Table 2.
DDIs with drug transporters.
| MKI | Substrate | Inhibits | Cmax | AUC | Clinical implications | Interaction potential | References |
|---|---|---|---|---|---|---|---|
| Afatinib | P-gp, BCRP | in vitro: P-gp, BCRP | Ritonavir: 38% increase Rifampicin: 22% decrease |
Ritonavir: 48% increase Rifampicin: 34% decrease |
For strong P-gp and BCRP inhibitors (e.g. ritonavir, cyclosporine); use staggered dosing, preferably 6 h or 12 h apart from afatinib. When afatinib is administered with a strong P-gp inducer (e.g. rifampicin) increase the afatinib dose with 10 mg with close monitoring of side effects. For substrates of P-gp and BCRP close monitoring of side effects is recommended. | Moderate | EMA;14 US FDA;15
Wind and colleagues43 |
| Alectinib | M4 is a P-gp substrate | in vitro: P-gp, BCRP | NA | NA | When alectinib is co-administered with P-gp or BCRP substrates appropriate monitoring of side effects of these substrates is recommended. | Minor | EMA;14 US FDA;15
Morcos and colleagues44 |
| Axitinib | P-gp, BCRP | in vitro: P-gp, BCRP | NA | NA | appropriate monitoring of side effects is recommended when axitinib is used with P-gp and BCRP substrates or inhibitors and inducers. | Minor, since there is only in vitro evidence and axitinib is only a weak P-gp and BCRP substrate | EMA;14 US FDA15 |
| Bosutinib | P-gp |
in vitro: P-gp, BCRP, OCT1 dabigatran (P-gp substrate): no effect on dabigatran pharmacokinetics |
NA | NA | Clinical relevant interactions with drug transporters are not likely to appear. | Minor | EMA;14 US FDA;15
Abbas and colleagues;18 Hsyu and colleagues45 |
| Cabozantinib | MRP2 | in vitro: P-gp, BCRP, MATE1, MATE2 | NA | NA | Appropriate monitoring is recommended when using substrates of P-gp of BCRP. Interactions with MATE1-2 in clinically relevant concentrations are unlikely. If necessary, a 20 mg dose alteration may be applied. Close monitoring of side effects is warranted when administered with strong MRP2 inhibitors (e.g. cyclosporine). | Moderate | EMA;14 US FDA15 |
| Ceritinib | P-gp | P-gp, BCRP | NA | NA | Concomitant administration with strong inducers or inhibitors of P-gp must be avoided since plasma concentration of ceritinib might be altered. Close monitoring of side effects is warranted when administered with P-gp or BCRP substrates. However CYP DDIs are of greater influence. | Minor, since interactions regarding CYP enzymes are of greater clinical importance | EMA;14 US FDA15 |
| Cobimetinib | P-gp | in vitro: BCRP, OATP1B1, OATP1B3, OCT1 | NA | NA | Concomitant administration with strong P-gp inducers or inhibitors must be avoided. Appropriate monitoring is recommended when using BCRP, OATP1B1, OATP1B3, OCT1 substrates. | Moderate | EMA;14 US FDA;15
Musib and colleagues21 |
| Crizotinib | P-gp | in vitro: P-gp, OCT1, OCT2 | NA | NA | Appropriate monitoring of side effects is recommended when using concomitant P-gp substrates, inhibitors and inducers. Furthermore, close monitoring is recommended when using P-gp, OCT1, OCT2 substrates. | Minor, since CYP interactions are of greater clinical importance | EMA;14 US FDA15 |
| Dabrafenib | P-gp, BCRP | in vitro: OATP1B1, OATP1B3, BCRP | Rosuvastatin: 160% increase | Rosuvastatin: 7% increase | Dabrafenib is not likely to have a clinically relevant interaction with OATP1B1, OATP1B3 and BCRP. Concomitant use with substrates of these transporters is considered safe. The influence of P-gp and BCRP inhibitors or inducers is considered to be small since the bioavailability of dabrafenib is high (95%), therefore only limited pharmacokinetic effects can be expected. | Minor | EMA;14 US FDA15 |
| Dasatinib | P-gp, BCRP | NA | NA | NA | Concomitant administration with strong inducers or inhibitors of P-gp and BCRP must be avoided or side effects must be monitored closely when administered with strong inhibitors. | Minor | EMA;14 US FDA;15
Haouala and colleagues46 |
| Erlotinib | P-gp, BCRP | in vitro: OCT2, OAT3 | NA | NA | Concomitant administration with strong inducers or inhibitors of P-gp or BCRP must be avoided since an altered plasma concentration is possible. Administration with OCT2 and OAT3 substrates should be avoided. | Moderate | EMA;14 US FDA;15
Marchetti and colleagues;47 Sprowl and colleagues; Elmeliegy and colleagues49 |
