Table 1.

PBPK models in product labels or FDA review documents: New drug as a victim of DDIs or genetic variations

ID	NME	Year of approval	Detail of predicted scenarios	Simulation results	Impact / outcome	Dataset or strategy for model development/validation	Referencesa
1	Aripiprazole lauroxil	2015	Combination of CYP3A/2D6 inhibitor and CYP2D6 pharmacogenetics	Clinically meaningful effects predicted	Predicted exposure change informed labeling recommendation (dose adjustments, avoid concomitant use, or no warnings)	DDI with ketoconazole and quinidine (aripiprazole) and CYP2D6 pharmacogenetics (aripiprazole and aripiprazole lauroxil)
2	Ceritinib	2014	CYP3A moderate inhibitor and inducer, inhibitor effect on lower ceritinib dose			DDI with ketoconazole and rifampin
3	Cobimetinib	2015	CYP3A moderate inhibitor, CYP3A strong and moderate inducer			DDI with itraconazole	27225997
4	Eliglustat	2014	Combination of CYP3A/2D6 inhibitor and CYP2D6 pharmacogenetics			DDI with ketoconazole, paroxetine, metoprolol, or rifampin and CYP2D6 pharmacogenetics
5	Ibrutinib	2013	CYP3A moderate and weak inhibitor, CYP3A moderate inducer			DDI with ketoconazole and rifampin	27367453
6	Macitentan	2013	DDI with ritonavir, inhibitor effect on multiple dose macitentan			DDI with ketoconazole (single‐dose macitentan)	26385839
7	Naloxegol	2014	CYP3A moderate inducer			DDI with ketoconazole, diltiazem, quinidine, and rifampin	27299937
8	Olaparib	2014	CYP3A moderate inhibitor & inducer			DDI with ketoconazole and rifampin
9	Panobinostat	2015	CYP3A strong inducer			DDI with ketoconazole
10	Simeprevir	2013	CYP3A strong and weak inhibitor, rifampin (single dose)			DDI with ritonavir, darunavir/ritonavir, efavirenz, erythromycin, cyclosporine A, and rifampin (multiple dose)	27896690
11	Sonidegib	2015	CYP3A moderate inhibitor and inducer			DDI with erythromycin and rifampin
12	Belinostat	2014	UGT1A1 pharmacogenetics (*28 genotype)		(See text for details)	No clinical DDI/pharmacogenetic study available for validation
13	Osimertinib	2015	CYP3A inhibitor and inducer	Results not available	No impact on labeling recommendation, PMR/PMC to conduct DDI studies	No clinical DDI study available for validation

CYP, cytochrome; DDI, drug‐drug interaction; ID, identification; NME, new molecular entity; PBPK, physiologically based pharmacokinetic; PMC, postmarketing commitment; PMR, postmarketing requirement; UGT1A1, UDP‐glucuronosyltransferase 1A1.

^aThe numbers in the Reference column represent PubMed ID (if physiologically based pharmacokinetic models were published in scientific journals). New drug application review documents can be found at Drugs@FDA (http://www.fda.gov/drugsatfda). If not specified, Simcyp was used for PBPK simulations.