TABLE 2.
Detailed overview of the results of DDI studies performed with the reviewed oral oncolytic drugs.
| Drug (year of market approval) | (Primary) metabolism | Target Verheijen et al. (2017) | Inter-patient variability (%CV) | Dose-linearity | DDI study with (interaction potential) | Change in AUC | Recommendations Summary of product Characteristics | Type of trial | References |
|---|---|---|---|---|---|---|---|---|---|
| Alectinib (2015) | CYP3A | ALK | 46% | Dose proportional exposure | Posaconazole (strong CYP3A inhibitor) | AUC0–∞ 75% ↑ (90% CI 57–95) | Be careful when combining alectinib with strong inhibitors of CYP3A | Clinical trial | Food and Drug Administration (2015a) and Morcos et al. (2017) |
| M4 AUC0–∞ 24.9% ↓ (90% CI 12.3–35.6) | |||||||||
| Sum alectinib and M4 AUC0–∞ 36% ↑ (90% CI 24–49) | |||||||||
| Rifampin (strong CYP3A inducer) | AUC0–∞ 73.2% ↓ (90% CI 69.9–76.2) | Be careful when combining alectinib with strong inducers of CYP3A | Clinical trial | Food and Drug Administration (2015a) and Morcos et al. (2017) | |||||
| M4 AUC0-∞ 79% ↑ (90% CI 58–102) | |||||||||
| Sum alectinib and M4 AUC0–∞ 18.4% ↓ (90% CI 9.9–26) | |||||||||
| Ceritinib (2014) | CYP3A | ALK | 74% | Nonlinear PK | Ketoconazole (strong CYP3A inhibitor) | Single dose AUC0–∞ 186% ↑ (90% CI 146–233) | Avoid coadministration of strong CYP3A inhibitors or reduce the dose of ceritinib to 150 mg QD | Clinical trial | Food and Drug Administration (2014a) |
| Steady–state AUC 51% ↑ (90% CI 43–59) | PBPK simulation | ||||||||
| Fluconazole (moderate CYP3A inhibitor) | AUC 37% ↑ (90% CI 31–42) | PBPK simulation | Food and Drug Administration (2014a) | ||||||
| Rifampin (strong CYP3A inducer) | Single dose AUC0–∞ 70% ↓ (90% CI 61–77) | Avoid coadministration of strong CYP3A inducers | Clinical trial | Food and Drug Administration (2014a) | |||||
| Steady-state AUC 67% ↓ (90% CI 64–70) | PBPK simulation | ||||||||
| Efavirenz (moderate CYP3A inducer) | AUC 43% ↓ (90% CI 38–48) | PBPK simulation | Food and Drug Administration (2014a) | ||||||
| Cobimetinib (2015) | CYP3A | MEK | 61% | Dose proportional exposure | Itraconazole (strong CYP3A inhibitor) | AUC0-∞ 572% ↑ (90% CI 464–702) | Avoid coadministration of strong and moderate CYP3A inhibitors or reduce the dose of cobimetinib to 20 mg QD (short term use) | Clinical trial | Food and Drug Administration (2014b) |
| Erythromycin (moderate CYP3A inhibitor) | AUC 335% ↑ | PBPK simulation | Food and Drug Administration (2014b) and Budha et al. (2016) | ||||||
| Diltiazem (moderate CYP3A inhibitor) | AUC 226% ↑ | PBPK simulation | Food and Drug Administration (2014b) and Budha et al. (2016) | ||||||
| Fluvoxamine (weak CYP3A inhibitor) | AUC 3% ↑ | PBPK simulation | Food and Drug Administration (2014b) and Budha et al. (2016) | ||||||
| Rifampin (strong CYP3A inducer) | AUC 83% ↓ | Avoid coadministration of strong and moderate CYP3A inducers | PBPK simulation | Food and Drug Administration (2014b) and Budha et al. (2016) | |||||
| Efavirenz (moderate CYP3A inducer) | AUC 72% ↓ | PBPK simulation | Food and Drug Administration (2014b) and Budha et al. (2016) | ||||||
| Vemurafenib (weak CYP3A inducer) | AUC0–24h 13% ↓ | Clinical trial | Food and Drug Administration (2014b) | ||||||