| Gefitinib | P-gp, BCRP | in vitro: BCRP, P-gp | NA | In vitro Irinotecan: AUC irinotecan 63% increase | Concomitant administration with P-gp and BCRP substrates should be avoided. BCRP inhibition is 10-fold stronger than P-gp inhibition. So especially be careful when gefitinib is combined with BCRP substrates. Avoid the use of strong BCRP or P-gp inhibitors or inducers since gefitinib plasma concentration may be altered. |
Moderate | EMA;14 US FDA;15
Stewart and colleagues50 |
| Ibrutinib | NA | in vitro: P-gp, BCRP | NA | NA | When P-gp or BCRP substrates are used, they should be taken at least 6 h before or after ibrutinib intake. Inhibitors or inducers of transporters are not likely to result in clinically meaningful changes in ibrutinib pharmacokinetics and can be used concomitantly. | Minor | EMA;14 US FDA;15
de Jong and colleagues51 |
| Imatinib | P-gp, BCRP | in vitro: BCRP | NA | NA | A clinical relevant interaction with P-gp or BCRP inhibitors or inducers may be possible. Close monitoring of substrate specific side effects is advised when used concomitantly with BCRP substrates. Although the interaction potential is considered to be low. | Minor | EMA;14 US FDA;15
Eechoute and colleagues52 |
| Lapatinib | P-gp, BCRP | in vitro: P-gp, BCRP, OATP1B1 | Digoxin (P-gp substrate): 100% increase (digoxin) | Digoxin (P-gp substrate): 60–80% increase (digoxin) | Lapatinib is highly susceptible for interactions regarding drug transporters. When using P-gp, BCRP, OATP1B1 substrates close monitoring of side effects is recommended. The use of strong P-gp and BCRP inhibitors or inducers should be avoided. | Major | EMA;14 US FDA;15
Koch and colleagues53 |
| Lenvatinib | P-gp, BCRP, MDR1 | in vitro: P-gp, BCRP, OATP1B3 | Ketoconazole: 19% increase single-dose rifampicin: 33% increase |
Ketoconazole: 15% increase single-dose rifampicin: 31% increase |
Clinical relevant interactions with strong inhibitors or inducers of P-gp, BCRP are not likely to appear, but close monitoring for lenvatinib specific side effects is recommended. Concomitant administration with P-gp, BCRP and OATP1B3 substrates should be avoided. | Minor | EMA;14 US FDA;15
Shumaker and colleagues 54,55 |
| Nilotinib | P-gp, BCRP | in vitro: P-gp, BCRP | NA | Imatinib (CYP3A4/P-gp inhibitor): nilotinib AUC increased with 18–40% | Concomitant administration with strong P-gp or BCRP inducers or inhibitors must be avoided since an altered plasma concentration is possible otherwise side effects should be monitored closely. | Minor | EMA;14 US FDA;15
Lemos and colleagues56 |
| Nintedanib | P-gp | in vitro: P-gp, OCT1, BCRP | Ketoconazole: 83% increase Rifampicin: 60% decrease |
Ketoconazole: 61% increase Rifampicin: 50% decrease |
when administered with strong P-gp inhibitors a 100 mg step-wise dose reduction must be considered. The duration of therapy with strong inducers must be minimized since inadequate plasma levels of nintedanib might occur. Concomitant administration with P-gp, BCRP and OCT1 substrates should be avoided. | Major | EMA;14 US FDA15 |
| Osimertinib | P-gp, BCRP | in vitro: P-gp, BCRP | Rosuvastatin (BCRP substrate): 72% increase | Rosuvastatin (BCRP substrate): 35% increase | Concomitant administration with strong P-gp and BCRP inducers or inhibitors must be avoided since an altered plasma concentration is likely. When co-administered with BCRP or P-gp substrates close monitoring of side effects is recommended. | Minor | EMA;14 US FDA15 |
| Pazopanib | P-gp, BCRP | in vitro: OATP1B1, P-gp, BCRP | Lapatinib (P-gp and BCRP inhibitor) 60% Increase | Lapatinib (P-gp and BCRP inhibitor): 50% increase | Co-administration with strong P-gp or BCRP inhibitors must be avoided. Close monitoring of side effects is advised when used concomitantly with P-gp or BCRP substrates. | Moderate | EMA;14 US FDA15 |
| Ponatinib | P-gp, BCRP | in vitro: P-gp, BCRP | NA | NA | Appropriate monitoring is recommended when co-administered with P-gp or BCRP substrates. Also, the use of strong inhibitors or inducers of P-gp, BCRP must be avoided, although DDI potential is considered to be low since ponatinib is only a weak substrate for P-gp and BCRP. | Minor | EMA;14 US FDA15 |
| Regorafenib | P-gp, BCRP |
in vitro: BCRP regorafenib has no effect on digoxin AUC |
Rosuvastatin (BCRP substrate): 360% increase | Rosuvastatin (BCRP substrate): 280% increase | BCRP substrates should be used with caution. When administered with strong inhibitors or inducers of P-gp and BCRP close observation of side effects is warranted. | Major | EMA;14 US FDA15 |
