Concurrent Administration of the Erythromycin Breath Test (EBT) and Oral Midazolam as In Vivo Probes for CYP3A Activity

McCrea, Jacqueline B.; Prueksaritanont, Thomayant; Gertz, Barry J.; Carides, Alexandra D.; Gillen, Lisa; Antonello, Suzanne; Brucker, Mary Jo; Miller‐Stein, Cynthia; Osborne, Barbara A.; Waldman, Scott A.

doi:10.1177/00912709922012015

Cited by 57 publications

(56 citation statements)

References 16 publications

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“…Therefore, we assumed that intraindividual variation of N 2 and N 3 was not so large. For oral midazolam clearance, McCrea et al (1999) reported that intrasubject CV% for midazolam AUC 0-last was 16.9%. However further studies of larger sample sizes, including females and people of different generations, are needed to evaluate the usefulness of N 2 and N 3 .…”

Section: Discussionmentioning

confidence: 99%

“…Formation of a minor primary metabolite, 4-hydroxymidazolam, and of a minor secondary metabolite 1ø, 4-dihydroxymidazolam, are also catalyzed by CYP3A, and these together, as glucuronide conjugates, comprise another 4% to 6% of the administered dose (Gorski et al 1994b). It has been suggested that the pharmacokinetics of midazolam following oral administration can be used as a cumulative measurement of CYP3A activity in the small intestine and liver (Wandel et al 1998;McCrea et al 1999). But midazolam clearance is also inconvenient in a daily clinical situation due to its necessity for periodical blood sampling.…”

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confidence: 99%

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Evaluation of Dextromethorphan N‐Demethylation Activity as a Biomarker for Cytochrome P450 3A Activity in Man

Kawashima

Hagiwara

Inoue³

et al. 2002

Pharmacology & Toxicology

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The present study evaluates the usefulness of dextromethorphan N-demethylation activity indices to reflect cytochrome P450 (CYP) 3A activity in man. Indices of dextromethorphan N-demethylation activity were categorized as N 1 Ω3-methoxymorphinan/dextromethorphan, N 2 Ω3-hydroxymorphinan/dextrorphan, N 3 Ω(3-methoxymorphinan π 3-hydroxymorphinan)/(dextromethorphan π dextrorphan). Two mg of midazolam were administered orally to 22 Japanese male volunteers, and midazolam clearance determined. Thirty mg of dextromethorphan were also orally administered to these volunteers and N 1 , N 2 and N 3 indices determined by 12 hr urine collection. Results showed N 2 and N 3 were highly correlated (rϾ0.99, PϽ0.001), and significantly correlated to oral midazolam clearance (rΩ0.45, PϽ0.05); suggesting that N 2 and N 3 are more suitable than N 1 when using dextromethorphan as an index of individual CYP3A activity.The cytochrome P450 3A (CYP3A) subfamily accounts for approximately 30% of total hepatic and 70% of total intestinal cytochrome P450 content (Slaughter & Edwards 1995). This subfamily of enzymes is responsible for the majority of the initial first-pass intestinal metabolism, and larger than 50% of the hepatic phase I drug metabolism (Spatzenegger & Jaeger 1995). CYP3A activity varies 5-20 times between individuals (Wilkinson 1996), and thus it is useful to determine the CYP3A activity of individuals to establish dosage regimens for drugs of substrates of CYP3A, which have a narrow therapeutic window, such as haloperidol and bromperidol (Fang et al. 1997;Sato et al. 2000).Several indices such as the urinary dapsone hydroxylation ratio, urinary 6b-hydroxycortisol/cortisol ratio, erythromycin breath test, and intravenous midazolam plasma clearance have been studied to determine individual CYP3A activity (Watkins 1994). One early model substrate of CYP3A, dapsone, is known now to be metabolized by more than one CYP (Kinirons et al. 1995). Although the urinary 6b-hydroxycortisol/cortisol ratio is considered useful for screening CYP3A induction (Kovacs et al. 1998), it is considered that this ratio at best only partially reflects liver CYP3A activity (Watkins 1994). The erythromycin breath test and intravenous midazolam plasma clearance are thought to be the most reliable indices for predicting liver CYP3A activity (Watkins 1994). However, these indices do not reflect the activity of CYP3A in the small intestine. Furthermore the erythromycin breath test, as it uses a Author for correspondence: Toshiyuki Someya, Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Niigata, 951-8510, Japan (fax π81 25 227 0777, e-mail someya/med.niigata-u.ac.jp). radioactive substance, is inconvenient in a daily clinical situation.Midazolam is metabolized almost exclusively by enzymes of the CYP3A subfamily ( fig. 1). After intravenous administration, midazolam is rapidly eliminated to a single major metabolite, 1ø-hydroxymidazolam, and urinary recovery of this metabolite...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Evaluation of Dextromethorphan N‐Demethylation Activity as a Biomarker for Cytochrome P450 3A Activity in Man

