Victim Drug | Victim Drug Dosing Regimena | Perpetrator | Perpetrator Dosing Regimena | Population/Study Design | AUC Ratio | Cmax 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 SDb | 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 SDc | 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 SDd | 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.