Pharmacokinetics of rifampicin, pyrazinamide and ethambutol in Tanzanian tuberculosis patients

Alma Tostmann12, Charles M. Mtabho3, Jossy van den Boogaard2 3, Hadija H. Semvua3, Constantine F. Irongo", Gibson S. Kibiki3, Martin J. Boeree 1 2, Rob E. Aarnoutse 5
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Even though first line standard TB treatment with isoniazid, rifampicin, pyrazinamide and ethambutol is able to cure more than 95% of the patients infected with normal sensitive Mycobacteria tuberculosis, often cure rates are lower. Pharmacokinetic variability may contribute to suboptimal response to TB drugs. There is limited data about the pharmacokinetics of TB drugs used in sub-Saharan African TB patients. To get more insight in determinants associated with PK of TB treatment and to be able to design study interventions that could improve plasma levels without increasing the risk on unwanted toxic effects, more pharmacokinetic data of TB drugs are needed.


We conducted a descriptive pharmacokinetic study in 20 Tanzanian TB patients who were recruited at an out-patient TB treatment clinic in Moshi, northern Tanzania. All patients were in the intensive phase of treatment and on medication for at least two weeks. Serial venous blood samples were collected just prior to, and at 1, 2, 3, 4, 6, 8, 10 and 24 hours after observed TB drug intake in the morning. All patients had breakfast within half an hour after drug intake. Peak plasma concentrations (Cmax) and area under the curve (AUC024h) were the main pharmacokinetic parameters.


The geometric mean Cmax was 8.9 mg/L (range 5.9-14.8) for rifampicin, 38.2 mg/L (range 29.0-50.8) for pyrazinamide and 3.3 mg/L (range 2.2-5.8) for ethambutol. The geometric mean AUC0 2ih was 39.9 h*mg/L (range 27.4-68.3) for rifampicin, 344 h*mg/L (range 209-610) for pyrazinamide and 20.2 h*mg/L (range 13.4-32.0) for ethambutol. 25% of the patients had a peak plasma level below the reference range of rifampicin (8-24 mg/L). The C of pyrazinamide and ethambutol were within the reference range, 20-50 mg/L and 2-6 mg/L, respectively. No differences in pharmacokinetic parameters were observed between HIV positive (n=7,ยท 35%) and HIV negative patients.


This is the first report of full 24-hour pharmacokinetics of TB drugs from this region. It could be questioned whether low rifampicin peak plasma concentrations are related to low treatment response rates: the relation between pharmacokinetics and pharmacodynamics in TB treatment are not fully understood and warrants more research. Currently, several clinical trials about a high dose of rifampicin (900 and 1200 mg) are m preparation in the Kilimanjaro Region.