Kawashima

Hagiwara

Inoue³

et al. 2002

Pharmacology & Toxicology

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“…The KTZ-MDZ interaction model was used to simulate five published KTZ-MDZ studies. These studies were designed to evaluate the effect of KTZ on MDZ AUC following a single 200-mg dose of KTZ, administered simultaneously or 2 h before MDZ (McCrea et al, 1999), 200 mg of KTZ every 12 h for 2 days, administered simultaneously (Tsunoda et al, 1999) or 12 h before MDZ (Eap et al, 2004), 200 mg of KTZ given once a day for up to 12 days (Lam et al, 2003), and 400 mg of KTZ administered once a day for 4 days (Olkkola et al, 1994). The ratio of MDZ AUC in the presence of KTZ to MDZ AUC in the absence of KTZ was used as a measure of inhibitory response.…”

Section: Methodsmentioning

confidence: 99%

Stochastic Prediction of Cyp3a-Mediated Inhibition of Midazolam Clearance by Ketoconazole

Chien¹,

Lucksiri²,

Ernest³

et al. 2006

Drug Metab Dispos

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ABSTRACT:Conventional methods to forecast CYP3A-mediated drug-drug interactions have not employed stochastic approaches that integrate pharmacokinetic (PK) variability and relevant covariates to predict inhibition in terms of probability and uncertainty. Empirical approaches to predict the extent of inhibition may not account for nonlinear or non-steady-state conditions, such as first-pass effects or accumulation of inhibitor concentration with multiple dosing. A physiologically based PK model was developed to predict the inhibition of CYP3A by ketoconazole (KTZ), using midazolam (MDZ) as the substrate. The model integrated PK models of MDZ and KTZ, in vitro inhibition kinetics of KTZ, and the variability and uncertainty associated with these parameters. This model predicted the time-and dose-dependent inhibitory effect of KTZ on MDZ oral clearance. The predictive performance of the model was validated using the results of five published KTZ-MDZ studies. The model improves the accuracy of predicting the inhibitory effect of increasing KTZ dosing on MDZ PK by incorporating a saturable KTZ efflux from the site of enzyme inhibition in the liver. The results of simulations using the model supported the KTZ dose of 400 mg once daily as the optimal regimen to achieve maximum inhibition by KTZ. Sensitivity analyses revealed that the most influential variable on the prediction of inhibition was the fractional clearance of MDZ mediated by CYP3A. The model may be used prospectively to improve the quantitative prediction of CYP3A inhibition and aid the optimization of study designs for CYP3A-mediated drug-drug interaction studies in drug development.Metabolism-based pharmacokinetic (PK) interactions are well recognized as a source of clinically significant adverse drug reactions Huang and Lesko, 2004). The early forecast of clinically significant metabolism-based pharmacokinetic drug-drug interactions is an increasingly important aspect of drug development. The assessment of drug-drug interaction potential before the conduct of a clinical trial often involves simple algebraic calculations. One such calculation is the ratio of the expected clinical exposure to the in vitro inhibition constant (K i ) of a new drug entity for a specific cytochrome P450 (Sahajwalla et al., 1999;Bjornsson et al., 2003). The primary sources of quantitative errors associated with this prediction approach are attributed to the experimental procedures used to determine the in vitro parameters, the variability in the intrinsic factors associated with PK properties of the inhibitor (e.g., absorption kinetics, plasma protein binding, and tissue partition coefficients), or the substrate (i.e., the fraction of total clearance attributed to the elimination pathway of interest), the extrinsic factors associated with the clinical study designs (e.g., dosing scheme, sampling design, and population demographics), and, most notably, the uncertainty in the effective concentration of the inhibitor at the enzyme site. In addition, complex drug disposition proper...

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“…Mean (SD) daily urine volume (ml) following tolvaptan or placebo alone or following co-administration with ketoconazole or rifampicin 43% decrease observed by McCrea et al [18] using the same regimen. A 30 mg dose of tolvaptan produced no change in the ERBT.…”

Section: Tablementioning

confidence: 97%

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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Concurrent Administration of the Erythromycin Breath Test (EBT) and Oral Midazolam as In Vivo Probes for CYP3A Activity

Cited by 57 publications

References 16 publications

Evaluation of Dextromethorphan N‐Demethylation Activity as a Biomarker for Cytochrome P450 3A Activity in Man

Evaluation of Dextromethorphan N‐Demethylation Activity as a Biomarker for Cytochrome P450 3A Activity in Man

Stochastic Prediction of Cyp3a-Mediated Inhibition of Midazolam Clearance by Ketoconazole

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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