TABLE 2

Physiologically based pharmacokinetic (PBPK) modeling and simulation results used to support label recommendations

Drug Name	Inhibition Study (AUC Ratio)	Labeling Impact	Induction Study (AUC Ratio)	Labeling Impact	Reference
As substrate
Abemaciclib^{^a}	Clarithromycin (3.37), clinical	Dose reduction with strong CYP3A inhibitors (except ketoconazole)	Rifampin (0.05), clinical	Avoided with strong CYP3A inducers	FDA (2017p)
	Ketoconazole (15.73), PBPK	Avoided with ketoconazole	Carbamazepine (0.20), PBPK	Avoided with strong CYP3A inducers
	Itraconazole (7.15), PBPK	Dose reduction with strong CYP3A inhibitors (except ketoconazole)
	Diltiazem (3.95), PBPK	None
	Verapamil (2.28), PBPK	None
Acalabrutinib	Itraconazole (4.96), clinical	Avoided with strong CYP3A inhibitors; if inhibitor is used, use of acalabrutinib should be interrupted	Rifampin (0.21), clinical	Avoided with strong CYP3A inducers; if not, dose increased to 200 mg twice daily	FDA (2017f)
	Clarithromycin (3.34), PBPK	Avoided with strong CYP3A inhibitors; if inhibitor is used, use of acalabrutinib should be interrupted	Carbamazepine (0.39), PBPK	Avoided with strong CYP3A inducers; if not, dose increased to 200 mg twice daily
	Erythromycin (2.76), PBPK	Dose reduction to 100 mg once daily	Efavirenz (0.39), PBPK	None
	Diltiazem (2.28), PBPK	Dose reduction to 100 mg once daily
	Fluconazole (2.43), PBPK	Dose reduction to 100 mg once daily
	Fluvoxamine (1.37), PBPK	None
Deflazacort	Clarithromycin (3.38), clinical	Dose reduction to 1/3 of the recommended dose with strong CYP3A inhibitors	Rifampin (0.06), clinical	Avoided with strong CYP3A inducers	FDA (2017g)
Deflazacort	Fluconazole (3.97), PBPK	Dose reduction to 1/3 of the recommended dose with moderate CYP3A inhibitors	Efavirenz (0.29), PBPK	Avoided with moderate CYP3A inducers
Naldemedine	Itraconazole (2.92), clinical	Monitoring for potential naldemedine-related adverse reactions with strong CYP3A inhibitors	Rifampin (0.17), clinical	Avoided with strong CYP3A inducers	FDA (2017o)
Naldemedine	Fluconazole (1.90), PBPK	Monitoring for potential naldemedine-related adverse reactions with moderate CYP3A inhibitors	Efavirenz (0.57), PBPK	Clinical consequence with moderate CYP3A inducer is unknown	FDA (2017o)
Ribociclib	Ritonavir (3.21), clinical	Avoided with strong CYP3A inhibitors; if not, dose reduction to 400 mg once daily	Rifampin (0.11),clinical	Avoided with strong CYP3A inducers	FDA (2017i)
	Ketoconazole (3.09), PBPK	Avoided with strong CYP3A inhibitors; if not, dose reduction to 400 mg once daily	Carbamazepine (0.48), PBPK	Avoided with strong CYP3A inducers
	Itraconazole (2.69), PBPK	Avoided with strong CYP3A inhibitors; if not, dose reduction to 400 mg once daily	Efavirenz (0.40), PBPK	None
	Erythromycin (1.93), PBPK	Avoided with strong CYP3A inhibitors; if not, dose reduction to 400 mg once daily
	Fluvoxamine (1.02), PBPK	None
Ertugliflozin	Mefenamic acid (1.51) PBPK	None	Rifampin (0.61), clinical	None	FDA (2017n)
As inhibitor
Ribociclib	Midazolam^{^b} (3.89), clinical	Caution with or reduce dose of CYP3A substrates with a NTI	Not applicable	Not applicable	FDA (2017i)
Ribociclib	Midazolam^{^c} (5.17), PBPK	Caution with or reduce dose of CYP3A substrates with a NTI	Not applicable	Not applicable	FDA (2017i)

NTI, narrow therapeutic index.
↵^a The effect of a moderate inducer on the pharmacokinetics of abemaciclib was requested as a postmarket requirement via PBPK models or clinical trials.
↵^b Midazolam was administered as 400 mg once daily for 8 days.
↵^c Midazolam was administered as 600 mg (recommended clinical dose) once daily for 8 days.