In Vitro–In Vivo Extrapolation of Intestinal Availability for Carboxylesterase Substrates Using Portal Vein–Cannulated Monkey

• Published in: Journal of pharmaceutical sciences Vol. 106; no. 3; pp. 898 - 905
• Main Authors: Trapa, Patrick E., Beaumont, Kevin, Atkinson, Karen, Eng, Heather, King-Ahmad, Amanda, Scott, Dennis O., Maurer, Tristan S., Di, Li
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2017
• Subjects: Administration, Oral; Animals; carboxylesterase; Carboxylesterase - administration & dosage; Carboxylesterase - blood; Catheterization - methods; Dogs; Female; fraction absorbed; gut first-pass extraction; Intestinal Absorption - drug effects; Intestinal Absorption - physiology; intestine S9; In vitro–in vivo extrapolation; Macaca fascicularis; Madin Darby Canine Kidney Cells; Male; Portal Vein - drug effects; Portal Vein - metabolism; portal vein–cannulated monkey; Substrate Specificity - physiology; Km; UGT; IVIVE; PBPK; MRT; Rb; LC-MS/MS; Fa; MDCK-LE; FaFg; gut first-pass extraction; PSA; Fg; UV; GI; Vmax; carboxylesterase; PAMPA; IV; CES; In vitro–in vivo extrapolation; intestine S9; CLint; portal vein–cannulated monkey; CAT; fraction absorbed; PK; PVC
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1016/j.xphs.2016.12.001

Prediction of intestinal availability (FaFg) of carboxylesterase (CES) substrates is of critical importance in designing oral prodrugs with optimal properties, projecting human pharmacokinetics and dose, and estimating drug-drug interaction potentials. A set of ester prodrugs were evaluated using in vitro permeability (parallel artificial membrane permeability assay and Madin–Darby canine kidney cell line-low efflux) and intestinal stability (intestine S9) assays, as well as in vivo portal vein–cannulated cynomolgus monkey. In vitro–in vivo extrapolation (IVIVE) of FaFg was developed with a number of modeling approaches, including a full physiologically based pharmacokinetic (PBPK) model as well as a simplified competitive-rate analytical solution. Both methods converged as in the PBPK simulations enterocyte blood flow behaved as a sink, a key assumption in the competitive-rate analysis. For this specific compound set, the straightforward analytical solution therefore can be used to generate in vivo predictions. Strong IVIVE of FaFg was observed for cynomolgus monkey with R2 of 0.71-0.93. The results suggested in vitro assays can be used to predict in vivo FaFg for CES substrates with high confidence.