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Effects of alectinib on others drugs: CYP substrates: In vitro studies indicate that neither alectinib nor its major active metabolite (M4) inhibits CYP1A2, CYP2B6, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant concentrations. Alectinib and M4 show weak time-dependent inhibition of CYP3A4. In vitro, alectinib exhibits a weak induction potential of CYP3A4 and CYP2B6 at clinical concentrations.
Results from a clinical drug-drug interaction study in ALK-positive NSCLC patients demonstrated that multiple doses of alectinib had no influence on the exposure of midazolam, a sensitive CYP3A substrate. Therefore, no dose adjustment is required for co-administered CYP3A substrates.
Although in vitro studies indicate that alectinib is an inhibitor of CYP2C8, physiologically based pharmacokinetic (PBPK) modeling supports that at clinically relevant concentrations alectinib does not have the potential to increase plasma concentrations of co-administered substrates of CYP2C8.
P-gp and BCRP substrates: In vitro, alectinib and M4 are inhibitors of the efflux transporters P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). Therefore, alectinib may have the potential to increase plasma concentrations of co-administered substrates of P-gp or BCRP transporters (the increase in exposure is not expected to be more than 2-fold). When alectinib is co-administered with P-gp or BCRP substrates with narrow therapeutic index (e.g. digoxin, dabigatran, methotrexate), appropriate monitoring is recommended.
Effects of other drugs on alectinib: Based on in vitro data, CYP3A4 is the primary enzyme mediating the metabolism of both alectinib and its major active metabolite M4, and CYP3A contributes to 40%-50% of total hepatic metabolism. M4 has shown similar in vitro potency and activity to alectinib against ALK.
CYP3A inducers: Co-administration of multiple oral doses of 600 mg rifampicin once daily, a strong CYP3A inducer, with a single oral dose of 600 mg alectinib exhibited a minor effect on combined exposure of alectinib and M4 (geometric mean ratio with/without rifampicin [90% confidence interval]: Cmax: 0.96 [0.88-1.05], AUCinf: 0.82 [0.74-0.90]). Therefore, no dose adjustments are required when Alecensa is co-administered with CYP3A inducers.
CYP3A inhibitors: Co-administration of multiple oral doses of 400 mg posaconazole twice daily, a strong CYP3A inhibitor, with a single oral dose of 300 mg alectinib had a minor effect on combined exposure of alectinib and M4 (geometric mean ratio with/without posaconazole [90% confidence interval]: Cmax: 0.93 [0.81-1.08], AUCinf: 1.36 [1.24-1.49]). Therefore, no dose adjustments are required when Alecensa is co-administered with CYP3A inhibitors.
Medicinal products that increase gastric pH: Although the aqueous solubility of alectinib in vitro is pH dependent, a dedicated clinical drug-drug interaction study with 40 mg esomeprazole once daily, a proton pump inhibitor, demonstrated no clinically relevant effect on the combined exposure of alectinib and M4. Therefore, no dose adjustments are required when Alecensa is co-administered with proton pump inhibitors or other drugs which raise gastric pH (e.g. H2 receptor antagonists or antacids).
Effect of transporters on alectinib disposition: Based on in vitro data, alectinib is not a substrate of P-gp. Alectinib and M4 are not substrates of BCRP or Organic anion-transporting polypeptide (OATP) 1B1/B3. In contrast, M4 is a substrate of P-gp. Alectinib inhibits P-gp, and therefore, it is not expected that co-medication with P-gp inhibitors has a relevant effect on M4 exposure.
