title: Reduced antituberculosis drug concentrations in HIV-infected patients who are men or have low weight: implications for international dosing guidelines.
abstract: Reduced antituberculosis drug concentrations may contribute to unfavorable treatment outcomes among HIV-infected patients with more advanced immune suppression, and few studies have evaluated pharmacokinetics of the first-line antituberculosis drugs in such patients given fixed-dose combination tablets according to international guidelines using weight bands. In this study, pharmacokinetics were evaluated in 60 patients on 4 occasions during the first month of antituberculosis therapy. Multilevel linear mixed-effects regression analysis was used to examine the effects of age, sex, weight, drug dose/kilogram, CD4(+) lymphocyte count, treatment schedule (5 versus 7 days/week), and concurrent antiretrovirals (efavirenz plus lamivudine plus zidovudine) on the area under the concentration-time curve from 0 to 12 h (AUC(0-12)) of the respective antituberculosis drugs and to compare AUC(0-12)s at day 8, day 15, and day 29 with the day 1 AUC(0-12). Median (range) age, weight, and CD4(+) lymphocyte count were 32 (18 to 47) years, 55.2 (34.4 to 98.7) kg, and 252 (12 to 500)/μl. For every 10-kg increase in body weight, the predicted day 29 AUC(0-12) increased by 14.1% (95% confidence interval [CI], 7.5, 20.8), 14.1% (95% CI, -0.7, 31.1), 6.1% (95% CI, 2.7, 9.6) and 6.0% (95% CI, 0.8, 11.3) for rifampin, isoniazid, pyrazinamide, and ethambutol, respectively. Males had day 29 AUC(0-12)s 19.3% (95% CI, 3.6, 35.1) and 14.0% (95% CI, 5.6, 22.4) lower than females for rifampin and pyrazinamide, respectively. Level of immune suppression and concomitant antiretrovirals had little effect on the concentrations of the antituberculosis agents. As they had reduced drug concentrations, it is important to review treatment responses in patients in the lower weight bands and males to inform future treatment guidelines, and revision of doses in these patients should be considered.
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa. helen.mcilleron@uct.ac.za
authors.forename: Helen
authors.initials: H
authors.lastname: McIlleron
authors.forename: Roxana
authors.initials: R
authors.lastname: Rustomjee
authors.forename: Mahnaz
authors.initials: M
authors.lastname: Vahedi
authors.forename: Thuli
authors.initials: T
authors.lastname: Mthiyane
authors.forename: Paolo
authors.initials: P
authors.lastname: Denti
authors.forename: Catherine
authors.initials: C
authors.lastname: Connolly
authors.forename: Wasima
authors.initials: W
authors.lastname: Rida
authors.forename: Alexander
authors.initials: A
authors.lastname: Pym
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Smith
authors.forename: Philip C
authors.initials: PC
authors.lastname: Onyebujoh
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000995:Antitubercular Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001724:Birth Weight / Q000187:drug effects; D018432:Drug Resistance, Multiple; D005260:Female; D015658:HIV Infections / Q000378:metabolism*; D006801:Humans; D007538:Isoniazid / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D011718:Pyrazinamide / Q000493:pharmacokinetics / Q000627:therapeutic use; D012189:Retrospective Studies; D012293:Rifampin / Q000493:pharmacokinetics / Q000627:therapeutic use; D012737:Sex Factors; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D011718:Pyrazinamide; D007538:Isoniazid; D012293:Rifampin