Substantial Effect of Efavirenz Monotherapy on Bilirubin Levels in Healthy Volunteers

Abstract

BackgroundEfavirenz exhibits multiple interactions with drug-metabolizing enzymes and transporters, and for this reason efavirenz-based HIV therapy is associated with altered pharmacokinetics of coadministered drugs. Probably by the same mechanism, efavirenz-based HIV therapy affects the disposition of endogenous compounds, but this effect is difficult to directly link with efavirenz because it is used in combination with other drugs.ObjectivesTo explore the effect of efavirenz monotherapy on biochemical laboratory values in a clinical trial of healthy volunteers.MethodsMen and women (aged 18–49 years) with body mass index ≤32 who were assessed to be healthy based on medical history, physical examination, and standard laboratory screening received a single (600 mg) and multiple doses (600 mg/d for 17 days) of efavirenz orally. This trial was designed to determine the pharmacokinetics and drug interactions of efavirenz. As part of this study, analysis of serum chemistries that were measured at study entry (screening) and 1 week after completion of the multiple dose study (exit) is reported.ResultsData from 60 subjects who fully completed and 13 subjects who partially completed the study are presented. Total bilirubin was substantially reduced at exit (by ~30%, with large intersubject variability) compared with screening values (P < 0.0001). The percent changes were in part explained by the intersubject differences in baseline total bilirubin because there was a significant correlation between baseline (screening) values and percent change at exit (r = 0.50; P < 0.0001). Hemoglobin and absolute neutropenia were also substantially decreased at exit compared with screening, but this may be due to intensive blood sampling rather than direct effect of efavirenz on these parameters. No significant correlation was found between percent change in hemoglobin versus percent change in bilirubin, indicating the effect of efavirenz on bilirubin is independent of its effects on hemoglobin.ConclusionsEfavirenz monotherapy significantly lowers plasma total bilirubin concentration in healthy volunteers independent of its effect on hemoglobin, probably through its effects on bilirubin metabolism and transport (uptake and efflux). These findings help explain reversal by efavirenz of hyperbilirubinemia induction observed by some protease inhibitor antiretroviral drugs (eg, atazanavir). Besides its well-documented role on drug interactions, efavirenz may alter the disposition of endogenous compounds relevant in physiologic homeostasis through its interaction with drug metabolizing enzymes and/or drug transporters. ClinicalTrials.gov identifier: NCT00668395.

Influence of Uridine Diphosphate Glucuronosyltransferase Family 1 Member A1 and Solute Carrier Organic Anion Transporter Family 1 Member B1 Polymorphisms and Efavirenz on Bilirubin Disposition in Healthy Volunteers

“…We found that chronic administration of efavirenz significantly reduced total, unconjugated, and conjugated (glucuronides) bilirubin by 33%, 36%, and 31%, respectively. These findings concur with our previous study showing a 30% decrease in total bilirubin levels by efavirenz (Metzger et al, 2014) and with those from other investigators in which efavirenz was shown to decrease unconjugated and conjugated bilirubin by 42% and 26%, respectively, in a small number of healthy volunteers (Lee et al, 2012). Although the exact mechanisms whereby efavirenz reduces bilirubin levels remains unknown, a useful, plausible insight can be obtained from a close look at the processes responsible for the hepatic disposition of unconjugated and conjugated bilirubin (Crawford et al, 1992;Bosma et al, 1995;Jedlitschky et al, 1997;Kadakol et al, 2000;van de Steeg et al, 2012;Sticova and Jirsa, 2013;Keppler, 2014) (see also Fig.…”

“…These interactions can lead to reduced or lack of efficacy or increased adverse reactions. Previously, we have shown that efavirenz monotherapy affects total bilirubin disposition in healthy volunteers (Metzger et al, 2014). This effect was highly variable among subjects.…”

“…The two protocols (NCT00668395 and NCT02401256) were primarily designed to test metabolism, pharmacokinetics, pharmacogenetics, and drug interactions of efavirenz after single (600-mg) oral dose and after multiple doses (after 600 mg/day for 17 days orally). The study designs of these trials have been described in detail elsewhere (Metzger et al, 2014;Masters et al, 2016;Robarge et al, 2016). Among others, standard laboratory results including bilirubin (total, conjugated, and unconjugated) were obtained during the screening phase (i.e., baseline, before any drug administration) and at exit (i.e., approximately 1 week after completion of 600 mg/day oral dose of efavirenz for 17 days).…”

“…Study subjects were judged healthy by medical history and standard screening laboratory tests. Inclusion and exclusion criteria of the subjects have been described in detail in our previous publications (Metzger et al, 2014;Masters et al, 2016;Robarge et al, 2016). Blood samples were obtained for DNA genotyping.…”

Efavirenz does not meaningfully affect the single dose pharmacokinetics of 1200 mg raltegravir

“…Efavirenz has been shown to increase the elimination of indinavir and dolutegravir . Additionally, efavirenz monotherapy has been shown to significantly reduce plasma total bilirubin concentration in healthy volunteers independent of its effect on hemoglobin, again very likely mediated via UGT1A1 .…”