Long‐Term Effect of Rifampicin‐Based Anti‐TB Regimen Coadministration on the Pharmacokinetic Parameters of Efavirenz and 8‐Hydroxy‐Efavirenz in Ethiopian Patients

Abstract

We compared the pharmacokinetic (PK) exposure parameters of efavirenz (EFV) and its major inactive metabolite, 8-hydroxy-efavirenz (8-OH-EFV), in an open-label, single-sequence, and parallel design of HIV-infected and tuberculosis (TB)-HIV-coinfected Ethiopian patients in the HIV-TB Pharmagene study with 20 and 33 patients, respectively. Both treatment groups underwent PK sampling following oral 600 mg EFV in week 16 of initiating EFV-based combination antiretroviral therapy. The TB-HIV-coinfected group repeated the PK sampling 8 weeks after stopping rifampin (RIF)-based anti-TB treatment. Between-treatment group analysis indicated no significant effect of RIF-based anti-TB cotreatment on PK exposure parameters of EFV, nor was there a significant effect after controlling for sex or CYP2B6 genotype. However, RIF-based therapy in TB-HIV-coinfected patients had significantly increased 8-OH-EFV PK exposure measures and metabolic ratio relative to HIV-only patients, AUC greater by 79%. The effect was more prominent in women and CYP2B6*6 carriers in within-sex and CYP2B6 genotype comparisons. Within-subject comparisons for AUC and C when "on" and "off" RIF-based anti-TB cotreatment showed geometric mean ratios (90% confidence intervals) of 100.5% (98.7%-102.3%) and 100.2% (98.1%-102.4%), respectively, for EFV and 98.6% (95.5%-101.7%-) and 97.6% (92.2%-103.0%), respectively, for 8-OH-EFV. We report no significant influence of RIF-based anti-TB cotherapy on the EFV PK exposure measures. The study also calls for caution related to higher exposure to 8-OH-EFV during simultaneous coadministration of EFV and RIF-based anti-TB regimens, which may be associated with neurotoxicity, particularly in female patients and CYP2B6*6 carriers.

Population Pharmacokinetic Model Linking Plasma and Peripheral Blood Mononuclear Cell Concentrations of Efavirenz and Its Metabolite, 8-Hydroxy-Efavirenz, in HIV Patients

“…Contradictory reports exist in the literature, though recent studies, including our noncompartmental PK and PK-pharmacodynamics (PD) relationship analyses reported on EFV using the same data, suggest the absence of a significant effect of a RIF-based anti-TB regimen (13,(31)(32)(33). The covariate analysis in the present study confirmed the absence of the effect of a RIF-based anti-TB regimen on the disposition of EFV and 8OHEFV.…”

“…This study was a PK substudy of an umbrella study (the HIV-TB Pharmagene study) that was previously described in detail (32,33). Briefly, the study was an open-label, two-arm, parallel-design, year-long prospective clinical study conducted in a tertiary level referral hospital and eight other health centers in Addis Ababa, Ethiopia.…”

Long-term efavirenz pharmacokinetics is comparable between Tanzanian HIV and HIV/Tuberculosis patients with the same CYP2B6*6 genotype

“…This hypothesis is also supported by several other studies, which compared efavirenz pharmacokinetics after at least 12 weeks of treatment when taken with or without rifampicin-based tuberculosis co-treatment. A study with similar design and comparable sample size as this study (twin study), but in Ethiopian subjects, had similar findings 31 . Similarly, Ramachandran et al .…”

“…Compared with single dose EFV clearance reported elsewhere, the estimated clearance in this study is considerably higher and this is consistent with EFV autoinduction properties. For subjects with CYP2B6*1*1 genotype, single dose EFV clearance have been reported to range between 4–7.5 L/h 49 – 51 while after multiple dosing EFV clearance is reported to range between 9.4–15.5 L/h 26 , 31 , 52 – 54 (Estimates obtained without normalizing clearance by body weight). Upon normalizing EFV clearance by body weight Matteeli et al .…”

“…We reported the association of CYP2B6*6 genotype with cART induced liver toxicity in Ethiopians 33 , 34 and Tanzanian patients 35 , and with neuropsychiatric toxicity in Ugandan 19 and Tanzanian patients 36 , and with CD4 recovery among Ethiopian patients 8 . Investigation of long-term efavirenz pharmacokinetics with and without rifampicin co-treatment among Ethiopian subjects has indicated the independence of EFV pharmacokinetics on RIF/EFV co-treatment even after adjusting for CYP2B6 polymorphisms 31 . However, we reported previously that the pharmacogenetics and pharmacokinetics of EFV display significant differences between Ethiopians and Tanzanians 13 , 16 .…”