1. Role of regional absorption and gastrointestinal motility on variability in oral absorption of a model drug
- Author
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Jennifer Pizzano, John Morrison, Jennifer Wang, Tami Orcutt, Huidong Gu, Ajit S. Narang, Sophie Beyer, Margaret Batchelder, Heidi Dulac, Sharon Aborn, Kenneth S. Santone, Jon Ehrmann, Eric Shields, Kimberley A. Lentz, Rod Ketner, Katrina Taylor, Anand Balakrishnan, Jinjiang Li, and Xujin Lu
- Subjects
Male ,Absorption (pharmacology) ,Drug ,Receptor, Metabotropic Glutamate 5 ,media_common.quotation_subject ,Cmax ,Administration, Oral ,Pharmaceutical Science ,02 engineering and technology ,Pharmacology ,030226 pharmacology & pharmacy ,Intestinal absorption ,03 medical and health sciences ,Dogs ,0302 clinical medicine ,Allosteric Regulation ,Gastrointestinal Agents ,Pharmacokinetics ,Animals ,media_common ,Gastrointestinal agent ,Gastric emptying ,Chemistry ,digestive, oral, and skin physiology ,General Medicine ,021001 nanoscience & nanotechnology ,Rats ,Bioavailability ,Macaca fascicularis ,stomatognathic diseases ,Gastric Emptying ,Intestinal Absorption ,Gastrointestinal Motility ,0210 nano-technology ,Biotechnology - Abstract
Variability in oral absorption in pre-clinical species makes human dose projection challenging. In this study, we investigated the mechanistic basis of variability in oral absorption of a model hydrophobic compound with pH-dependent solubility, BMS-955829, after oral dosing in rats, dogs, and cynomolgus monkeys. The contribution of regional absorption to pharmacokinetic variability was assessed in ported monkeys by direct intraduodenal and intraileal administration. The effect of BMS-955829 on gastric emptying and intestinal motility was investigated by radiography after co-administration of barium. BMS-955829 exhibited species dependent oral bioavailability, with high variability in monkeys. During regional absorption studies, highest rate of drug absorption was observed after direct intraduodenal administration. Radiography studies indicated that BMS-955829 slowed gastric emptying and intestinal motility. The effect of rate and site of drug release on oral exposure was studied using different drug product formulations. Reducing the rate of drug release reduced oral exposure variability without compromising exposure in cynomolgus monkeys. This effect was likely mediated by avoidance of rapid initial absorption and drug effect on gastric emptying and intestinal transit within the biorelevant timeframe. Thus, drug release rate can modulate the effect of physiological factors on variability in the oral absorption of sensitive compounds.
- Published
- 2017