title: 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, AUC0-24greater by 79%. The effect was more prominent in women and CYP2B6*6 carriers in within-sex and CYP2B6 genotype comparisons. Within-subject comparisons for AUC0-24and Cmaxwhen "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.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Union University, Jackson, TN, USA.|Division of Clinical Pharmacology, Department of Lab Medicine, Karolinska Institutet Hospital Huddinge, Stockholm, Sweden.|Department of Pharmacology, School of Medicine, Addis Ababa University, Addis Ababa, Ethiopia.
authors.forename: Abiy
authors.initials: A
authors.lastname: Habtewold
authors.affiliation: Section of Pharmacogenetics, Department of Physiology & Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Eleni
authors.initials: E
authors.lastname: Aklillu
authors.affiliation: Department of Pharmacology, School of Medicine, Addis Ababa University, Addis Ababa, Ethiopia.
authors.forename: Eyasu
authors.initials: E
authors.lastname: Makonnen
authors.affiliation: Department of Internal Medicine, School of Medicine, Addis Ababa University, Addis Ababa, Ethiopia.
authors.forename: Wondwossen
authors.initials: W
authors.lastname: Amogne
authors.affiliation: Department of Pharmacology, School of Medicine, Addis Ababa University, Addis Ababa, Ethiopia.
authors.forename: Getnet
authors.initials: G
authors.lastname: Yimer
authors.affiliation: Department of Internal Medicine, School of Medicine, Addis Ababa University, Addis Ababa, Ethiopia.
authors.forename: Getachew
authors.initials: G
authors.lastname: Aderaye
authors.affiliation: Division of Clinical Pharmacology, Department of Lab Medicine, Karolinska Institutet Hospital Huddinge, Stockholm, Sweden.
authors.forename: Leif
authors.initials: L
authors.lastname: Bertilsson
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Union University, Jackson, TN, USA.
authors.forename: Joel S
authors.initials: JS
authors.lastname: Owen
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University Hospital of Heidelberg, Heidelberg, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Burhenne
mesh_terms: D000328:Adult; D000480:Alkynes; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D048588:Benzoxazines / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6 / Q000097:blood; D065695:Cytochrome P-450 CYP2B6 Inducers / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D004359:Drug Therapy, Combination; D005002:Ethiopia / Q000453:epidemiology; D005260:Female; D015658:HIV Infections / Q000097:blood* / Q000188:drug therapy / Q000453:epidemiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D012293:Rifampin / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D013997:Time Factors; D016896:Treatment Outcome; D014376:Tuberculosis / Q000097:blood* / Q000188:drug therapy / Q000453:epidemiology; D055815:Young Adult
chemical_list: D000480:Alkynes; D000995:Antitubercular Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D065695:Cytochrome P-450 CYP2B6 Inducers; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; C098320:efavirenz; D012293:Rifampin
keywords: 8-hydroxy-efavirenz; CYP2B6; Ethiopian; TB-HIV; efavirenz; rifampicin