Pharmacokinetic Parameters of Co-trimoxazole

Summary

Rationale: Treatment of multidrug or extensively drug resistant tuberculosis (MDR/XDR-TB) is a real challenge as failure in response to treatment and serious side-effects are frequently encountered. New, more effective drugs with less side effects are therefore urgently needed to solve this problem. Although several new drugs against TB are in the pipeline, physicians currently have limited treatment options for treatment of complicated MDR/XDR-TB cases. Therefore, drugs developed and labeled for other infectious diseases are evaluated for TB. Co-trimoxazole consists of sulfamethoxazole and trimethoprim. Sulfamethoxazole could be effective in the treatment of tuberculosis as shown by Forgacs et al. and Huang et al. Furthermore, with dried blood spot (DBS) analysis, the exposure to co-trimoxazole could be analyzed with only some blood drops withdrawn with a finger prick on paper. This paper is suitable for storage, transportation and subsequently analysis without additional cooling or storage requirements. Objective: The main objective of this prospective clinical trial is to evaluate pharmacokinetics of 960 mg co-trimoxazole in TB patients. This clinical trial will provide important information on PK of co-trimoxazole in TB patients for future studies. The second objective is to calculate the T\>MIC and AUC0-24h/Minimal inhibitory concentration (MIC) ratio as efficacy predicting parameter. Furthermore, the analysis of dried blood spots will be clinically validated by comparing results of blood samples withdrawn from venous blood versus withdrawn by finger prick and transferred to filter paper. Retrospectively, data from this study can be used for limited sampling strategies for co-trimoxazole based on a pharmacokinetic population model constructed from the full PK curves of the patients. Study design: A prospective pharmacokinetic study. Study population: 12 TB patients. Intervention: on 4 to 6 days, 960 mg co-trimoxazole daily will be added to the normal treatment regimen. Main study parameters/endpoints: The pharmacokinetic parameters (Vd, Cl, AUC, etc) of co-trimoxazole are the primary endpoints of the study. The T\>MIC and AUC0-24h/Minimal inhibitory concentration (MIC) ratio are most likely the best predictive parameters for efficacy of co-trimoxazole treatment and will be calculated for a range of M tuberculosis isolates.

Timeline

Start

2013-10

Primary completion

2014-08

Completion

2014-08

Publications

• Background Alsaad N, van Altena R, Pranger AD, van Soolingen D, de Lange WC, van der Werf TS, Kosterink JG, Alffenaar JW. Evaluation of co-trimoxazole in the treatment of multidrug-resistant tuberculosis. Eur Respir J. 2013 Aug;42(2):504-12. doi: 10.1183/09031936.00114812. Epub 2012 Oct 25.
• Background Huang TS, Kunin CM, Yan BS, Chen YS, Lee SS, Syu W Jr. Susceptibility of Mycobacterium tuberculosis to sulfamethoxazole, trimethoprim and their combination over a 12 year period in Taiwan. J Antimicrob Chemother. 2012 Mar;67(3):633-7. doi: 10.1093/jac/dkr501. Epub 2011 Nov 29.
• Background Forgacs P, Wengenack NL, Hall L, Zimmerman SK, Silverman ML, Roberts GD. Tuberculosis and trimethoprim-sulfamethoxazole. Antimicrob Agents Chemother. 2009 Nov;53(11):4789-93. doi: 10.1128/AAC.01658-08. Epub 2009 Jun 29.
• Alsaad N, Dijkstra JA, Akkerman OW, de Lange WC, van Soolingen D, Kosterink JG, van der Werf TS, Alffenaar JW. Pharmacokinetic Evaluation of Sulfamethoxazole at 800 Milligrams Once Daily in the Treatment of Tuberculosis. Antimicrob Agents Chemother. 2016 Jun 20;60(7):3942-7. doi: 10.1128/AAC.02175-15. Print 2016 Jul.

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