Gavreto Drug Interactions

Pharmacokinetic interactions: In vitro data indicate that pralsetinib is primarily metabolised by CYP3A4 and transported by P-gp. Therefore, inducers and inhibitors of CYP3A4 and P-gp may alter the plasma concentrations of pralsetinib.
Active substances that may have an effect on pralsetinib: Strong CYP3A4 inhibitors or combined P-gp and strong CYP3A4 inhibitors: Co-administration of pralsetinib with strong CYP3A4 inhibitors or combined P-gp and strong CYP3A4 inhibitors can increase pralsetinib plasma concentrations, which may increase the incidence and severity of adverse reactions of pralsetinib. Co-administration of 200 mg pralsetinib once daily with itraconazole 200 mg once daily (a strong CYP3A4 and P-gp inhibitor) increased pralsetinib C_max by 84% and AUC_0-∞ by 251%, compared to pralsetinib administered alone.
Therefore, co-administration of pralsetinib with strong CYP3A4 inhibitors or combined P-gp and strong CYP3A4 inhibitors (including, but not limited to, ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole nefazodone, grapefruit or Seville oranges) should be avoided (see Precautions). If co-administration with strong CYP3A4 inhibitors or combined P-gp and strong CYP3A4 inhibitors cannot be avoided, reduce the current dose of pralsetinib (see Dosage & Administration).
Strong CYP3A4 inducers: Co-administration of pralsetinib with strong CYP3A4 inducers can decrease pralsetinib plasma concentrations, which may decrease the efficacy of pralsetinib. Co-administration of 400 mg pralsetinib as a single dose with rifampin 600 mg once daily (a strong CYP3A4 inducer) decreased pralsetinib C_max by 30% and AUC_0-∞ by 68%. Based on a population PK analysis, CYP3A4 weak inducers decreased pralsetinib exposures, but were not clinically significant in patients with NSCLC.
Therefore, co-administration of pralsetinib with strong CYP3A4 inducers (including, but not limited to, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin and St. John's Wort [Hypericum perforatum]) should be avoided (see Precautions). If co-administration cannot be avoided, increase the pralsetinib dose (see Dosage & Administration).
Sensitive substrates of CYP3A4, CYP2C8, CYP2C9, P-gp, BCRP, OATP1B1, OATP1B3, OAT1, MATE1 and MATE2-K with narrow therapeutic index: Co-administration of pralsetinib can alter the exposure of sensitive substrates of CYP enzymes (CYP3A4, CYP2C9 and CYP2C8) and transporters (P-gp, BCRP, OATP1B1, OATP1B3, OAT1, MATE1 and MATE2-K). Substrate drugs of these CYP enzymes and transporters with narrow therapeutic index (including, but not limited to cyclosporine, paclitaxel and warfarin) should be avoided.