title: Pharmacokinetics of rifampin and isoniazid in tuberculosis-HIV-coinfected patients receiving nevirapine- or efavirenz-based antiretroviral treatment.
abstract: This is a substudy of the Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS) Comparison of Nevirapine and Efavirenz for the Treatment of HIV-TB Co-infected Patients (ANRS 12146-CARINEMO) trial, which assessed the pharmacokinetics of rifampin or isoniazid with or without the coadministration of nonnucleoside reverse transcriptase inhibitor-based HIV antiretroviral therapy in HIV-tuberculosis-coinfected patients in Mozambique. Thirty-eight patients on antituberculosis therapy based on rifampin and isoniazid participated in the substudy (57.9% males; median age, 33 years; median weight, 51.9 kg; median CD4(+) T cell count, 104 cells/μl; median HIV-1 RNA load, 5.5 log copies/ml). The daily doses of rifampin and isoniazid were 10 and 5 mg/kg of body weight, respectively. Twenty-one patients received 200 mg of nevirapine twice a day (b.i.d.), and 17 patients received 600 mg of efavirenz once a day (q.d.) in combination with lamivudine and stavudine from day 1 until the end of the study. Blood samples were collected at regular time-dosing intervals after morning administration of a fixed-dose combination of rifampin and isoniazid. When rifampin was administered alone, the median maximum concentration of drug in serum (Cmax) and the area under the concentration-time curve (AUC) at steady state were 6.59 mg/liter (range, 2.70 to 14.07 mg/liter) and 27.69 mg · h/liter (range, 11.41 to 109.75 mg · h/liter), respectively. Concentrations remained unchanged when rifampin was coadministered with nevirapine or efavirenz. When isoniazid was administered alone, the median isoniazid Cmax and AUC at steady state were 5.08 mg/liter (range, 1.26 to 11.51 mg/liter) and 20.92 mg · h/liter (range, 7.73 to 56.95 mg · h/liter), respectively. Concentrations remained unchanged when isoniazid was coadministered with nevirapine; however, a 29% decrease in the isoniazid AUC was observed when isoniazid was combined with efavirenz. The pharmacokinetic parameters of rifampin and isoniazid when coadministered with nevirapine or efavirenz were not altered to a clinically significant extent in these severely immunosuppressed HIV-infected patients. Patients experienced favorable clinical outcomes. (This study has been registered at ClinicalTrials.gov under registration no. NCT00495326.).
authors.affiliation: Instituto Nacional de Saúde, Ministério da Saúde, Maputo, Mozambique Instituto de Pesquisa Clínica Evandro Chagas, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.
authors.forename: N B
authors.initials: NB
authors.lastname: Bhatt
authors.affiliation: Assistance Publique Hôpitaux de Paris, Bicêtre Hospital, Hôpitaux Universitaires Paris Sud, Clinical Pharmacy, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Barau
authors.affiliation: Assistance Publique Hôpitaux de Paris, Bicêtre Hospital, Hôpitaux Universitaires Paris Sud, Clinical Pharmacy, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Amin
authors.affiliation: Epicentre, Paris, France.
authors.forename: E
authors.initials: E
authors.lastname: Baudin
authors.affiliation: Instituto Nacional de Saúde, Ministério da Saúde, Maputo, Mozambique.
authors.forename: B
authors.initials: B
authors.lastname: Meggi
authors.affiliation: Epicentre, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Silva
authors.affiliation: Assistance Publique Hôpitaux de Paris, Bicêtre Hospital, Hôpitaux Universitaires Paris Sud, Clinical Pharmacy, Paris, France.
authors.forename: V
authors.initials: V
authors.lastname: Furlan
authors.affiliation: Instituto de Pesquisa Clínica Evandro Chagas, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.
authors.forename: B
authors.initials: B
authors.lastname: Grinsztejn
authors.affiliation: Assistance Publique Hôpitaux de Paris, Bicêtre Hospital, Hôpitaux Universitaires Paris Sud, Clinical Pharmacy, Paris, France EA4123, Faculty of Pharmacy, University Paris Sud, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Barrail-Tran
authors.affiliation: Epicentre, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Bonnet
authors.affiliation: Assistance Publique Hôpitaux de Paris, Bicêtre Hospital, Hôpitaux Universitaires Paris Sud, Clinical Pharmacy, Paris, France anne-marie.taburet@bct.aphp.fr.
authors.forename: A M
authors.initials: AM
authors.lastname: Taburet
mesh_terms: D000328:Adult; D000480:Alkynes; D000995:Antitubercular Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D048588:Benzoxazines / Q000009:adverse effects / Q000627:therapeutic use*; D060085:Coinfection; D003521:Cyclopropanes; D005260:Female; D015658:HIV Infections / Q000150:complications* / Q000188:drug therapy*; D006207:Half-Life; D006801:Humans; D007538:Isoniazid / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D019829:Nevirapine / Q000009:adverse effects / Q000627:therapeutic use*; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D012293:Rifampin / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D016896:Treatment Outcome; D014376:Tuberculosis / Q000150:complications* / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D000480:Alkynes; D000995:Antitubercular Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D018894:Reverse Transcriptase Inhibitors; D019829:Nevirapine; C098320:efavirenz; D007538:Isoniazid; D012293:Rifampin