Rozlytrek Drug Interactions

Effects of entrectinib on others drugs: CYP substrates: Based on the in vitro studies in human liver microsomes, entrectinib exhibits inhibitory potential toward CYP3A.
In vitro studies indicate that entrectinib and its major active metabolite, M5, do not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP2D6 at clinically relevant concentrations.
In vitro results indicate entrectinib has weak induction potential toward CYP3A and CYP2C8/9.
In a clinical study, co-administration of multiple doses of entrectinib and midazolam, a sensitive CYP3A substrate, increased the systemic exposure of midazolam by approximately 50% indicating a weak inhibitory effect of entrectinib on the metabolism of midazolam (Geometric mean ratio (GMR) with/without entrectinib for AUCinf (90% CI) was 150% (129%, 173%)).
Therefore, no dose adjustment is required when ROZLYTREK is co-administered with CYP3A substrates.
P-gp substrates: In vitro data suggest that entrectinib has inhibitory potential towards P-gp.
In a clinical study, co-administration of a single oral dose of entrectinib with a sensitive P-gp substrate, digoxin, increased the digoxin C_max by approximately 28% and overall exposure by approximately 18% (GMR with/without entrectinib for C_max (90% CI) was 128% (98.2%, 167%) and AUC_inf (90% CI) was 118% (106%, 132%)). The renal clearance of digoxin was similar between treatments of digoxin alone and digoxin co-administered with entrectinib, indicating minimal effect of entrectinib on renal clearance of digoxin.
These results indicate that entrectinib is a weak P-gp inhibitor and that no clinically significant interaction exists between digoxin, as a P-gp substrate, and entrectinib. Therefore, no dose adjustment is required when ROZLYTREK is co-administered with P-gp substrates.
BCRP substrates: As with P-gp, a mild inhibition of BCRP was observed in in vitro studies. Given that no clinically significant interaction was observed with the P-gp substrate digoxin, an interaction with BCRP is not predicted. No dose adjustment is required when ROZLYTREK is co-administered with BCRP substrates.
Other transporter substrates: In vitro data indicate that entrectinib has weak inhibitory potential toward organic anion-transporting polypeptide (OATP) 1B1 and multidrug and toxin extrusion protein 1 (MATE1).
Oral Contraceptive: Physiologically-based pharmacokinetic simulation of the effects of co-administration of multiple oral doses of entrectinib with ethinyl estradiol, an oral contraceptive, predicted no drug-drug interaction. GMR with/without entrectinib for AUC_inf (90% CI) of 112% (111%, 113%) and C_max (90% CI) was 112% (111%, 113%).
Therefore, ROZLYTREK can be co-administered with an oral contraceptive.
Effects of other drugs on entrectinib: Based on in vitro data, CYP3A4 is the predominant enzyme mediating the metabolism of entrectinib and formation of its major active metabolite M5.
CYP3A inducers: Co-administration of multiple oral doses of rifampin, a strong CYP3A inducer, with a single oral dose of entrectinib reduced the systemic exposure of entrectinib by 77%. GMR with/without rifampin for AUC_inf (90% CI) was 23.3% (18.4%, 29.5%) and C_max (90% CI) was 44.4% (35.3%, 55.9%).
Co-administration of ROZLYTREK with CYP3A inducers should be avoided (see Dosage & Administration).
CYP3A inhibitors: Co-administration of a single oral dose of entrectinib with multiple oral doses of itraconazole, a strong CYP3A4 inhibitor, increased the systemic exposure of entrectinib by 500%. GMR with/without itraconazole for AUC_inf (90% CI) was 604% (454%, 804%) and C_max (90% CI) was 173% (137%, 218%).
Co-administration of strong and moderate CYP3A inhibitors (including, but not limited to, anti-fungal agents, anti-retroviral agents) with ROZLYTREK should be avoided or limited to 14 days. If concurrent use is unavoidable, dose adjustment of ROZLYTREK is required as described in Dosage & Administration.
Medicinal products that increase gastric pH: The aqueous solubility of entrectinib in vitro is pH dependent. In a clinical study, administration of entrectinib with lansoprazole (a proton pump inhibitor (PPI)), resulted in a 25% decrease in entrectinib systemic exposure which is not clinically relevant. GMR with/without lansoprazole for AUC_inf (90% CI) was 74.5% (64.7%, 85.9%) and C_max (90% CI) was 76.5% (67.6%, 86.6%).
Therefore, no dose adjustments are required when ROZLYTREK is co-administered with PPIs or other drugs that raise gastric pH (e.g., H2 receptor antagonists or antacids).
Effect of transporters on Entrectinib disposition: Based on the in vivo brain-to-plasma concentration ratio (≥0.6) at steady-state in rats and dogs as well as lack of sensitivity to a P-gp inhibitor in vitro in a P-gp expressing cell assay, entrectinib is considered a poor substrate of P-gp. M5 is a substrate of P-gp.
Entrectinib is not a substrate of BCRP but M5 is a substrate of BCRP. Entrectinib and M5 are not substrates of OATP1B1 or OATP1B3.