Key result
Clopidogrel pretreatment markedly decreased the AUC of 8,14-dihydroxyefavirenz compared with placebo (ratio 95% CI 0.55-0.73), and the metabolite ratio correlated with efavirenz clearance.
Why the study?
Does clopidogrel or itraconazole alter the disposition of efavirenz and its hydroxyl metabolites in healthy subjects?
RCT (n=17)
randomized
Does clopidogrel or itraconazole alter the disposition of efavirenz and its hydroxyl metabolites in healthy subjects?
The 8,14-dihydroxyefavirenz to efavirenz AUC ratio is sensitive to CYP2B6 activity alterations and may serve as a useful in vivo phenotyping index.
Clopidogrel inhibits CYP2B6-mediated efavirenz metabolism; supports 8,14-dihydroxyefavirenz ratio as CYP2B6 phenotyping index.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Cytochrome P450 (CYP) 2B6 is the enzyme primarily responsible for the metabolism of many clinically important drugs, including efavirenz, which it converts to 8‐hydroxyefavirenz and then to 8,14‐hydroxyefavirenz. • The CYP2B6*6 polymorphism influences efavirenz pharmacokinetics, but a validated phenotyping method for predicting CYP2B6 activity in human subjects is not yet available. • The disposition of 8,14‐dihydroxyefavirenz in humansin vivois unknown. WHAT THIS STUDY ADDS • This study is the first quantitative examination of 8,14‐dihydroxyefavirenz pharmacokinetics in human subjects. • The 8,14‐dihydroxyefavirenz : efavirenz AUC(0,120 h) ratio correlates with efavirenz oral clearance and is sensitive and specific to CYP2B6 activity alterations. • The 8,14‐dihydroxyefavirenz : efavirenz AUC(0,120 h) ratio may be a useful phenotyping index for CYP2B6 activityin vivo. AIMSTo evaluate the effects of clopidogrel and itraconazole on the disposition of efavirenz and its hydroxyl metabolites in relation to theCYP2B6*6genotype and explore potential phenotyping indices for CYP2B6 activityin vivousing a low dose of oral efavirenz. METHODSWe conducted a randomized three phase crossover study in 17 healthy Korean subjects pre‐genotyped for theCYP2B6*6allele (CYP2B6*1/*1,n= 6; *1/*6,n= 6; *6/*6,n= 5). Subjects were pretreated with clopidogrel (75 mg day−1for 4 days), itraconazole (200 mg day−1for 6 days), or placebo and then given a single dose of efavirenz (200 mg). The plasma (0–120 h) and urine (0–24 h) concentrations of efavirenz and its metabolites (7‐ and 8‐hydroxyefavirenz and 8,14‐dihydroxyefavirenz) were determined by LC/MS/MS. RESULTSThis study is the first to delineate quantitatively the full (phase I and II) metabolic profile of efavirenz and its three hydroxyl metabolites in humans. Clopidogrel pretreatment markedly decreased AUC(0,48 h),Cmaxand Ae(0,24 h) for 8,14‐dihydroxyefavirenz, compared with placebo; 95% CI of the ratios were 0.55, 0.73, 0.30, 0.45 and 0.25, 0.47, respectively. The 8,14‐dihydroxyefavirenz : efavirenz AUC(0,120 h) ratio was significantly correlated with the weight‐adjusted CL/Fof efavirenz (r2≈ 0.4,P< 0.05), differed withCYP2B6*6genotype and was affected by clopidogrel pretreatment (P< 0.05) but not by itraconazole pretreatment. CONCLUSIONSThe disposition of 8,14‐dihydroxy‐EFV appears to be sensitive to CYP2B6 activity alterations in human subjects. The 8,14‐dihydroxyefaviremz : efavirenz AUC(0,120 h) ratio is attractive as a candidate phenotyping index for CYP2B6 activityin vivo.
No takes yet. Share an insight, caveat, or question.
Jiang et al. (2012) conducted an RCT in Healthy subjects (n=17). Clopidogrel and itraconazole vs. Placebo was evaluated on AUC(0,48 h) ratio for 8,14-dihydroxyefavirenz (clopidogrel vs placebo) (95% CI 0.55-0.73). Clopidogrel pretreatment markedly decreased the AUC of 8,14-dihydroxyefavirenz compared with placebo (ratio 95% CI 0.55-0.73), and the metabolite ratio correlated with efavirenz clearance.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: