Pharmacokinetics of rifampin and isoniazid in tuberculosis-HIV-coinfected patients receiving nevirapine- or efavirenz-based antiretroviral treatment

Antimicrob Agents Chemother. 2014 Jun;58(6):3182-90. doi: 10.1128/AAC.02379-13. Epub 2014 Mar 24.

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.).

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alkynes
  • Antitubercular Agents / adverse effects
  • Antitubercular Agents / pharmacokinetics*
  • Antitubercular Agents / therapeutic use*
  • Benzoxazines / adverse effects
  • Benzoxazines / therapeutic use*
  • Coinfection
  • Cyclopropanes
  • Female
  • HIV Infections / complications*
  • HIV Infections / drug therapy*
  • Half-Life
  • Humans
  • Isoniazid / adverse effects
  • Isoniazid / pharmacokinetics*
  • Isoniazid / therapeutic use*
  • Male
  • Middle Aged
  • Nevirapine / adverse effects
  • Nevirapine / therapeutic use*
  • Reverse Transcriptase Inhibitors / therapeutic use*
  • Rifampin / adverse effects
  • Rifampin / pharmacokinetics*
  • Rifampin / therapeutic use*
  • Treatment Outcome
  • Tuberculosis / complications*
  • Tuberculosis / drug therapy*
  • Young Adult

Substances

  • Alkynes
  • Antitubercular Agents
  • Benzoxazines
  • Cyclopropanes
  • Reverse Transcriptase Inhibitors
  • Nevirapine
  • efavirenz
  • Isoniazid
  • Rifampin

Associated data

  • ClinicalTrials.gov/NCT00495326