TABLE 1

Drug interactions with area under the time-plasma concentration curve (AUC) changes ≥5

Victim Drug	Victim Drug Dosing Regimen^{^a}	Perpetrator	Perpetrator Dosing Regimen^{^a}	Population/Study Design	AUC Ratio	C_max Ratio	Enzyme/ Transporters Possibly Involved	Labeling Impact	Reference
Inhibition DDIs, NMEs as substrates
Abemaciclib	50 or 200 mg SD	Ketoconazole	Dose to assume 100% CYP3A inhibition	Healthy subjects/PBPK modeling	15.73	NP	CYP3A (P-gp)	Avoided with ketoconazole	FDA (2017p)
Midostaurin	50 mg SD	Ketoconazole	400 mg once daily for 10 days	Healthy subjects/parallel, placebo-controlled	10.4, 3.51 (CGP62221), 1.21 (CGP52421)	1.83	CYP3A4	Monitor for increased risk of adverse reactions and consider alternative therapies	FDA (2017m)
Voxilaprevir	100 mg SD	Cyclosporine	600 mg SD	Healthy subjects/random crossover	9.73	14.29	OATP1B1, OATP1B3, P-gp, BCRP	Not recommended with OATP inhibitors	FDA (2017q)
Glecaprevir	Glecaprevir/ pibrentasvir 300/120 mg SD	Rifampin	600 mg SD	Healthy subjects/one sequence	8.55	6.52	OATP1B1, OATP1B3	Contraindication with rifampin due to induction	FDA (2017j)
Voxilaprevir	100 mg SD	Rifampin	600 mg SD	Healthy subjects/random crossover	7.96	8.74	OATP1B1, OATP1B3	Contraindicated with rifampin	FDA (2017q)
Abemaciclib	50 or 200 mg SD	Itraconazole	Dose to assume 90% CYP3A inhibition	Healthy subjects/PBPK modeling	7.15, 2.20 (abemaciclib, M2, M18, and M20)	NP	CYP3A (P-gp)	Dose reduction with strong CYP3A inhibitors (except ketoconazole)	FDA (2017p)
Glecaprevir	Glecaprevir/ pibrentasvir 300/120 mg once daily for 21 days	Atazanavir/ ritonavir	300/100 mg once daily for 14 days	Healthy subjects/one sequence	6.53	4.51	OATP1B1, OATP1B3 (P-gp, BCRP)	Contraindicated with atazanavir and not recommended with ritonavir	FDA (2017j)
Glecaprevir	Glecaprevir/ pibrentasvir 300/120 mg SD	Cyclosporine	400 mg SD	Healthy subjects/one sequence	5.08	4.51	OATP1B1, OATP1B3, P-gp, and BCRP	Not recommended with cyclosporine in subjects requiring stable cyclosporine doses >100 mg per day	FDA (2017j)
Neratinib	240 mg SD	Ketoconazole	400 mg once daily for 5 days	Healthy subjects/random crossover	5.16	3.63	CYP3A4 (P-gp)	Avoided with strong or moderate CYP3A inhibitors	FDA (2017k), Abbas et al., 2011)
Induction DDIs, NMEs as substrates
abemaciclib	200 mg SD	Rifampin	600 mg once daily for 14 days	Healthy subjects/one sequence	0.05, 0.35, 1.31, 0.20 (abemaciclib, M2, M18, and M20)	0.08, 0.96, 4.26, 0.64 (abemaciclib, M2, M18, and M20)	CYP3A (P-gp)	Avoided with strong CYP3A inducers	FDA (2017p)
Deflazacort	18 mg SD	Rifampin	600 mg once daily for 10 days	Not provided/not provided	0.06 (21-desacetyl deflazacort)	0.08	CYP3A4 (P-gp)	Avoided with strong or moderate CYP3A4 inducers	FDA (2017g)
Midostaurin	50 mg SD	Rifampin	600 mg once daily for 14 days	Healthy subjects/parallel, placebo-controlled	0.06 (CGP62221), 0.41 (CGP52421)	0.63 (CGP62221), 0.65 (CGP52421)	CYP3A4	Avoided with strong CYP3A4 inducers	Dutreix et al.(2013), FDA (2017m)