| Dabrafenib (2013) | CYP2C8/CYP3A | BRAF | 38% | Dose proportional exposure at single dose, but less than dose-proportional after repeat twice daily dosing (likely due to auto-induction) | Ketoconazole (strong CYP3A inhibitor) | AUC0–12h 71% ↑ (90% CI 55–90) | Be careful when combining dabrafenib with strong inhibitors of CYP3A | Clinical trial | Food and Drug Administration (2012), Suttle et al. (2015), and European Medicines Agency Committee for Medicinal Products For Human Use (CHMP) (2018) |
| Hydroxy-dabrafenib AUC0–12h 82% ↑ (90% CI 61–105) | |||||||||
| Desmethyl-dabrafenib AUC0–12h 68% ↑ (90% CI 47–93) | |||||||||
| Carboxy-dabrafenib AUC0–12h 16% ↓ (90% CI 4–27) | |||||||||
| Rifampin (strong CYP3A inducer) | AUC 34% ↓ | Avoid coadministration of CYP3A inducers | Clinical trial | European Medicines Agency Committee for Medicinal Products For Human Use (CHMP) (2018) | |||||
| Desmethyl-dabrafenib AUC 30% ↓ | |||||||||
| Carboxy-dabrafenib AUC 73% ↑ | |||||||||
| Everolimus (2003) | CYP3A/P-gp | mTOR | 36% | Dose proportional exposure | Ketoconazole (strong CYP3A inhibitor) | AUC0–∞ 1,430% ↑ (90% CI 1020–2,150) | Avoid coadministration of strong CYP3A inhibitors. Avoid coadministration of moderate CYP3A inhibitors or reduce the dose of everolimus to 2.5 or 5 mg QD | Clinical trial | Kovarik et al. (2005b) and Food and Drug Administration (2008) |
| Erythromycin (moderate CYP3A inhibitor) | AUC0–∞ 340% ↑ (90% CI 250–440) | Clinical trial | (European Medicines Agency Committee for Medicinal Products For Human Use (CHMP); Kovarik et al. (2005c) and Food and Drug Administration (2008) | ||||||
| Verapamil (moderate CYP3A inhibitor) | AUC0–∞ 250% ↑ (90% CI 210–290) | Clinical trial | (European Medicines Agency Committee for Medicinal Products For Human Use (CHMP); Kovarik et al., (2005a) and Food and Drug Administration (2008) | ||||||
| Everolimus (2003) | CYP3A/P-gp | mTOR | 36% | Dose proportional exposure | Imatinib (moderate CYP3A inhibitor) | AUC 270% ↑ | Avoid coadministration of strong CYP3A inhibitors. Avoid coadministration of moderate CYP3A inhibitors or reduce the dose of everolimus to 2.5 or 5 mg QD | Clinical trial | (European Medicines Agency Committee for Medicinal Products For Human Use (CHMP), 2006) |
| Cyclosporine (moderate CYP3A inhibitor) | Neoral® AUC0–∞ 168% ↑ (90% CI 122–224) | Clinical trial | Kovarik et al. (2002b) and Kovarik et al., 2006) | ||||||
| Sandimmune® AUC0–∞ 74% ↑ (90% CI 49–104) | |||||||||
| Rifampin (strong CYP3A inducer) | AUC 63% ↓ (90% CI 54–70) | Avoid coadministration of strong CYP3A inducers or increase the dose of everolimus to 10 or 20 mg QD | Clinical trial | (European Medicines Agency Committee for Medicinal Products For Human Use (CHMP); Kovarik et al. (2002a) and Food and Drug Administration (2008) | |||||
| Imatinib (2001) | CYP3A | KIT, PDGFR, Bcr-Abl | 40–60% | Dose proportional exposure | Ketoconazole (strong CYP3A inhibitor) | Single dose AUC0–∞ 40.1% ↑ (90% CI 31–49.9) | Be careful when combining imatinib with inhibitors of CYP3A | Clinical trial | Food and Drug Administration, (2008); European Medicines Agency Committee for Medicinal Products For Human Use (CHMP) (2006) |
| N-desmethylimatinib AUC0–∞ 5% ↓ (90% CI −3–12.5) | |||||||||
| Ritonavir (strong CYP3A inhibitor) | Steady-state AUC0–24h 3.1% ↓ (90% CI −12.5–16.5) | Clinical trial | Van Erp et al. (2007) | ||||||
