title: Dependence of efavirenz- and rifampicin-isoniazid-based antituberculosis treatment drug-drug interaction on CYP2B6 and NAT2 genetic polymorphisms: ANRS 12154 study in Cambodia.
abstract: We investigated the population pharmacokinetics and pharmacogenetics of efavirenz in 307 patients coinfected with human immunodeficiency virus and tuberculosis and included in the Cambodian Early vs Late Initiation of Antiretrovirals trial (CAMELIA) in Cambodia. Efavirenz (600 mg/d) and stavudine plus lamivudine were administered in addition to standard antituberculosis treatment, including rifampicin and isoniazid. Blood samples were obtained a mean of 14 hours after efavirenz intake at weeks 2 and 6 after initiation of efavirenz and weeks 22 (efavirenz plus antituberculosis drugs) and 50 (efavirenz alone) after initiation of antituberculosis treatment. Ten patients participated in an extensive pharmacokinetic study after week 50. CYP2B6 G516T and C485-18T polymorphisms were the most significant covariates, with weight showing a significant minor effect. Change in efavirenz apparent clearance in patients taking both efavirenz and antituberculosis treatment was highly dependent on NAT2 polymorphism, as a possible surrogate of isoniazid exposure. Patients carrying the CYP2B6 516 TT genotype and slow-acetylation NAT2 phenotype had the lowest efavirenz apparent clearance. These data suggest that the inducing effect of rifampicin is counterbalanced by a concentration-dependant inhibitory effect of isoniazid on efavirenz clearance.
authors.affiliation: Genetics Institute, University College London, United Kingdom.
authors.forename: Julie
authors.initials: J
authors.lastname: Bertrand
authors.forename: Céline
authors.initials: C
authors.lastname: Verstuyft
authors.forename: Monidarin
authors.initials: M
authors.lastname: Chou
authors.forename: Laurence
authors.initials: L
authors.lastname: Borand
authors.forename: Phalla
authors.initials: P
authors.lastname: Chea
authors.forename: Kuy Huong
authors.initials: KH
authors.lastname: Nay
authors.forename: François-Xavier
authors.initials: FX
authors.lastname: Blanc
authors.forename: France
authors.initials: F
authors.lastname: Mentré
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Taburet
mesh_terms: D000480:Alkynes; D019380:Anti-HIV Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D000995:Antitubercular Agents / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D048588:Benzoxazines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002160:Cambodia; D002853:Chromatography, Liquid; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6; D004347:Drug Interactions; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy; D006801:Humans; D007538:Isoniazid / Q000627:therapeutic use*; D019259:Lamivudine / Q000627:therapeutic use; D010949:Plasma / Q000737:chemistry; D020641:Polymorphism, Single Nucleotide; D012293:Rifampin / Q000627:therapeutic use*; D013056:Spectrophotometry, Ultraviolet; D018119:Stavudine / Q000627:therapeutic use; D014376:Tuberculosis / Q000150:complications / Q000188:drug therapy
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D000995:Antitubercular Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D019259:Lamivudine; D018119:Stavudine; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; C098320:efavirenz; D007538:Isoniazid; D012293:Rifampin