Dependence of Efavirenz- and Rifampicin-Isoniazid–Based Antituberculosis Treatment Drug-Drug Interaction on CYP2B6 and NAT2 Genetic Polymorphisms: ANRS 12154 Study in Cambodia

作者：Julie Bertrand, Céline Verstuyft, Monidarin Chou, Laurence Borand, Phalla Chea, Kuy Huong Nay, F.–X. Blanc, France Mentré, Anne‐Marie Taburet, the CAMELIA (ANRS 1295-CIPRA KH001) Study Group, Sok Thim, Anne E. Goldfeld, F.–X. Blanc, Didier Laureillard, Olivier Marcy, Marcelo Fernandez, Sarin Chan, Eric Nerrienet, Sirenda Vong, Yoann Madec, Claire Rekacewicz, Manil Saman, Chanthy Leng, Sao Sarady Ay, Phearavin Pheng, Lay Heng Chan, Sophea Suom, Nimul Roat Men, Kerya Phon, Sopheap Kun, Sokéo Chea, Pichda Toeung, Yong Yoeun, Keo Kunthea Dy, Pheakun Kry, Keolinelyanneth Meardey, Bertrand Guillard, Chanthan Srey, Chantary Keo, Sopheak Ngin, Borann Sar, Janin Nouhin, Sreymom Ken, Kimlay Chea, Kunthea Kong, Sophy Tun, Leakhena Say, Kim Eng Sok, Hok Kean Lim · 发表于：The Journal of Infectious Diseases · 年份：2013 · DOI：10.1093/infdis/jit466 · 被引用次数：50 · 研究领域：HIV/AIDS drug development and treatment、Pneumocystis jirovecii pneumonia detection and treatment、HIV Research and Treatment

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.