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Dosage Efficacy Interactions Prescribing Information Quality of Life Safety Information Testing and Method of Administration Patient Resource Materials
InteractionsXALKORI® (crizotinib) is a substrate of CYP3A4/5 and also a moderate, time-dependent inhibitor of CYP3A1

XALKORI® (crizotinib) is an inhibitor of CYP2B6 in vitro. XALKORI® (crizotinib) may have the potential to increase plasma concentrations of coadministered medicines that are predominantly metabolised by CYP2B61

Coadministration of crizotinib with medicines that increase gastric pH:1
The aqueous solubility of crizotinib is pH dependent, with low (acidic) pH resulting in higher solubility. Administration of a single 250 mg crizotinib dose following treatment with esomeprazole 40 mg once daily for 5 days resulted in an approximately 10 % decrease in crizotinib total exposure (AUCinf) and no change in peak exposure (Cmax); the extent of the change in total exposure was not clinically meaningful. Therefore, starting dose adjustment is not required when crizotinib is coadministered with medicines that increase gastric pH (such as proton-pump inhibitors, H2 blockers or antacids).

Coadministration of crizotinib and CYP3A substrates1
  • Crizotinib has been identified as an inhibitor of CYP3A both in vitro and in vivo. Following 28 days of crizotinib dosing at 250 mg taken twice daily in cancer patients, the oral midazolam AUC was 3,7-fold (90 % CI: 2,63 - 5,07) those seen when midazolam was administered alone, suggesting that crizotinib is a moderate inhibitor of CYP3A.
Coadministration of crizotinib and CYP3A inhibitors1
  • Coadministration of a single 150 mg oral dose of crizotinib in the presence of ketoconazole (200 mg twice daily), a strong CYP3A inhibitor, resulted in increases in crizotinib systemic exposure, with crizotinib AUCinf and Cmax values that were approximately 3,2-fold and 1,4-fold respectively, those seen when crizotinib was administered alone. However, the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been established.
Coadministration of crizotinib and CYP3A inducers1
  • Coadministration of crizotinib (250 mg twice daily) with rifampin (600 mg once daily), a strong CYP3A inducer, resulted in 84 % and 79 % decreases in crizotinib steady-state AUCtau and Cmax, respectively, compared to when crizotinib was given alone.
Coadministration with other CYP substrates:1
  • In vitro studies indicated that clinical drug-drug interactions are unlikely to occur as a result of crizotinib-mediated inhibition of the metabolism of medicines that are substrates for CYP1A2, CYP2C8, CYP2C9, CYP2C19 or CYP2D6. Crizotinib is an inhibitor of CYP2B6 in vitro. Therefore, crizotinib may have the potential to increase plasma concentrations of coadministered medicines that are predominantly metabolised by CYP2B6.
  • In vitro studies in human hepatocytes indicated that clinical interactions are unlikely to occur as a result of crizotinib-mediated induction of the metabolism of medicines that are substrates for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP3A.
References:Pfizer Laboratories (Pty) Ltd. XALKORI® 200 mg and 250 mg capsules Package Insert, approved 20 March 2018.

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