Clinical investigation of the biopharmaceutical characteristics of nifurtimox tablets - Implications for quality control and application.

Autor: Stass H; Bayer AG, Research & Development - Pharmaceuticals, Clinical PK CV, Building 0431 - 403, 42096 Wuppertal, Germany. Electronic address: heino.stass@bayer.com., Just S; Bayer AG, Research & Development - Pharmaceuticals, Clinical PK CV, Building 0431 - 403, 42096 Wuppertal, Germany., Weimann B; Chrestos Concept GmbH & Co. KG, 45131 Essen, Germany., Ince I; Bayer AG, 51368 Leverkusen, Germany., Willmann S; Bayer AG, Research & Development - Pharmaceuticals, Clinical PK CV, Building 0431 - 403, 42096 Wuppertal, Germany., Feleder E; FP Clinical Pharma, Buenos Aires, Argentina., Freitas C; Bayer AG, Research & Development - Pharmaceuticals, Clinical PK CV, Building 0431 - 403, 42096 Wuppertal, Germany., Yerino G; FP Clinical Pharma, Buenos Aires, Argentina., Münster U; Bayer AG, Research & Development - Pharmaceuticals, Clinical PK CV, Building 0431 - 403, 42096 Wuppertal, Germany.
Jazyk: angličtina
Zdroj: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences [Eur J Pharm Sci] 2021 Nov 01; Vol. 166, pp. 105940. Date of Electronic Publication: 2021 Jul 12.
DOI: 10.1016/j.ejps.2021.105940
Abstrakt: Nifurtimox is approved in Chagas disease and has been used in endemic countries since the 1960s. Nifurtimox, available as a 120 mg tablet, is administered with food typically three times daily, and dose is adjusted for age and bodyweight. Accurately or reproducibly fragmenting the 120 mg tablet for dose adjustment in young children and those with low bodyweight is problematic. Based on the existing tablet formulation, new nifurtimox 30 mg and 120 mg tablets have been developed in a format that can be divided accurately into 15 mg and 60 mg fragments. In adults with chronic Chagas disease, we investigated whether nifurtimox bioavailability is affected by tablet dissolution rate, and whether different diets affect nifurtimox bioavailability. In an open-label, three-period cross-over study (n=36; ClinicalTrials.gov, NCT03350295), patients randomly received three 30 mg tablet formulations (slow, medium, or fast dissolution; a 4 × 30 mg dose of one formulation per period). In an open-label, four-period cross-over study (n=24; ClinicalTrials.gov, NCT03334838) patients randomly fasted or received one of three meal types (high-fat/high-calorie, low-fat, dairy-based) before ingesting nifurtimox (a 4 × 30 mg dose per period). Acceptance criteria for no difference between groups were 90% confidence intervals (CIs) of exposure ratios in the range 0.8-1.25. Nifurtimox bioavailability was unaffected by tablet dissolution kinetics. Ratios of area under the curve at final assessment (AUC (0-tlast) [90% CI]) were: fast/medium dissolution, 1.061 (0.990-1.137); slow/medium dissolution, 0.964 (0.900-1.033); fast/slow dissolution, 1.100 (1.027-1.179). Compared with a fasting state, nifurtimox bioavailability increased by 73% after a high-fat/high-calorie meal (AUC (0-tlast) ratio [90% CI], 1.732 [1.581-1.898]); smaller increases were seen with the other meal types (low-fat: 1.602 [1.462-1.755]; dairy-based: 1.340 [1.222-1.468]). Although type of diet can affect bioavailability, taking nifurtimox with food is most important.
(Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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