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Effect of efavirenz-based antiretroviral therapy and high-dose rifampicin on the pharmacokinetics of isoniazid and acetyl-isoniazid

2018; Oxford University Press; Linguagem: Inglês

10.1093/jac/dky378

1460-2091

Maxwell Chirehwa, Helen McIlleron, Lubbe Wiesner, Dissou Affolabi, Oumou Bah‐Sow, Corinne Merle, Paolo Denti, Alimatou N’Diaye, Ibrahima Mariétou Mbaye, Bouke C. de Jong, Séverin Anagonou, Salim Diatema, Ibrahima Khalil Gomina, Severin Gossa, Blanche Tanimomo, Wilfried Bekou, Tatiana Galpérine, André Furco, Mouctar Diallo, Boubacar Bah, Falilou Bah, Nene S. Barry, Abdourahmane Barry, Sadjo Barry, Mamadou Telly Barry, Aissatou Bah Sylla, Alpha Mamadou Barry, Marie Sarr, Ndéye Fatou Ngom, Kine Ndiaye, Diama Sakho, Justine Ngom, Fatoumata Ba, Amadou Seck, André Furco, Sian Floyd, Keith Branson, Judith R. Glynn, D. L. Phillips, Nadia Oubaya, Caroline Saint-Martin,

Pneumocystis jirovecii pneumonia detection and treatment

To describe the pharmacokinetics of isoniazid and acetyl-isoniazid in TB/HIV-coinfected patients, and assess the effects of efavirenz co-administration and a 50% increase in the dose of rifampicin on the pharmacokinetic parameters of isoniazid and acetyl-isoniazid.TB/HIV-coinfected patients participating in the three-treatment-arm RAFA randomized controlled trial conducted in West Africa were recruited into the pharmacokinetics sub-study. Five serial blood samples were collected on a single visit between 4 and 8 weeks after initiation of antituberculosis treatment. Concentration-time data for isoniazid and acetyl-isoniazid were analysed using non-linear mixed-effects models.Isoniazid concentrations from 150 patients were available for analysis, and 79 of these (53%) also had concentrations of acetyl-isoniazid. Isoniazid pharmacokinetics was best described with a two-compartment disposition model with lagged first-order absorption and elimination using a semi-mechanistic model describing hepatic extraction. The model identified two elimination pathways, separating formation of acetyl-isoniazid from other routes of metabolism. The predicted AUC0-24 is reduced by 29% in patients who are fast acetylators of isoniazid and receiving efavirenz-based ART (6.73 versus 4.68 mg·h/L). In slow acetylators, efavirenz-based ART had no effect on isoniazid exposure (AUC0-24 = 17.5 mg·h/L).Efavirenz-based ART affects the acetylation metabolic pathway amongst rapid acetylators, resulting in reduced exposure to isoniazid. Pharmacokinetics of isoniazid and acetyl-isoniazid were not influenced by the 50% increase in rifampicin dose.