Efavirenz (EFV) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with a long half-life, allowing for once-daily dosing. Although it is generally well-tolerated and widely used, a major disadvantage of EFV is its relatively low barrier to resistance. The single K103N mutation confers high-level resistance to EFV, as well as to all other NNRTIs. Acquisition of HIV-1 resistance is likely to result from repeated exposure of the virus to subtherapeutic drug concentrations. ? ? When terminating EFV therapy it is recommended that EFV be stopped 1-2 weeks earlier than concomitant antiretrovirals (ARVs) to account for its long washout period. Alternatively, substituting EFV with a protease inhibitor for 1 to 4 weeks has also been recommended. Both strategies attempt to avoid prolonged EFV exposure following discontinuation of concomitant ARVs, thereby lowering the risk of acquiring new resistance mutations. Though widely utilized, neither method has been validated by pharmacokinetic or clinical studies. Genetic differences in CYP2B6 have been shown to contribute greatly to observed variability in EFV clearance; hence, inter-patient genetic differences may significantly influence the manner in which efavirenz should be discontinued in order to reduce the risk of acquiring HIV-1 resistance mutations. Multiple polymorphisms in CYP2B6 have been identified. Substitutions at positions 516, 785, and 1459 are the most common variants, and appear to be associated with alterations in CYP2B6 activity. ? ? We propose a 2-part study. Part I is to be conducted in HIV-negative volunteers, and consists of: (1) determination of EFV pharmacokinetic (PK) values (following 13-15 days of EFV 600 mg/day) for comparison between CYP2B6 genotypes (including wild-type and allelic variants at positions 516, 785 and 1459), (2) measurement of single EFV plasma concentrations 7, 14, 21, and 28 days after the drug is stopped to assess for differences in EFV exposure between CYP2B6 genotypes, and (3) comparison of bupropion PK values following administration of a single bupropion dose (a) prior to EFV administration and (b) after 13-15 days of EFV, to evaluate whether EFV modulates CYP2B6 metabolism using bupropion as a probe for CYP2B6 metabolic activity. ? ? Part II is to be conduced in HIV-positive patients who are planning to discontinue (d/c) their EFV therapy, and includes: (1) determination of EFV PK values prior to d/c of therapy for comparison between different CYP2B6 genotypes, (2) measurement of single EFV plasma concentrations 7, 14, 21 and 28 days post-EFV to assess for differences in exposure across CYP2B6 genotypes, and (3) genotypic evaluation of HIV-1 drug resistance performed in any patient with an HIV RNA ! 1,000 copies/mL, prior to and after EFV discontinuation (up to 12 months after stopping EFV), as a preliminary study to evaluate the incidence of EFV resistance mutations based on CYP2B6 genotype.? ? Part I of the study has now been completed and results are as follows: Thirteen healthy males and females completed the study. The ratio of OH-bupropion:bupropion AUC increased 2.3-fold from Phase I to Phase II (P=0.0001). Bupropion AUC and Cmax decreased by 55% and 34%, respectively (P<0.002), while OH-bupropion AUC was unchanged. OH-bupropion T1/2 decreased from 24 hours to 16 hours (P=0.0002). None of the CYP2B6 genotypes evaluated appeared to affect bupropion PK in the presence or absence of EFV. ? Our results indicate that EFV induces CYP2B6 metabolism in vivo, as demonstrated by induction of bupropion hydroxylation. Interestingly, OH-bupropion AUC was unchanged, while its T1/2 was significantly decreased. This suggests EFV may also increase the elimination of OH-bupropion, a pharmacologically active metabolite whose elimination has not been described. A 55% decrease in bupropion exposure may have important clinical consequences for patients on EFV therapy who take bupropion for smoking cessation or the treatment of depression. Other drugs metabolized by CYP2B6 may also have reduced exposure when coadministered with EFV; as such, CYP2B6 substrates should be used with caution in patients receiving EFV.
