Assessing Supersaturation and Its Impact on In Vivo Bioavailability of a Low-Solubility Compound ABT-072 With a Dual pH, Two-Phase Dissolution Method.
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.
NCE-Formulation Sciences, Drug Product Development, Abbvie Inc., North Chicago, Illinois 60064. Electronic address: yi.shi@abbvie.com.
Yi
Y
Shi
NCE-Formulation Sciences, Drug Product Development, Abbvie Inc., North Chicago, Illinois 60064.
Bryan
B
Erickson
NCE-Formulation Sciences, Drug Product Development, Abbvie Inc., North Chicago, Illinois 60064.
Adivaraha
A
Jayasankar
Discovery, Abbvie Inc., North Chicago, Illinois 60064.
Liangjun
L
Lu
Experimental Science, Abbvie Inc., North Chicago, Illinois 60064.
Kennan
K
Marsh
Clinical Pharmacokinetics and Pharmacodynamics, Abbvie Inc., North Chicago, Illinois 60064.
Rajeev
R
Menon
NCE-Formulation Sciences, Drug Product Development, Abbvie Inc., North Chicago, Illinois 60064. Electronic address: ping.gao@abbvie.com.
Ping
P
Gao
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000493:pharmacokinetics*; D001682:Biological Availability; D018592:Cross-Over Studies; D003596:Cytosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D004285:Dogs; D004339:Drug Compounding; D005079:Excipients; D006801:Humans; D006863:Hydrogen-Ion Concentration; D012995:Solubility; D013449:Sulfonamides / Q000737:chemistry* / Q000493:pharmacokinetics*; D013607:Tablets; D014867:Water
C000625346:ABT-072; D000998:Antiviral Agents; D005079:Excipients; D013449:Sulfonamides; D013607:Tablets; D014867:Water; D003596:Cytosine
absorption; clinical pharmacokinetics; dissolution; in vitro models; in vitro/in vivo correlations (IVIVC); precipitation; preclinical pharmacokinetics