TABLE 2

Examples of PBPK modeling impacting regulatory communications in GlaxoSmithKline (GSK)

Drug	Scenario	Simulation	Impact
GSK1	Extensive hepatic metabolism, less than 10% renal clearance	Simulation of drug clearance in renal and hepatic impaired patients—mild (hepatic only), moderate, severe	FDA and EMA support GSK’s proposal to include only patients with moderate hepatic impairment as an initial study design and reduced study design including severe renal impaired patients
Case 1	Extensive hepatic metabolism, less than 10% renal clearance
GSK2	CYP3A4/PGP substrate	Simulation of victim drug interactions with weak, moderate, and strong CYP3A4 inhibitors	FDA supports GSK’s proposal for a ketoconazole drug interaction study to investigate CYP3A4/PGP inhibition
GSK3	CYP2D6/PGP substrate	Simulation of CYP2D6 poor metabolizers	FDA supports inclusion of CYP2D6/PGP inhibitors on phase III clinical trials