Evidence-Based Design of Fixed-Dose Combinations: Principles and Application to Pediatric Anti-Tuberculosis Therapy
Year: 2017
Type: article
Abstract: BACKGROUND AND OBJECTIVES: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.
Source: Clinical Pharmacokinetics
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,990
Funders: European Federation of Pharmaceutical Industries and Associations, European Commission, National Research Foundation, Swedish Foundation for International Cooperation in Research and Higher Education, Vetenskapsrådet, Universiteit Stellenbosch, Innovative Medicines Initiative, National Institutes of Health, National Institute of Child Health and Human Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G1073258374, G1732308444, G2051892919, G2109279595, G2560876791, Optimal dosing of 1st line antituberculosis and antiretroviral drugs in children, Model-based preclinical development of anti-tuberculosis drug combinations, G2973790809, G3207356259, G393177772, G5112945946, G5586235199, G5702163051, G697251206, G729914321, G7966348980, G944422060
OpenAlex ID: W2743570739