Assessing Supersaturation and Its Impact on In Vivo Bioavailability of a Low-Solubility Compound ABT-072 With a Dual pH, Two-Phase Dissolution Method

• Published in: Journal of pharmaceutical sciences Vol. 105; no. 9; pp. 2886 - 2895
• Main Authors: Shi, Yi, Erickson, Bryan, Jayasankar, Adivaraha, Lu, Liangjun, Marsh, Kennan, Menon, Rajeev, Gao, Ping
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2016
• Subjects: absorption; Animals; Antiviral Agents - chemistry; Antiviral Agents - pharmacokinetics; Biological Availability; clinical pharmacokinetics; Cross-Over Studies; Cytosine - analogs & derivatives; Cytosine - chemistry; Cytosine - pharmacokinetics; dissolution; Dogs; Drug Compounding; Excipients; Humans; Hydrogen-Ion Concentration; in vitro models; in vitro/in vivo correlations (IVIVC); precipitation; preclinical pharmacokinetics; Solubility; Sulfonamides - chemistry; Sulfonamides - pharmacokinetics; Tablets; Water; precipitation; in vitro models; absorption; dissolution; clinical pharmacokinetics; in vitro/in vivo correlations (IVIVC); preclinical pharmacokinetics
• ISSN: 0022-3549; 1520-6017; 1520-6017
• DOI: 10.1016/j.xphs.2016.04.036

ABT-072 is a candidate drug evaluated for treatment of hepatitis C virus. It is an acidic compound with extremely low intrinsic aqueous solubility. An in vitro dissolution-partition system, referred as biphasic test method, was used to characterize ABT-072 prototype formulations. This test used 2 aqueous dissolution media of pH 2 and 6.5 in a sequential manner to simulate the transition of drug in gastrointestinal tract. The biphasic test used in this work effectively differentiated various ABT-072 formulations derived from conventional and enabling technologies. In vitro profiles of these formulations indicate a complex interplay among the 3 competitive kinetic processes including dissolution, precipitation, and partition in the aqueous media. The relative amount of drug partitioned into the organic phase (i.e., octanol) from different formulations was found to be directly related to their in vivo exposures observed in both dogs and human subjects, respectively. An in vitro-in vivo relationship was obtained between ABT-072 concentrations in octanol at t = 2 h from these formulations and the relative bioavailabilities in dogs and human subjects. This work revealed the significance of polymeric precipitation inhibition by sustaining a supersaturated state of ABT-072 and its impact on in vivo exposure in human subjects.