title: Pharmacokinetic Evaluation of Sulfamethoxazole at 800 Milligrams Once Daily in the Treatment of Tuberculosis.
abstract: 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 (ƒAUC)/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 theƒAUC/MIC ratio was 14.3 (IQR, 13.0 to 17.5). The percentage of ƒT > 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.).
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands.
authors.forename: N
authors.initials: N
authors.lastname: Alsaad
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands.
authors.forename: J A
authors.initials: JA
authors.lastname: Dijkstra
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases and Tuberculosis, Groningen, The Netherlands University of Groningen, University Medical Center Groningen, Tuberculosis Center Beatrixoord, Haren, The Netherlands.
authors.forename: O W
authors.initials: OW
authors.lastname: Akkerman
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases and Tuberculosis, Groningen, The Netherlands University of Groningen, University Medical Center Groningen, Tuberculosis Center Beatrixoord, Haren, The Netherlands.
authors.forename: W C M
authors.initials: WC
authors.lastname: de Lange
authors.affiliation: National Tuberculosis Reference Laboratory, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands Radboud University Nijmegen Medical Center, Departments of Pulmonary Diseases and Medical Microbiology, Nijmegen, The Netherlands.
authors.forename: D
authors.initials: D
authors.lastname: van Soolingen
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands University of Groningen, Department of Pharmacy, Section Pharmacotherapy and Pharmaceutical Care, Groningen, The Netherlands.
authors.forename: J G W
authors.initials: JG
authors.lastname: Kosterink
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases and Tuberculosis, Groningen, The Netherlands University of Groningen, University Medical Center Groningen, Department of Internal Medicine/Infectious Diseases, Groningen, The Netherlands.
authors.forename: T S
authors.initials: TS
authors.lastname: van der Werf
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands j.w.c.alffenaar@umcg.nl.
authors.forename: J W C
authors.initials: JW
authors.lastname: Alffenaar
mesh_terms: D000328:Adult; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D000995:Antitubercular Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D011446:Prospective Studies; D013420:Sulfamethoxazole / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014376:Tuberculosis / Q000188:drug therapy* / Q000378:metabolism; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D000995:Antitubercular Agents; D013420:Sulfamethoxazole