title: Prediction of pH dependent absorption using in vitro, in silico, and in vivo rat models: Early liability assessment during lead optimization.
abstract: Weakly basic compounds which have pH dependent solubility are liable to exhibit pH dependent absorption. In some cases, a subtle change in gastric pH can significantly modulate the plasma concentration of the drug and can lead to sub-therapeutic exposure of the drug. Evaluating the risk of pH dependent absorption and potential drug-drug interaction with pH modulators are important aspects of drug discovery and development. In order to assess the risk around the extent of decrease in the systemic exposure of drugs co-administered with pH modulators in the clinic, a pH effect study is carried out, typically in higher species, mostly dog. The major limitation of a higher species pH effect study is the resource and material requirement to assess this risk. Hence, these studies are mostly restricted to promising or advanced leads. In our current work, we have used in vitro aqueous solubility, in silico simulations using GastroPlus™ and an in vivo rat pH effect model to provide a qualitative assessment of the pH dependent absorption liability. Here, we evaluate ketoconazole and atazanavir with different pH dependent solubility profiles and based on in vitro, in silico and in vivo results, a different extent of gastric pH effect on absorption is predicted. The prediction is in alignment with higher species and human pH effect study results. This in vitro, in silico and in vivo (IVISIV) correlation is then extended to assess pH absorption mitigation strategy. The IVISIV predicts pH dependent absorption for BMS-582949 whereas its solubility enhancing prodrug, BMS-751324 is predicted to mitigate this liability. Overall, the material requirement for this assessment is substantially low which makes this approach more practical to screen multiple compounds during lead optimization.
authors.affiliation: Biopharmaceutics, Biocon Bristol-Myers Squibb R&D Centre (BBRC), Syngene International Ltd., Biocon Park, Plot 2 & 3, Bommasandra IV Phase, Bangalore 560099, India. Electronic address: ajay.saxena@syngeneintl.com.
authors.forename: Ajay
authors.initials: A
authors.lastname: Saxena
authors.affiliation: Pharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb R&D Centre (BBRC), Syngene International Ltd., Biocon Park, Plot 2 & 3, Bommasandra IV Phase, Bangalore 560099, India.
authors.forename: Devang
authors.initials: D
authors.lastname: Shah
authors.affiliation: Pharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb R&D Centre (BBRC), Syngene International Ltd., Biocon Park, Plot 2 & 3, Bommasandra IV Phase, Bangalore 560099, India.
authors.forename: Shweta
authors.initials: S
authors.lastname: Padmanabhan
authors.affiliation: Pharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb R&D Centre (BBRC), Syngene International Ltd., Biocon Park, Plot 2 & 3, Bommasandra IV Phase, Bangalore 560099, India.
authors.forename: Shashyendra Singh
authors.initials: SS
authors.lastname: Gautam
authors.affiliation: Biopharmaceutics, Biocon Bristol-Myers Squibb R&D Centre (BBRC), Syngene International Ltd., Biocon Park, Plot 2 & 3, Bommasandra IV Phase, Bangalore 560099, India.
authors.forename: Gajendra Singh
authors.initials: GS
authors.lastname: Chowan
authors.affiliation: Pharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb R&D Centre (BBRC), Syngene International Ltd., Biocon Park, Plot 2 & 3, Bommasandra IV Phase, Bangalore 560099, India.
authors.forename: Sandhya
authors.initials: S
authors.lastname: Mandlekar
authors.affiliation: Integrated Product Development Organization, Dr. Reddy's Laboratories, Bengaluru 560100, India.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Desikan
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000069446:Atazanavir Sulfate / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D002626:Chemistry, Pharmaceutical; D003198:Computer Simulation; D055808:Drug Discovery / Q000379:methods*; D065570:Gastric Absorption; D005744:Gastric Acid / Q000378:metabolism; D005753:Gastric Mucosa / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007654:Ketoconazole / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D008954:Models, Biological; D017208:Rats, Wistar; D012995:Solubility; D013045:Species Specificity
chemical_list: D000069446:Atazanavir Sulfate; D007654:Ketoconazole
keywords: Atazanavir; Exposure; Gastric pH; GastroPlus™; Ketoconazole; Rat pH dependent absorption model; pH dependent solubility