Neratinib	240 mg SD with a standard meal	Rifampin	600 mg once daily for 8 days	Healthy subjects/one sequence	0.12	0.23	CYP3A4 (P-gp)	Avoided with strong or moderate CYP3A4 inducers	FDA (2017k)
Glecaprevir	Glecaprevir/ pibrentasvir 300/120 mg SD^{^b}	Rifampin	600 mg once daily for 17 days	Healthy subjects/one sequence	0.12	0.14	P-gp (CYP3A)	Contraindicated with rifampin	FDA (2017j)
Ribociclib	600 mg SD	Rifampin	600 mg once daily for 14 days	Healthy subjects/one sequence	0.11	0.19	CYP3A (P-gp)	Avoided with strong CYP3A inducers and consider alternative therapies	FDA (2017i)
Pibrentasvir	Glecaprevir/ pibrentasvir 300/120 mg SD^{^c}	Rifampin	600 mg once daily for 17 days	Healthy subjects/one sequence	0.13	0.17	P-gp	Contraindicated with rifampin	FDA (2017j)
Acalabrutinib	100 mg twice daily	Rifampin	600 mg once daily	Healthy subjects/PBPK modeling	0.17 (acalabrutinib), 0.39 (ACP-5862)	NP	CYP3A (P-gp)	Avoided with strong CYP3A inducers; if not, increase acalabrutinib dose	FDA (2017f)
Naldemedine	0.2 mg SD	Rifampin	600 mg once daily for 17 days	Healthy subjects/one sequence	0.17 (naldemedine), 2.45 (nornaldemedine)	0.61 (naldemedine), 3.17 (nornaldemedine)	CYP3A4 (P-gp)	Avoided with strong CYP3A4 inducers	FDA (2017o)
Pibrentasvir	Glecaprevir/ pibrentasvir 300/120 mg SD^{^d}	Rifampin	600 mg once daily for 17 days	Healthy subjects/one sequence	0.17	0.21	P-gp	Contraindicated with rifampin	FDA (2017j)
Brigatinib	180 mg SD	Rifampin	600 mg once daily for 7 days	Healthy subjects/one sequence	0.20	0.40	CYP3A, CYP2C8 (P-gp)	Avoided with strong CYP3A inducers	FDA (2017c)
Abemaciblib	200 mg SD	Carbamazepine	400 mg twice daily for 24 days	Healthy subjects/PBPK modeling	0.20	N/P	CYP3A  (P-gp)	Avoided with strong CYP3A inducers	FDA (2017p)
Inhibition DDIs, NMEs as inhibitors
Glecaprevir/ pibrentasvir	Glecaprevir/ pibrentasvir 300/120 mg once daily 10 days	Atorvastatin	10 mg once daily for 14 days	Healthy subjects/one sequence	8.28	22.00	OATP1B1, OATP1B3 (CYP3A)	Not recommended with atorvastatin	FDA (2017j)
Voxilaprevir	Sofosbuvir/ velpapasvir/voxilaprevir + voxilaprevir 400/100 per 100 mg + 100 mg once daily with food for 15 days	Rosuvastatin	10 mg SD	Healthy subjects/one sequence	7.35	17.96	BCRP, OATP1B1, OATP1B3	Not recommended with BCRP substrates	FDA (2017q)
Ribociclib	600 mg once daily for 8 days	Midazolam	5 mg SD	Healthy subjects/PBPK modeling	5.17	2.41	CYP3A	Caution or dose reduction with CYP3A substrates with an NTI	FDA (2017i)

DDI, drug-drug interaction; NME, new molecular enzyme; NP, not provided; NTI, narrow therapeutic index; PBPK, physiologically based pharmacokinetics; P-gp, P-glycoprotein; SD, single dose.
↵^a All drugs were administered orally under fasting conditions unless otherwise specified.
↵^b Alone on day 1 of period 1, then 1 day after rifampin pretreatment (day 18 of period 2).
↵^c Alone on day 1 of period 1 then 1 day after rifampin pretreatment (day 18 of period 2).
↵^d Alone on day 1 of period 1 then with rifampin on day 14 of period 2.