title: Use of preclinical dog studies and absorption modeling to facilitate late stage formulation bridging for a BCS II drug candidate.
abstract: Formulation changes are common during drug development either due to clinical or manufacturing considerations. These changes especially at later stages of drug development oftentimes raise questions on the potential impact of a new formulation on bioavailability. In this work, the preclinical assessment of formulation bridging risk for a Biopharmaceutics Classification System II development compound is presented. Early clinical studies were conducted using a liquid-filled capsule (LFC). To assess the feasibility of a conventional solid dosage form, an initial analysis was conducted using absorption modeling which indicated conventional formulation of micronized active pharmaceutical ingredient (API) could be a viable option. Subsequently, test formulations were prepared and tested in vivo in dogs. The solid formulations were able to match exposures of the LFC capsule in the dog model; in addition, a sensitivity to API PSD was observed in line with the modeling predictions. When tested in the clinic, the conventional solid formulation resulted in exposures of approximately 25% lower compared to the LFC on an equivalent dose basis; however, bridging with a small dose adjustment would be feasible. The outcome of the clinical study was better predicted by the modeling approach while the dog model appeared to somewhat overestimate absorption. Through the use of preclinical tools and modeling and simulation, a risk assessment around formulation bridging can be conducted and inform formulation decisions or subsequent clinical study designs.
authors.forename: Filippos
authors.initials: F
authors.lastname: Kesisoglou
mesh_terms: D000042:Absorption; D000818:Animals; D001702:Biopharmaceutics / Q000379:methods*; D002214:Capsules / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004285:Dogs; D004304:Dosage Forms; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D008297:Male; D008954:Models, Biological; D018570:Risk Assessment
chemical_list: D002214:Capsules; D004304:Dosage Forms
references.citation: Eur J Pharm Biopharm. 2010 Sep;76(1):95-104
references.pmid: 20576487
references.citation: Int J Pharm. 2010 Mar 15;387(1-2):103-9
references.pmid: 20006692
references.citation: AAPS J. 2013 Jan;15(1):143-58
references.pmid: 23139017
references.citation: Pharm Res. 1989 Apr;6(4):332-7
references.pmid: 2748521
references.citation: J Pharm Sci. 2010 Dec;99(12):4940-54
references.pmid: 20821390
references.citation: Int J Pharm. 2007 Aug 16;341(1-2):1-19
references.pmid: 17658228
references.citation: AAPS J. 2012 Dec;14(4):895-903
references.pmid: 22965626
references.citation: Adv Drug Deliv Rev. 2001 Oct 1;50 Suppl 1:S41-67
references.pmid: 11576695
references.citation: AAPS J. 2009 Mar;11(1):45-53
references.pmid: 19184451
references.citation: AAPS J. 2008 Dec;10(4):516-25
references.pmid: 19002590
references.citation: AAPS J. 2011 Mar;13(1):59-71
references.pmid: 21207216
references.citation: Eur J Pharm Sci. 2007 Oct;32(2):128-39
references.pmid: 17689226
references.citation: AAPS J. 2009 Jun;11(2):323-34
references.pmid: 19430911
references.citation: Pharm Res. 1995 Mar;12(3):413-20
references.pmid: 7617530