Influence of Cyp2b6 Genotype on Variability in Efavirenz Pharmacokinetic and the Associated QT Interval Prolongation
Efavirenz (EFV)-based regimens have strong virological efficacy toward human immunodeficiency virus (HIV) type 1 infections. However, the high rates of EFV-associated toxicity limits its use in some patients. Efavirenz variability in efficacy and toxicity is largely attributed to its unique pharmacokinetic profile. Efavirenz is extensively metabolized by cytochrome P450 (CYP) mediated hydroxylation in addition to minor glucuronidation pathways. Several in vitro and in vivo studies report the contribution of the highly polymorphic CYP2A6, 2B6, and 3A4/5 to EFV metabolism and hence the considerable variability in its pharmacokinetics and therapeutic outcomes. The first objective of this research was to develop a pharmacogenetic-based pharmacokinetic model that adequately described the disposition of EFV and its major metabolites. Plasma concentrations of EFV and its major metabolites were determined (0-120h) following a single oral dose of 200 mg. Population pharmacokinetic analysis using non-linear mixed effects modeling was performed to assess the influence of various patients covariated on EFV disposition. CYP2B6 genotype was the primary pharmacogenetic covariate that influenced EFV exposure. The model-based predictions of EFV steady-state concentrations following 200, 400, and 600 mg daily doses were performed using the developed model. Daily doses of 600 mg achieved significantly higher steady-state concentration among CYP2B6*6/*6 compared to the other CYP2B6 genotype patient groups. This suggests that CYP2B6*6/*6 may be at increased risk of adverse events which includes the well-established central nervous system toxicity and the potential cardiotoxicity. Efavirenz has been associated with potential cardiotoxicity in the form of QT-interval prolongation and torsade de pointes, which is a life-threatening polymorphic ventricular tachycardia. Drugs that prolong QT-interval, inhibit the rapid component of the delayed rectifier potassium current (IKr) which is coded by the human Ether-a-go-go-Related Gene (hERG). Inhibition of the hERG-related potassium channel and hence inhibition of IKr in cardiac tissue results in prolonged ventricular repolarization, and consequently lengthening of the QT interval on electrocardiograms. Consequently, the effect of EFV was assessed on human embryonic kideney (HEK293) cells stably expressing hERG as an underlying mechanism for the potential EFV associated QT-interval lengthening. Potassium tail currents through hERG channels were recorded in this cellular model using the whole cell patch clamp technique after exposure to ascending EFV concentrations (0-2.5 µg/mL). The effect of EFV on hERG currents was studied inthe presence and absence of functional expression of CYP2B6 enzyme. Efavirenz inhibited hERG currents (both inward and outward) in a concentration dependent manner at physiologically relevant concentrations. Maximum inhibitory effect was estimated to be 92% ± 255% and 55% ± 4% for both inward and outward currents respectively (P<0.05). The inhibitory concentration at half the maximal effect (IC50) was estimated to be 0.2 ± 0.2 µg/mL (inward) and 1.9 ± 3.2 µg/mL (outward). Functional expression of CYP2B6 attenuated EFV-inhibitory effect on hERG currents (P<0.05). ^ In a placebo-controlled clinical trial, EFV-associated QT-interval prolongation did not exceed the United States Food and Drug Administration (FDA)-adopted threshold of QT-prolonging medications. However, the underlying pharmacogenetics of the metabolizing enzymes, specifically CYP2B6 was not reported. Therefore the ability of EFV to lengthen the QT-interval was assessed in healthy volunteers with respect to CYP2B6 genotype. QT intervals were measured from electrocardiograms of healthy subjects (n=57), who received EFV 600 mg/day for 17 days. The time-matched difference in Fridericia- corrected Δ(QTc)F intervals were calculated. Calculated Δ(QTc)F was compared to the FDA-adopted threshold which is defined by a mean change of +5 msec with an upper bound of the two-sided 90% confidence interval (CI) of 10 msec. The FDA-adopted threshold was not met among CYP2B6*1/*1 subjects (normal metabolizers). Among, intermediate metabolizers (CYP2B6*1/*6), the FDA-threshold was exceeded at 6 hours following EFV administration with a mean Δ(QTc)F of +6 msec and 90% CI [1; 11]. A larger change was observed among slow metabolizers (CYP2B6*6/*6) at 6 and 12 hours following EFV administration of +11 msec; 90% CI [8; 14] and +15 msec; 90% CI [1; 28] respectively. This suggests that CYP2B6*6 allele carriers may be at an increased risk for EFV-induced (QT c)F interval lengthening at steady-state.^
Brian R. Overholser, Purdue University.