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.

Figures

Fig 1

Peak concentrations (boxes show IQR divided by the median) for each of the antituberculosis drugs according to the different dosing weight bands (indicated by the number of tablets: 2, 3, 4, or 5) at each sampling day (days 1, 8, 15, and 29). Antituberculosis treatment was delivered to patients in 2 (n = 1 [2%]), 3 (n = 26 [43%]), 4 (n = 26 [43%]), or 5 (n = 7 [12%]) tablets according to baseline body weight. The median (IQR) doses for rifampin, isoniazid, pyrazinamide, and ethambutol in the respective weight bands are shown beneath each graph. The dashed lines indicate the lower limit of the target peak concentration ranges (27).

Fig 2

Doses of the key drugs rifampin and isoniazid, expressed in milligrams per kilogram of body weight as recommended by WHO guidelines (39) (rifampin, upper solid black line; isoniazid, lower solid gray line) and the American Thoracic Society (3) (rifampin, fine dotted line; isoniazid, gray dashed line) and those used in seminal early studies (10) (rifampin, black dashed line; isoniazid, gray dashed line).