| Ruxolitinib | NA | in vitro: P-gp, BCRP | NA | NA | When ruxolitinib is administered with P-gp or BCRP substrates close monitoring of side effects is advised for these substrates. DDI potential can be minimized if time between administration is kept apart as long as possible. | Minor | EMA;14 US FDA15 |
| Sorafenib | P-gp, OATP1B1, OATP1B3, MRP2-3 | P-gp | NA | NA | Concomitant administration with strong inhibitors or inducers of P-gp, OATP1B1, OATP1B3 and MRP2-3 should be avoided. Administration with P-gp substrates should be done with caution. | Moderate | EMA;14 US FDA;15
Bins and colleagues57 |
| Sunitinib | P-gp |
in vitro: P-gp, BCRP co-administration with gefitinib (BCRP inhibitor) did not result in significant AUC changes of sunitinib |
NA | NA | Appropriate monitoring is recommended when co-administered with P-gp or BCRP substrates. Also, the use of strong inhibitors or inducers of P-gp must be avoided. | Minor | EMA;14 US FDA15 |
| Tivozanib | NA | in vitro: BCRP | NA | NA | Co-administration with BCRP substrates must be avoided or side effects must be monitored closely. | Minor | EMA;14 US FDA15 |
| Trametinib | P-gp | in vitro: P-gp, BCRP, OAT1, OAT3, OATP1B1, OATP1B3, OATP2B1, OCT2, and MATE1 | NA | NA | Co-administration of strong inhibitors or inducers of P-gp must be avoided. When P-gp, BCRP, OAT1, OAT3, OATP1B1, OATP1B3, OCT2 and MATE1 substrates are used, staggered dosing must be applied (at least 2 h apart) to minimize DDI risk. However, based on the low dose and low clinical systemic exposure relative to the in vitro inhibition or induction potential this is not expected to be of in vivo significance. | Minor | EMA;14 US FDA15 |
| Vandetanib | NA | in vitro: P-gp, BCRP, OCT2 | Metformin (OCT-2 substrate) increased with 50% Digoxin (P-gp substrate) increased with 29% |
Metformin (OCT-2 substrate) increased with 74% Digoxin (P-gp substrate) increased with 23% |
Co-administration with P-gp, BCRP, OCT2 substrates must be avoided and side effects must be monitored closely. Concomitant intake with strong inhibitors or inducers of drug transporters is safe. | Moderate | EMA;14 US FDA;15
Johansson and colleagues35 |
| Vemurafenib | P-gp, BCRP | in vitro: P-gp, BCRP | Digoxin (P-gp substrate) increased 50% | Digoxin (P-gp substrate) increased 80% | Concomitant administration with strong inhibitors or inducers of P-gp and BCRP should be avoided. Appropriate monitoring is recommended when co-administered with P-gp or BCRP substrates. | Major | EMA;14 US FDA;15
Zhang and colleagues59 |
Clinical relevance is scored by means of the US FDA Clinical Drug Interaction Studies, Study Design, Data Analysis, and Clinical Implications Guidance for Industry as a guideline as major (AUC increase ⩾80%), moderate (AUC increase ⩾50 to <80%), minor (AUC increase ⩾20 to <50%) taken into account the available evidence for both change in AUC of MKI and change in AUC for transporter substrates, since there is no separate scoring system for drug transporter interactions. If there was no clinical evidence, clinical relevance was estimated on the basis of available evidence regarding inhibitory concentrations and the assessment report. Interaction potential was then scored as minor or at most moderate.
Strong drug transporter inhibitors: P-gp: amiodarone, carvedilol, clarithromycin, dronedarone, itraconazole, lapatinib, lopinavir, propafenone, quinidine, ranolazine, ritonavir, saquinavir, telaprevir, tipranavir and ritonavir, verapamil. BCRP: curcumin, cyclosporine, eltrombopag OATP1B1/OATP1B3: atazanavir, ritonavir, clarithromycin, cyclosporine, erythromycin, gemfibrozil, lopinavir, rifampin (single dose), simeprevir OAT1/OAT3: p-aminohippuric acid (PAH), probenecid, teriflunomide, MATE1/MATE2-K: cimetidine, dolutegravir, isavuconazole, ranolazine, trimethoprim, vandetanib strong drug transporter inducers: P-gp: rifampicin, carbamazepine, phenytoin, St. John’s wort, ritonavir.10,41,58
AUC, area under the curve; BCRP, breast cancer resistance protein (ABCG2); DDI, drug–drug interaction; EMA, European Medicines Agency; MATE; multi-antimicrobial extrusion protein; MKI, multikinase inhibitor; MRP, multidrug resistance associated protein; NA, not applicable or only preclinical data available; OAT, organic anion transporters; OATP, organic anion transporting peptides; OCT, organic cation transporters; P-gp, P-glycoprotein (ABCB1); US FDA, United States Food and Drug Administration.