Pharmacogenetic interactions of rifapentine plus isoniazid with efavirenz or nevirapine

Abstract

Objectives: The effect of rifapentine plus isoniazid on efavirenz pharmacokinetics was characterized in AIDS Clinical Trials Group protocol A5279 (NCT01404312). The present analyses characterize pharmacogenetic interactions between these drugs, and with nevirapine.

Methods: A subset of HIV-positive individuals receiving efavirenz- or nevirapine-containing antiretroviral therapy in A5279 underwent pharmacokinetic evaluations at baseline, and again weeks 2 and 4 after initiating daily rifapentine plus isoniazid. Associations with polymorphisms relevant to efavirenz, nevirapine, isoniazid, and rifapentine pharmacokinetics were assessed.

Results: Of 128 participants, 101 were evaluable for associations with rifapentine and its active 25-desacetyl metabolite, 87 with efavirenz, and 38 with nevirapine. In multivariable analyses, NAT2 slow acetylators had greater week 4 plasma concentrations of rifapentine (P = 2.6 × 10) and 25-desacetyl rifapentine (P = 7.0 × 10) among all participants, and in efavirenz and nevirapine subgroups. NAT2 slow acetylators also had greater plasma efavirenz and nevirapine concentration increases from baseline to week 4, and greater decreases from baseline in clearance. CYP2B6 poor metabolizers had greater efavirenz concentrations at all weeks and greater nevirapine concentrations at baseline. None of 47 additional polymorphisms in 11 genes were significantly associated with pharmacokinetics.

Conclusions: Among HIV-positive individuals receiving efavirenz or nevirapine, and who then initiated rifapentine plus isoniazid in A5279, NAT2 slow acetylators had greater rifapentine and 25-desacetyl rifapentine concentrations, and greater increases from baseline in plasma efavirenz and nevirapine concentrations. These associations are likely mediated by greater isoniazid exposure in NAT2 slow acetylators.

Figure 1.. Relationships between CYP2B6 metabolizer genotype, NAT2 acetylator genotype, and plasma efavirenz concentrations among 85 efavirenz group participants.

Each panel indicates which CYP2B6 metabolizer genotype and NAT2 acetylator genotype is represented. The percentages in each panel represent individuals in whom efavirenz concentrations increased from baseline (week 0) to week 2. Red lines and markers represent individuals in whom efavirenz concentrations increased from baseline to week 2. Note that Y-axes differ among the graphs. The graphs only include individual who also had data for BMI, sex, and efavirenz concentration data between 9 hours and 30 hours post dose. EFV = efavirenz. * Not represented is one individual with nevirapine concentrations of 38,061 ng/mL and 58,589 ng/mL at baseline and week 2, respectively. Green dashed lines represent an efavirenz concentration of 4000 ng/mL, the suggested threshold for increased toxicity [21].

Figure 2.. Relationships between CYP2B6 metabolizer genotype, NAT2 acetylator genotype, and plasma nevirapine concentrations among 35 nevirapine group participants.

Each panel indicates which CYP2B6 metabolizer genotype and NAT2 acetylator genotype is represented. The percentages in each panel represent individuals in whom nevirapine concentrations increased from baseline (week 0) to week 2. Red lines and markers represent individuals in whom nevirapine concentrations increased from baseline to week 2. Note that Y-axes differ among the graphs. The graphs only include individual who also had data for sex, and nevirapine concentration data between 10 hours and 15 hours post dose. NVP = nevirapine.

Figure 3.. Relationships between NAT2 acetylator genotype and plasma concentrations of rifapentine and 25-desacetyl rifapentine at week 4.

Panel A: associations of rifapentine with NAT2 acetylator genotype among all participants, and in the efavirenz (EFV) group, and the nevirapine (NVP) group analyzed separately. Panel B: associations of plasma 25-desacetyl rifapentine with NAT2 acetylator genotype among all participants, and in the efavirenz (EFV) group, and the nevirapine (NVP) group analyzed separately. RAP, rapid; INT, intermediate; SLO, slow. P-values are from linear regression models that included CYP2B6 genotype, BMI, sex, and hours since rifapentine dose. The graphs only include individual who also had data for CYP2B6 genotype, BMI, sex, and rifapentine concentration data between 10 hours and 36 hours post dose. Error bars indicate medians and 75^th percentiles.