Pharmacokinetic Parameters of Co-trimoxazole

Sponsor

University Medical Center Groningen (Other)

Overall Status

Completed

CT.gov ID

NCT01832987

Collaborator

(none)

Enrollment

Location

Arm

Duration (Months)

1.2

Patients Per Site Per Month

Study Details

Study Description

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with dried blood spot (DBS) analysis, the exposure to co-trimoxazole could be analyzed with only some blood drops withdrawn with a finger prick on paper.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 Furthermore, the analysis of dried blood spots will be clinically validated by comparing results of blood samples withdrawn from venous blood versus withdrawn by finger prick and transferred to filter paper.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

Condition or Disease	Intervention/Treatment	Phase
Tuberculosis	Drug: co-trimoxazole	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

12 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Official Title:

Pharmacokinetic Parameters of 960 mg Co-trimoxazole Once Daily in Patients With Tuberculosis

Study Start Date :

Oct 1, 2013

Actual Primary Completion Date :

Aug 1, 2014

Actual Study Completion Date :

Aug 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: co-trimoxazole On 4, 5 or 6 consecutive days, 960 mg co-trimoxazole (oral) will be added to the normal treatment of tuberculosis.	Drug: co-trimoxazole On 4, 5 or 6 consecutive days, co-trimoxazole 960 mg will be added to the normal treatment regimen Other Names: Sulfamethoxazole/trimethoprim

Arm

Intervention/Treatment

Experimental: co-trimoxazole

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

Drug: co-trimoxazole

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

Other Names:

Sulfamethoxazole/trimethoprim

Outcome Measures

Primary Outcome Measures

AUC [4th, 5th or 6th day]
Measuring the AUC over 24 hours of sulfamethoxazole, one out of two compounds of co-trimoxazole after obtaining steady state (960 mg co-trimoxazole).

Secondary Outcome Measures

Determination of the AUC/MIC and T>MIC [4th, 5th or 6th day]
Determination of the area under the curve divided by the mean inhibitory concentration and the time above MIC.
Validating DBS analysis [4th, 5th or 6th day]
Validating the analysis of dried blood spots for therapeutic drug monitoring by comparing the concentration measured in venous blood with the concentration measured using the dried blood spot method.

Other Outcome Measures

Population pharmacokinetic model and limited sampling strategies [4th, 5th or 6th day]
Developing a population pharmacokinetic model to predict pharmacokinetic parameters of sulfamethoxazole. With this population pharmacokinetic model, a limited sampling strategy will be developed.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 64 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.