| N-desmethylimatinib | |||||||||
| AUC0–24h 38.5% ↑ (90% CI 15.9–65.6) | |||||||||
| Rifampin (strong CYP3A inducer) | AUC0–∞ 74% ↓ (90% CI 71–76) | Avoid coadministration of strong CYP3A inducers | Clinical trial | Bolton et al. (2004) and European Medicines Agency Committee for Medicinal Products For Human Use (CHMP) (2006) | |||||
| N-desmethylimatinib AUC0–∞ 11.7% ↓ (90% CI 3.3–19.4) | |||||||||
| Imatinib (2001) | CYP3A | KIT, PDGFR, Bcr-Abl | 40–60% | Dose proportional exposure | Enzyme-inducing antiepileptic drugs (EIAEDs; e.g., carbamazepine, oxcarbazepine and phenytoin) | AUC0–∞ 72.5% ↓ | Avoid coadministration of strong CYP3A inducers | Clinical trial | Wen et al. (2006) |
| (mixed potency; carbamazepine and phenytoin are potent inducers; oxcarbazepine is a weak inducer) | N-desmethylimatinib AUC0–∞ 9.8% ↓ | ||||||||
| St John’s Wort (weak CYP3A inducer) | Study 1 AUC0–∞ 30.2% ↓ (90% CI 25–34.9) | Clinical trial | Frye et al. (2004) | ||||||
| N-desmethylimatinib AUC0–72h 4.1% ↑ (90% CI −8.4–18.3) | Smith et al. (2004) | ||||||||
| Study 2 AUC0–∞ 44% ↓ (90% CI 30–54) | |||||||||
| Lenvatinib (2015) | CYP3A | VEGFR | 36–78% | Dose proportional exposure | Itraconazole (strong CYP3A inhibitor) | AUC0–∞ 14.5% ↑ (90% CI 8.5–20.9) | None | Clinical trial | Food and Drug Administration (2015b) and Shumaker et al. (2015) |
| Rifampin (strong CYP3A inducer) | Single dose AUC0–∞ 30.6% ↑ (90% CI 22.7–39) | Clinical trial | Shumaker et al. (2014) and Food and Drug Administration (2015b) | ||||||
| Multiple doses AUC0–∞ 18.2% ↓ (90% CI 8.7–26.7) | |||||||||
| Olaparib (2014) | CYP3A | PARP | 38% | Dose-proportionality cannot be concluded based on available PK data | Itraconazole (strong CYP3A inhibitor) |
Study 1; tablet AUC0–∞ 170% ↑ (90% CI 144–197) Study 2; capsule AUC 152% ↑ (95% CI 139–167) |
Reduce dose of olaparib to 150 mg BID when combined with strong CYP3A inhibitors and reduce dose to 200 mg BID when combined with moderate CYP3A inhibitors (tablets) | Clinical trial | Food and Drug Administration (2014c) and Dirix et al. (2016) |
| PBPK simulation | Pilla Reddy et al. (2019) | ||||||||
| Fluconazole (moderate CYP3A inhibitor) |
Study 1; tablet AUC 126% ↑ (95% CI 115–130) Study 2; tablet AUC 121% ↑ (95% CI 114–128) Study 2; capsule AUC 98% ↑ (95% CI 92–105) |
PBPK simulation | Food and Drug Administration (2014c) | ||||||
| PBPK simulation | Pilla Reddy et al. (2019) | ||||||||
| Olaparib (2014) | CYP3A | PARP | 38% | Dose-proportionality cannot be concluded based on available PK data | Fluvoxamine (weak CYP3A inhibitor) | Tablet AUC 2% ↑ (95% CI 1–2) | Reduce dose of olaparib to 150 mg BID when combined with strong CYP3A inhibitors and reduce dose to 200 mg BID when combined with moderate CYP3A inhibitors (tablets) | PBPK simulation | Pilla Reddy et al. (2019) |
| Capsule AUC 1% ↑ (95% CI 1–2) | |||||||||
| Rifampin (strong CYP3A inducer) | Study 1; tablet AUC0–∞ 87% ↓ (90% CI 84–89) | Avoid coadministration of strong and moderate CYP3A inducers | Clinical trial | Food and Drug Administration, (2014c); Dirix et al. (2016) | |||||
| Study 2; capsule AUC 71% ↓ (95% CI 69–73) | PBPK simulation | Pilla Reddy et al. (2019) | |||||||
