title: Physiologically based and population PK modeling in optimizing drug development: A predict-learn-confirm analysis.
abstract: Physiologically based pharmacokinetic (PBPK) modeling and classical population pharmacokinetic (PK) model-based simulations are increasingly used to answer various drug development questions. In this study, we propose a methodology to optimize the development of drugs, primarily cleared by the kidney, using model-based approaches to determine the need for a dedicated renal impairment (RI) study. First, the impact of RI on drug exposure is simulated via PBPK modeling and then confirmed using classical population PK modeling of phase 2/3 data. This methodology was successfully evaluated and applied to an investigational agent, orteronel (nonsteroidal, reversible, selective 17,20-lyase inhibitor). A phase 1 RI study confirmed the accuracy of model-based predictions. Hence, for drugs eliminated primarily via renal clearance, this modeling approach can enable inclusion of patients with RI in phase 3 trials at appropriate doses, which may be an alternative to a dedicated RI study, or suggest that only a reduced-size study in severe RI may be sufficient.
authors.affiliation: Clinical Pharmacology, Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
authors.forename: A
authors.initials: A
authors.lastname: Suri
authors.affiliation: Ann Arbor Pharmacometrics Group, Ann Arbor, Michigan, USA.
authors.forename: S
authors.initials: S
authors.lastname: Chapel
authors.affiliation: Drug Metabolism and Pharmacokinetics, Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
authors.forename: C
authors.initials: C
authors.lastname: Lu
authors.affiliation: Clinical Pharmacology, Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
authors.forename: K
authors.initials: K
authors.lastname: Venkatakrishnan
mesh_terms: D017321:Clinical Trials, Phase I as Topic; D017326:Clinical Trials, Phase III as Topic; D003198:Computer Simulation; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055808:Drug Discovery / Q000379:methods*; D054796:Drug Dosage Calculations; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007668:Kidney / Q000378:metabolism* / Q000503:physiopathology; D007674:Kidney Diseases / Q000378:metabolism* / Q000503:physiopathology; D008954:Models, Biological; D009281:Naphthalenes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D017711:Nonlinear Dynamics; D065667:Renal Elimination; D015203:Reproducibility of Results; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D007093:Imidazoles; D009281:Naphthalenes; D013254:Steroid 17-alpha-Hydroxylase; C571806:orteronel