Preclinical Bioavailability Strategy for Decisions on Clinical Drug Formulation Development: An In Depth Analysis

• DOI: 10.1021/acs.molpharmaceut.8b00172
• Publication Date: 2018-05-25T19:35:31Z
• Authors: An Van den Bergh; Sandy Van Hemelryck; Jan Bevernage; Achiel Van Peer; Marcus Brewster; Claire Mackie; Erik Mannaert
• Keywords: Biopharmaceutical; Bioequivalence

The aim of the presented retrospective analysis was to verify whether a previously proposed Janssen Biopharmaceutical Classification System (BCS)-like decision tree, based on preclinical bioavailability data solution and suspension formulation, would facilitate informed making clinical formulation development strategy. In addition, predictive value (in vitro) selection criteria, such as solubility, human permeability, and/or dose number (Do), were evaluated, potentially reducing additional supporting studies in animals. absolute (Fabs,sol) relative (Frel, susp/sol) an oral suspension, respectively, rat or dog anticipated BCS classification analyzed for 89 compounds with 28 these having Frel,susp/sol Fabs,sol both at doses around 10 5 mg/kg, respectively. outcomes aligned well BCS-like upon solubility active pharmaceutical ingredient (API) biorelevant media, while alignment less clear rat. A clinically tested formulations set 12 confirmed that animal bioavailability-based tree facilitated decisions type, most discriminative species. Furthermore, showed Do standard 100 mg aqueous similar type have been selected compared one suggested by data. However, concept did not distinguish between enhancing enabling does consider API hence, it produces risk slow incomplete absorption poor intestinal permeability. cases where estimations are available early development, calculations, used guide selection, may be performed more relevant instead dose. It should noted, however, unlike late there is uncertainty estimated phases because usually only vitro vivo pharmacology models, biomarker information. Therefore, strategies adjusted emerging doses. summary, combined information vitro-assessed suspension/solution relation intravenous clearance, metabolic pathways can strengthen decisions. always fully conventional (e.g., taken food), enhancing, formulations. avoid overinvestment complex expensive technologies, useful evaluate (and/or permeability) under fasted fed conditions, part first-in-human study subsequent study, high Do, low Frel,susp/sol, caused precipitation solubilized API.