Pharmacokinetic Evaluation of Sulfamethoxazole at 800 Milligrams Once Daily in the Treatment of Tuberculosis
SourceAntimicrobial Agents and Chemotherapy, 60, 7, (2016), pp. 3942-3947
Article / Letter to editor
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Antimicrobial Agents and Chemotherapy
SubjectRadboudumc 4: lnfectious Diseases and Global Health RIHS: Radboud Institute for Health Sciences
For treatment of multidrug-resistant tuberculosis (MDR-TB), there is a scarcity of antituberculosis drugs. Co-trimoxazole is one of the available drug candidates, and it is already frequently coprescribed for TB-HIV-coinfected patients. However, only limited data are available on the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of co-trimoxazole in TB patients. The objective of this study was to evaluate the PK parameters and in vitro PD data on the effective part of co-trimoxazole: sulfamethoxazole. In a prospective PK study in patients infected with drug-susceptible Mycobacterium tuberculosis (drug-susceptible TB patients) (age, >18), sulfamethoxazole-trimethoprim (SXT) was administered orally at a dose of 960 mg once daily. One-compartment population pharmacokinetic modeling was performed using MW\Pharm 3.81 (Mediware, Groningen, The Netherlands). The area under the concentration-time curve for the free, unbound fraction of a drug (fAUC)/MIC ratio and the period in which the free concentration exceeded the MIC (fT > MIC) were calculated. Twelve patients received 960 mg co-trimoxazole in addition to first-line drugs. The pharmacokinetic parameters of the population model were as follows (geometric mean +/- standard deviation [SD]): metabolic clearance (CLm), 1.57 +/- 3.71 liters/h; volume of distribution (V), 0.30 +/- 0.05 liters . kg lean body mass(-1); drug clearance/creatinine clearance ratio (fr), 0.02 +/- 0.13; gamma distribution rate constant (ktr_po), 2.18 +/- 1.14; gamma distribution shape factor (n_po), 2.15 +/- 0.39. The free fraction of sulfamethoxazole was 0.3, but ranged between 0.2 and 0.4. The median value of the MICs was 9.5 mg/liter (interquartile range [IQR], 4.75 to 9.5), and that of thefAUC/MIC ratio was 14.3 (IQR, 13.0 to 17.5). The percentage of fT > MIC ranged between 43 and 100% of the dosing interval. The PK and PD data from this study are useful to explore a future dosing regimen of co-trimoxazole for MDR-TB treatment. (This study has been registered at ClinicalTrials.gov under registration no. NCT01832987.).
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