timing of the onset and offset of this response. AIMSIn vitro studies indicated CYP3A4 alone was responsible for tolvaptan metabolism. To determine the effect of a CYP3A4 inhibitor (ketoconazole) and a CYP3A4 inducer (rifampicin) on tolvaptan pharmacokinetics (PK) and pharmacodynamics (PD), two clinical trials were performed. METHODSFor CYP3A4 inhibition, a double-blind, randomized (5:1), placebo-controlled trial was conducted in 24 healthy subjects given either a single 30 mg dose of tolvaptan (n = 19) or matching placebo (n = 5) on day 1 with a 72 h washout followed by a 3 day regimen of 200 mg ketoconazole, once daily with 30 mg tolvaptan or placebo also given on day 5. For CYP3A4 induction, 14 healthy subjects were given a single dose of 240 mg tolvaptan with 48 h washout followed by a 7 day regimen of 600 mg rifampicin, once daily, with 240 mg tolvaptan also given on the seventh day. RESULTSWhen co-administered with ketoconazole, mean Cmax and AUC(0,•) of tolvaptan were increased 3.48-and 5.40-fold, respectively. Twenty-four hour urine volume increased from 5.9 to 7.7 l. Erythromycin breath testing showed no difference following a single dose of tolvaptan. With rifampicin, tolvaptan mean Cmax and AUC were reduced to 0.13-and 0.17-fold of tolvaptan administered alone. Twenty-four hour urine volume decreased from 12.3 to 8.8 l. CONCLUSIONSTolvaptan is a sensitive CYP3A4 substrate with no inhibitory activity. Due to the saturable nature of tolvaptan's effect on urine excretion rate, changes in the pharmacokinetic profile of tolvaptan do not produce proportional changes in urine output.

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Effect of Different Durations of Ketoconazole Dosing on the Single‐Dose Pharmacokinetics of Midazolam: Shortening the Paradigm

Cited by 40 publications

References 20 publications

Optimization of Drug-Drug Interaction Study Design: Comparison of Minimal Physiologically Based Pharmacokinetic Models on Prediction of CYP3A Inhibition by Ketoconazole

Optimization of Drug-Drug Interaction Study Design: Comparison of Minimal Physiologically Based Pharmacokinetic Models on Prediction of CYP3A Inhibition by Ketoconazole

Evaluation of Pharmacokinetic Interaction between PA-824 and Midazolam in Healthy Adult Subjects

Effects of CYP3A4 inhibition and induction on the pharmacokinetics and pharmacodynamics of tolvaptan, a non‐peptide AVP antagonist in healthy subjects

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