| Efavirenz (moderate CYP3A inducer) | Study 1; tablet AUC 59% ↓ (95% CI 58–62) | PBPK simulation | Food and Drug Administration, (2014c) | ||||||
| Study 2; tablet AUC 60% ↓ (95% CI 57–62) | PBPK simulation | Pilla Reddy et al. (2019) | |||||||
| Study 2; capsule AUC 53% ↓ (95% CI 50–56) | |||||||||
| Dexamethasone (weak CYP3A inducer) | Tablet AUC 0 (95% CI −1–0) | PBPK simulation | Pilla Reddy et al. (2019) | ||||||
| Capsule AUC 0 (95% CI −1–0) | |||||||||
| Osimertinib (2015) | CYP3A | EGFR | 37% | Dose proportional exposure | Itraconazole (strong CYP3A inhibitor) | AUC0–∞ 24.2% ↑ (90% CI 14.6–34.5) | None | Clinical trial | European Medicines Agency Committee for Medicinal Products For Human Use (CHMP) (2016a) and Vishwanathan et al. (2018) |
| AZ5104 AUC0–∞ 8.3% ↑ (90% CI −5.6–24.2) | |||||||||
| AZ7550 AUC 51% ↓ (90% CI 45–56.3) | |||||||||
| Rifampin (strong CYP3A inducer) | AUC0-24h 78.5% ↓ (90% CI 76.2–80.5) | Avoid coadministration of strong and moderate CYP3A inducers | Clinical trial | European Medicines Agency Committee for Medicinal Products For Human Use (CHMP) (2016a) and Vishwanathan et al. (2018) | |||||
| AZ5104 AUC0-24h 81.2% ↓ (90% CI 78.8–83.4) | |||||||||
| AZ7550 AUC0-24h 29.8% ↑ (19.1–41.4) | |||||||||
| Efavirenz (moderate CYP3A inducer) | AUC 42% ↓ (95% CI 40–44) | PBPK simulation | Reddy et al. (2018) | ||||||
| Dexamethasone (weak CYP3A inducer) | AUC 0.001% ↓ (95% CI 0.001–0.001) | PBPK simulation | Reddy et al. (2018) | ||||||
| Palbociclib (2015) | CYP3A | CDK4/6 | 29% | Dose proportional exposure | Itraconazole (strong CYP3A inhibitor) | AUC0–∞ 86.8% ↑ (90% CI 72.9–101.9) | Avoid coadministration of strong CYP3A inhibitors or reduce dose of palbociclib to 75 mg QD | Clinical trial | Food and Drug Administration (2014d) and European Medicines Agency Committee for Medicinal Products For Human Use (CHMP) (2016b) |
| Diltiazem (moderate CYP3A inhibitor) | AUC0–216h 42% ↑ | PBPK simulation | Yu et al. (2017) | ||||||
| Verapamil (moderate CYP3A inhibitor) | AUC0–216h 38% ↑ | PBPK simulation | Yu et al. (2017) | ||||||
| Fluvoxamine (weak inhibitor) | AUC0–216h 0.4% ↑ | PBPK simulation | Yu et al. (2017) | ||||||
| Fluoxetine (weak CYP3A inhibitor) | AUC0–216h 0.3% ↑ | PBPK simulation | Yu et al. (2017) | ||||||
| Rifampin (strong CYP3A inducer) | AUC0–∞ 85.2% ↓ (90% CI 81.4–88.2) | Avoid coadministration of strong CYP3A inducers | Clinical trial | Food and Drug Administration (2014d) | |||||
| Efavirenz (moderate CYP3A inducer) | AUC0–168h 38% ↓ | PBPK simulation | Yu et al. (2017) | ||||||
| Palbociclib (2015) | CYP3A | CDK4/6 | 29% | Dose proportional exposure | Modafinil (moderate CYP3A inducer) | AUC0–∞ 32% ↓ | Avoid coadministration of strong CYP3A inducers | Clinical trial | European Medicines Agency Committee for Medicinal Products For Human Use (CHMP) (2016b) |
| Sonidegib (2015) | CYP3A | Smooth-ened | CL/F 67% V/F 213% | Dose proportional exposure with doses up to 400 mg, with higher dose less than pro-portional (due to dose-dependent absorption) | Ketoconazole (strong CYP3A inhibitor) | Study 1; healthy subjects AUC0–240h 125% ↑ (90% CI 78–186) | Reduce dose of sonidegib to 200 mg every other day when combined with strong CYP3A inhibitors | Clinical trial | European Medicines Agency Committee for Medicinal Products For Human Use (CHMP), (2015c), and Food and Drug Administration (2015d) |
