Quantification of 3-month intraindividual variability and the influence of sex and menstrual cycle phase on CYP3A activity as measured by phenotyping with intravenous midazolam*

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ABSTRACT:The objective of this study was to evaluate the duration of oral pleconaril (a picornavirus inhibitor) effect on intestinal and hepatic cytochrome P450 (P450) 3A activity as assessed by oral midazolam. Healthy adults received oral midazolam (0.075 mg/kg) on days 1 (baseline), 7, 9, 13, 20, 27, and 34. Oral pleconaril (400 mg) three times daily for 15 doses was administered on days 2 through 7. Blood samples were collected during each day of midazolam dosing to determine plasma midazolam concentrations. On days 5, 6, and 7, blood samples were collected to determine plasma pleconaril concentrations. Midazolam pharmacokinetics were determined by noncompartmental analyses, with bioequivalence assessed by least-squares geometric mean ratios (LS-GMR) and 90% confidence intervals (90% CI). Eighteen subjects completed the study. Midazolam C max (LS-GMR; 90% CI) decreased 24% on day 7 (0.76; 0.66-0.87). Midazolam oral clearance increased 53% on day 7 (1.53; 1.38-1.69). Midazolam oral clearance remained different on days 9 (1.38; 1.25-1.52) and 13 (1.19; 1.07-1.31) versus day 1. Midazolam volume of distribution (1.82; 1.57-2.11) and elimination half-life (1.19; 1.03-1.38) were also different on day 7 in comparison with day 1. Oral pleconaril increased intestinal and hepatic CYP3A activity. The duration of increased CYP3A activity by pleconaril was at least 6 days (but no longer than 13 days) after pleconaril discontinuation.Pleconaril is a novel agent under evaluation for treatment of infections caused by rhinoviruses and enteroviruses, which cause the common cold, acute exacerbation of asthma and chronic obstructive pulmonary disease, viral meningitis, and encephalitis (Rotbart, 1994(Rotbart, , 1995Chidekel et al., 1997;Makela et al., 1998). Pleconaril antiviral activity is attributed to the disruption of viral replication and subsequent attenuation of viral attachment to the intercellular adhesion molecule 1 cellular receptor (Billich, 2000;Florea et al., 2003).In vitro and animal studies showed a lack of cytochrome P450 (P450) 3A inhibition and induction by pleconaril (data on file, ViroPharma, Inc., Exton, PA; . In healthy adults, oral pleconaril increases hepatic CYP3A activity after intravenous midazolam administration (Ma et al., 2006). Because of the prolonged half-life (ϳ180 h) of pleconaril (Rhodes and Liu, 2001a,b;Florea et al., 2003), the duration of increased CYP3A activity may be an important parameter in evaluating potential drug interactions with pleconaril. The purpose of this study was to evaluate the duration and extent of increased hepatic and intestinal CYP3A activity by pleconaril in healthy adults as assessed by oral midazolam. Materials and MethodsSubjects. This study was approved by the Institutional Review Board of Bassett Healthcare, Cooperstown, NY, with written informed consent obtained from each subject. All subjects underwent a medical history, physical examination, electrocardiogram, and blood and urine laboratory tests. Subjects were 18 to 55 years of age, healthy, nonsmokers (for...

Section: Methodsmentioning

confidence: 99%

Duration of Pleconaril Effect on Cytochrome P450 3a Activity in Healthy Adults Using the Oral Biomarker Midazolam

Joseph

Nafziger²,

Rhodes³

et al. 2006

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“…The findings from clinical studies have been inconsistent or inconclusive. For example, mean MDZ clearances were greater in women in several investigations, reaching statistical significance in some (Greenblatt et al, 1984;Gorski et al, 1998Gorski et al, , 1999Zhu et al, 2003;Chen et al, 2006c;Chung et al, 2006;Kharasch et al, 2007;Hu et al, 2009), whereas other studies found equivalence (Kashuba et al, 1998;Dresser et al, 2003;Floyd et al, 2003;Gorski et al, 2003;Eap et al, 2004;Chen et al, 2006a) or even insignificantly higher clearances in men (Thummel et al, 1996). Results of the largest-scale investigation (41 women and 58 men) showed that systemic clearances were 30% greater in women, but there was no sex difference for oral MDZ (Kharasch et al, 2007).…”

Section: Introductionmentioning

confidence: 91%

Sex-Dependent Differences in Cytochrome P450 3A Activity as Assessed by Midazolam Disposition in Humans: A Meta-Analysis

