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Tuberculosis | Pharmacokinetic Parameters of Co-trimoxazole

Tuberculosis research study

What is the primary objective of this study?

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with dried blood spot (DBS) analysis, the exposure to co-trimoxazole could be analyzed with only some blood drops withdrawn with a finger prick on paper.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 Furthermore, the analysis of dried blood spots will be clinically validated by comparing results of blood samples withdrawn from venous blood versus withdrawn by finger prick and transferred to filter paper.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.

Who is eligible to participate?

Inclusion Criteria: - TB Patients with normal susceptible Mycobacterium tuberculosis - Patients older than 17 and younger than 64 years. Exclusion Criteria: - Pregnancy or breast feeding - Patients with hypersensitivity to sulfonamide or trimethoprim - Concomitant treatment with vitamin K antagonists (acenocoumarol) - Patients with preexisting renal dysfunction or concomitant treatment of angiotensin converting enzyme inhibitors and potassium -sparing diuretics) that may exacerbate the hyperkalemic effect of SXT. - Patients treated with methotrexate, phenytoin, sulfonylureas (glibenclamide, gliclazide, glimepiride en tolbutamide) or procainamide hydrochloride. - Patients that have gastrointestinal complaints like diarrhea and vomiting (observed) - Patients that have experienced an adverse effect to SXT or similar antibiotic drugs. - Patients with HIV or AIDS.

Which medical condition, disease, disorder, syndrome, illness, or injury is researched?

Tuberculosis

Study Interventions

Interventions can include giving participants drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available or noninvasive approaches such as surveys, education, and interviews.

Drug:co-trimoxazoleOn 4, 5 or 6 consecutive days, co-trimoxazole 960 mg will be added to the normal treatment regimen

Study Arms

Research studies and clinical trials typically have two or more research arms. An arm is a group of people who receive the same treatment in the study.

co-trimoxazoleOn 4, 5 or 6 consecutive days, 960 mg co-trimoxazole (oral) will be added to the normal treatment of tuberculosis.

Study Status

Completed

Start Date: October 2013

Completed Date: August 2014

Phase: Phase 2

Type: Interventional

Design:

Primary Outcome: AUC

Secondary Outcome: Determination of the AUC/MIC and T>MIC

Study sponsors, principal investigator, and references

Principal Investigator: Jan-Willem C Alffenaar, PharmD PhD

Lead Sponsor: University Medical Center Groningen

Collaborator:

More information:https://clinicaltrials.gov/show/NCT01832987

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.

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