Dongzhou Liu, Ph.D., medical affairs and clinical development, new products R&D at GlaxoSmithKline (GSK), discussed advances in predictive methods and applications in ADME and biological properties profiling. His main theme was earlier and iterative in vivo modeling to ease the translation from in vitro to in vivo in an attempt to address the fact that over 90% of drugs fail after first-in-man studies. Earlier assessment of drug absorption, transport, and bioavailability is vital, Dr. Liu concluded.
Finally, Vikash Sinha, M.D., clinical pharmacology leader, global clinical pharmacology and pharmacokinetics at J&J Pharmaceutical Research & Development, discussed the application of physiologically based pharmacokinetic modeling (PBPK) in drug development. PK properties of a molecule cover its distribution, clearance, and absorption, and influence how much drug should be administered and how often.
PBPK looks at organs as compartments with physiological, anatomical, biochemical, and physicochemical properties. “Although PBPK is more complex than empirical approaches, it gives mechanistic insights into the compound and a fuller profile,” claimed Dr. Sinha. PBPK also predicts pediatric PK and drug-drug interactions.
At J&J, PBPK is being put to the test with new software including GastroPlus™ and SimCYP, which have a number of predictive features. GastroPlus allows in silico predictions from molecular descriptors, while SimCYP can predict drug-drug interactions and also PK in special patient populations, such as those with renal failure or diabetes.
In one J&J case study, the physicochemical properties of a small, poorly soluble molecule were known and prediction of its human PK properties made—as the dose increased its bioavailability decreased. In a second case study, there was a big mismatch between predicted and actual plasma profile over time, the reason was determined to be extrahepatic metabolism in the lung. This compound was found to be a PGP substrate, something that would not have otherwise been revealed, Dr. Sinha said.
PBPK also addresses questions about the impact of food on the absorption process, whether reducing the particle size of a compound will improve its absorption, or whether the compound is a potential candidate for a controlled-release formulation. PBPK can also improve the design of clinical trials and was used to determine the dose selection of a third J&J compound, Dr. Sinha said. “Industry is still in the learning phase with PBPK, but there is more and more support from management for these approaches as part of our growth.”