| Study 2; cancer patients, sonidegib 1 day, ketoconazole 14 days AUC0–24h 42% ↑ (90% CI 39–45) | PBPK simulation | Food and Drug Administration (2015d) and Einolf et al. (2017) | |||||||
| Study 2; sonidegib 120 days, ketoconazole 120 days AUC0-24h 253% ↑ (90% CI 231–276) | |||||||||
| Study 2; sonidegib 133 days, ketoconazole 14 days AUC0–24h 101% ↑ (90% CI 92–111) | |||||||||
| Study 2; sonidegib QOD 133 days, ketoconazole 14 days AUC0–24h 93% ↑ (90% CI 84–102) | |||||||||
| Sonidegib (2015) | CYP3A | Smooth-ened | CL/F 67% V/F 213% | Dose proportional exposure with doses up to 400 mg, with higher dose less than proportional (due to dose-dependent absorption) | Erythromycin (moderate CYP3A inhibitor) | Sonidegib 1 day, erythromycin 14 days AUC0–24h 36% ↑ (90% CI 33–39) | Reduce dose of sonidegib to 200 mg every other day when combined with strong CYP3A inhibitors | PBPK simulation | Food and Drug Administration (2015d) and Einolf et al. (2017) |
| Sonidegib 120 days, erythromycin 120 days AUC0–24h 179% ↑ (90% CI 76–361) | |||||||||
| Sonidegib 133 days, erythromycin 14 days AUC0–24h 79% ↑ (90% CI 71–86) | |||||||||
| Rifampin (strong CYP3A inducer) | Study 1; healthy subjects AUC0–240h 72.4% ↓ (90% CI 65.1–78.1) | Avoid coadministration of strong CYP3A inducers, but if necessary, consider to increase the dose to 400–800 mg | Clinical trial | European Medicines Agency Committee for Medicinal Products For Human Use (CHMP) (2015c) and Food and Drug Administration (2015d) | |||||
| Study 2; cancer patients, sonidegib 1 day, rifampin 14 days AUC0–24h 66% ↓ (90% CI 63–68) | PBPK simulation | Food and Drug Administration (2015d) and Einolf et al. (2017) | |||||||
| Study 2; sonidegib 120 days, rifampin 120 days AUC0-24h 88% ↓ (90% CI 87–89) | |||||||||
| Study 2; sonidegib 133 days, rifampin 14 days AUC0–24h 80% ↓ (90% CI 78–82) | |||||||||
| Sonidegib (2015) | CYP3A | Smooth-ened | CL/F 67% V/F 213% | Dose proportional exposure with doses up to 400 mg, with higher dose less than proportional (due to dose-dependent absorption) | Efavirenz (moderate CYP3A inducer) | Sonidegib 1 day, efavirenz 14 days AUC0–24h 29% ↓ (90% CI 26–31) | Avoid coadministration of strong CYP3A inducers, but if necessary, consider to increase the dose to 400–800 mg | PBPK simulation | Food and Drug Administration (2015d) and Einolf et al. (2017) |
| Sonidegib 120 days, efavirenz 120 days AUC0-24h 65% ↓ (90% CI 62–67) | |||||||||
| Sonidegib 133 days, efavirenz 14 days AUC0–24h 53% ↓ (90% CI 50–56) | |||||||||
| Sunitinib (2006) | CYP3A | VEGFR | 40% | Dose proportional exposure | Ketoconazole (strong CYP3A inhibitor) | Sum sunitinib and SU12662 AUC0–∞ 51% ↑ | Reduce dose of sunitinib to 37,5 mg QD in GIST and MRCC patients and to 25 mg QD in pancreatic/NET patients when combined with strong CYP3A inhibitors | Clinical trial | Food and Drug Administration (2005) |
| Grapefruit juice (moderate CYP3A inhibitor) | AUC0–24h 11% ↑ | Clinical trial | Van Erp et al. (2011) | ||||||
| Rifampin (strong CYP3A inducer) | Sum sunitinib and SU12662 AUC0–∞ 46% ↓ | Increase the dose of sunitinib in steps of 12.5 mg with a maximum of 87.5 mg QD when combined with CYP3A inducers | Clinical trial | Food and Drug Administration (2005) |