Hu¹,

Zhao²

2010

ABSTRACT:Controversy exists concerning the sex-dependent differences in cytochrome P450 3A activity in humans. Meta-analysis of selected studies may address this question. Meta-analysis was performed on published or unpublished data in terms of sex-dependent differences in midazolam (MDZ) disposition in humans. The following pharmacokinetic parameters were included for the analysis: MDZ oral and systemic clearance, area under the concentration-time curve (AUC) of oral and intravenous MDZ, MDZ oral bioavailability (F), and MDZ gastrointestinal extraction (E G ). Ten studies including 409 healthy volunteers were identified. Women exhibited 16% higher weight-corrected MDZ oral clearance (P < 0.001) and 20% higher systemic clearance (P ‫؍‬ 0.002) than men. No significant difference in the AUC after oral dosing of MDZ was noted between sexes. Women showed lower AUC of intravenous MDZ than men (P ‫؍‬ 0.02). No sex-dependent differences were observed in F and E G . In conclusion, women showed significantly greater hepatic CYP3A activity than men, whereas no sex-dependent difference in intestinal CYP3A activity was observed.The enzyme subfamily cytochrome P450 3A and its two major members-CYP3A4 and, to a lesser extent, CYP3A5-are considered the most important drug-metabolizing enzymes by virtue of their high concentration, strategic localization, and wide substrate specificity (Thummel and Wilkinson, 1998).Midazolam (MDZ) is a selective substrate of CYP3A4 and CYP3A5 and is almost exclusively metabolized by CYP3A to form the primary metabolite 1-hydroxymidazolam. Systemic or apparent oral clearance of MDZ is the most widely tested and accepted biomarker for hepatic and intestinal CYP3A activity (Streetman et al., 2000). Intravenous administration of MDZ reflects only hepatic CYP3A activity, whereas orally administered MDZ is a measure of intestinal and hepatic CYP3A activities (Thummel et al., 1996;Gorski et al., 1998;Streetman et al., 2000).Numerous studies have examined potential sex differences in the metabolic activity of CYP3A. These studies include prospective clinical studies and retrospective analysis of data from previous studies. The findings from clinical studies have been inconsistent or inconclusive. For example, mean MDZ clearances were greater in women in several investigations, reaching statistical significance in some (Greenblatt et al., 1984;Gorski et al., 1998Gorski et al., , 1999Zhu et al., 2003;Chen et al., 2006c;Chung et al., 2006;Kharasch et al., 2007;Hu et al., 2009), whereas other studies found equivalence (Kashuba et al., 1998;Dresser et al., 2003;Floyd et al., 2003;Gorski et al., 2003;Eap et al., 2004;Chen et al., 2006a) or even insignificantly higher clearances in men (Thummel et al., 1996). Results of the largest-scale investigation (41 women and 58 men) showed that systemic clearances were 30% greater in women, but there was no sex difference for oral MDZ (Kharasch et al., 2007).There were two retrospective studies on this topic, and both studies showed significant sex-dependent difference...

“…Liquid chromatography-tandem mass spectrometry using alprazolam as the internal standard was used. The assay has been described previously (Kashuba et al, 1998;Chung et al, 2006). Pharmacokinetic parameters were analyzed by noncompartmental analysis using WinNonlin version 3.2 (Pharsight Corporation, Mountain View, CA) (Chung et al, 2006).…”

Section: Subjectsmentioning

confidence: 99%

Drug-Metabolizing Enzyme Inhibition by Ketoconazole Does Not Reduce Interindividual Variability of CYP3A Activity as Measured by Oral Midazolam

Chen¹,

Nafziger²,

Bertino³

2006

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ABSTRACT:Variable interindividual expression of cytochrome P450 3A presents a challenge in dosing drugs. The use of potent inhibitors of CYP3A such as ketoconazole has been explored to reduce the clearance of CYP3A substrates, thereby resulting in smaller dose requirements; however, the impact of CYP3A inhibition on interindividual variability has not been well characterized. Our objective was to examine the effect of ketoconazole inhibition on CYP3A metabolic variability as measured by the CYP3A biomarker oral midazolam. A single dose of midazolam (0.075 mg/kg) was administered to 19 healthy Caucasian adults (38.7 ؎ 8.8 years, nine male/10 female) at baseline and concurrently with ketoconazole (400 mg daily for 10 days) on day 6 or 9 of ketoconazole. Plasma samples were collected over 6 to 30 h. A paired t test and percent coefficient of variation (CV%) were used to evaluate differences in midazolam clearance and interindividual variability during both phases. Monte Carlo simulation was performed to determine probability distribution of area under the concentration-time curves (AUCs). Midazolam apparent oral clearance decreased by 89% (p < 0.0001) during inhibition. C max increased from 23 ng/ml (95% CI 19-29 ng/ml) to 55 ng/ml (95% CI 46-66 ng/ml), p < 0.0001. CV% increased from 41 to 58% from baseline to ketoconazole inhibition. AUCs [median (range)] were 0.20 mg ⅐ min/ml (0.05-0.81 mg ⅐ min/ml) and 1.94 mg ⅐ min/ml (0.25-25.4 mg ⅐ min/ml) at baseline and inhibition phase, with CV% of 41 and 61%, respectively. Ketoconazole decreased CYP3A activity but did not reduce interindividual variability. Use of a CYP3A inhibitor to standardize dosing of CYP3A substrates may not be feasible in clinical practice.