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- Title
Evidence-Based Design of Fixed-Dose Combinations: Principles and Application to Pediatric Anti-Tuberculosis Therapy.
- Authors
Svensson, Elin M.; Yngman, Gunnar; Denti, Paolo; McIlleron, Helen; Kjellsson, Maria C.; Karlsson, Mats O.
- Abstract
<bold>Background and Objectives: </bold>Fixed-dose combination formulations where several drugs are included in one tablet are important for the implementation of many long-term multidrug therapies. The selection of optimal dose ratios and tablet content of a fixed-dose combination and the design of individualized dosing regimens is a complex task, requiring multiple simultaneous considerations.<bold>Methods: </bold>In this work, a methodology for the rational design of a fixed-dose combination was developed and applied to the case of a three-drug pediatric anti-tuberculosis formulation individualized on body weight. The optimization methodology synthesizes information about the intended use population, the pharmacokinetic properties of the drugs, therapeutic targets, and practical constraints. A utility function is included to penalize deviations from the targets; a sequential estimation procedure was developed for stable estimation of break-points for individualized dosing. The suggested optimized pediatric anti-tuberculosis fixed-dose combination was compared with the recently launched World Health Organization-endorsed formulation.<bold>Results: </bold>The optimized fixed-dose combination included 15, 36, and 16% higher amounts of rifampicin, isoniazid, and pyrazinamide, respectively. The optimized fixed-dose combination is expected to result in overall less deviation from the therapeutic targets based on adult exposure and substantially fewer children with underexposure (below half the target).<bold>Conclusion: </bold>The development of this design tool can aid the implementation of evidence-based formulations, integrating available knowledge and practical considerations, to optimize drug exposures and thereby treatment outcomes.
- Subjects
TUBERCULOSIS in children; ANTITUBERCULAR agents; DRUG dosage; EVIDENCE-based medicine; HEALTH outcome assessment; THERAPEUTICS
- Publication
Clinical Pharmacokinetics, 2018, Vol 57, Issue 5, p591
- ISSN
0312-5963
- Publication type
journal article
- DOI
10.1007/s40262-017-0577-6