Long-term effect of rifampicin-based Anti-TB regimen coadministration on the pharmacokinetic parameters of efavirenz and 8-Hydroxy-Efavirenz in ethiopian patients

• Verfasst von: Habtewold, Abiy [VerfasserIn]
• Verfasst von: Burhenne, Jürgen [VerfasserIn]
• Titel: Long-term effect of rifampicin-based Anti-TB regimen coadministration on the pharmacokinetic parameters of efavirenz and 8-Hydroxy-Efavirenz in ethiopian patients
• Verf.angabe: Abiy Habtewold, PhD, Eleni Aklillu, PhD, Eyasu Makonnen, PhD, Wondwossen Amogne, MD, PhD, Getnet Yimer, MD, PhD3, Getachew Aderaye, MD, PhD, Leif Bertilsson, PhD, Joel S.Owen, PhD, and Jürgen Burhenne, PhD
• Umfang: 12 S.
• Fussnoten: Gesehen am 07.12.2017
• Titel Quelle: Enthalten in: Journal of clinical pharmacology
• Jahr Quelle: 2016
• Band/Heft Quelle: 56(2016), 12, S. 1538-1549
• ISSN Quelle: 1552-4604
• DOI: doi:10.1002/jcph.756
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 156614566X

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, AUC0-24 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 AUC0-24 and Cmax 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.