Pharmacokinetic Parameters of Co-trimoxazole

NCT01832987 | Completed Phase 2

• 1 other identifier: SXT8469
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

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with dried blood spot (DBS) analysis, the exposure to co-trimoxazole could be analyzed with only some blood drops withdrawn with a finger prick on paper.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 Furthermore, the analysis of dried blood spots will be clinically validated by comparing results of blood samples withdrawn from venous blood versus withdrawn by finger prick and transferred to filter paper.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

Conditions

Tuberculosis

Keywords

co-trimoxazole; sulfamethoxazole; tuberculosis; pharmacokinetics

Outcome Measures

Primary Outcomes (1)

• AUC

  Measuring the AUC over 24 hours of sulfamethoxazole, one out of two compounds of co-trimoxazole after obtaining steady state (960 mg co-trimoxazole).

  4th, 5th or 6th day

Secondary Outcomes (2)

• Determination of the AUC/MIC and T>MIC

  4th, 5th or 6th day

• Validating DBS analysis

  4th, 5th or 6th day

Other Outcomes (1)

• Population pharmacokinetic model and limited sampling strategies

  4th, 5th or 6th day

Study Arms (1)

co-trimoxazole

EXPERIMENTAL

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

Drug: co-trimoxazole

Interventions

co-trimoxazole DRUG

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

Also known as: Sulfamethoxazole/trimethoprim

co-trimoxazole

Eligibility Criteria

• Age: 18 Years - 64 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• TB Patients with normal susceptible Mycobacterium tuberculosis
• Patients older than 17 and younger than 64 years.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University Medical Center Groningen: lead

Study Sites (1)

UMCG - Tuberculosis Center

Groningen, Netherlands

Location

Related Publications (4)

• 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.

  PMID: 23100498 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.

  PMID: 22127584 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.

  PMID: 19564358 BACKGROUND

• 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.

  PMID: 27067336 DERIVED

MeSH Terms

Conditions

Tuberculosis

Interventions

Trimethoprim, Sulfamethoxazole Drug Combination

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Sulfamethoxazole; Benzenesulfonamides; Sulfonamides; Amides; Organic Chemicals; Sulfanilamides; Aniline Compounds; Amines; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sulfones; Sulfur Compounds; Trimethoprim; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Drug Combinations; Pharmaceutical Preparations

Study Officials

• Jan-Willem C Alffenaar, PharmD PhD

  University Medical Center Groningen

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: PhD PharmD Clinical Pharmacologist

Study Record Dates

• First Submitted: April 11, 2013
• First Posted: April 16, 2013
• Study Start: October 1, 2013
• Primary Completion: August 1, 2014
• Study Completion: August 1, 2014
• Last Updated: September 16, 2014

Record last verified: 2014-09

Locations

NL (1)