Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

Tucatinib is primarily metabolised by CYP2C8. Tucatinib is a metabolism-based inactivator of CYP3A and inhibits renal transporters of metformin and creatinine. Tucatinib is a substrate of P–gp.

Effects of other medicinal products on tucatinib

CYP3A/CYP2C8 inducers
A clinical drug interaction study found that co-administration of a single dose of 300 mg tucatinib with rifampicin (a strong CYP3A and moderate CYP2C8 inducer) resulted in a reduction in tucatinib concentrations (0.6-fold Cmax (90% CI: 0.5, 0.8) and 0.5-fold AUC (90% CI: 0.4, 0.6)).
Co-administration of tucatinib with strong CYP3A or moderate CYP2C8 inducers such as rifampicin, phenytoin, St. John's wort, or carbamazepine should be avoided as this may result in decreased activity of tucatinib (see section 4.4).

CYP2C8 inhibitors
A clinical drug interaction study found that co-administration of a single dose of 300 mg tucatinib with gemfibrozil (a strong CYP2C8 inhibitor) resulted in an increase in tucatinib concentrations (1.6-fold Cmax (90% CI: 1.5, 1.8) and 3.0-fold AUC (90% CI: 2.7, 3.5)). Co-administration of tucatinib with strong CYP2C8 inhibitors such as gemfibrozil should be avoided as this may result in increased risk of tucatinib toxicity (see section 4.4).

CYP3A inhibitors
A clinical drug interaction study found that co-administration of a single dose of 300 mg tucatinib with itraconazole (a strong CYP3A inhibitor) resulted in an increase in tucatinib concentrations (1.3-fold Cmax (90% CI: 1.2, 1.4) and 1.3-fold AUC (90% CI: 1.3, 1.4)). No dose adjustment is required.

Proton pump inhibitors
Based on clinical drug interaction studies conducted with tucatinib, no drug interactions were observed when tucatinib is combined with omeprazole (a proton pump inhibitor). No dose adjustment is required.


Effects of tucatinib on other medicinal products
CYP3A substrates
Tucatinib is a strong CYP3A inhibitor. A clinical drug interaction study found that co-administration of tucatinib with midazolam (a sensitive CYP3A substrate) resulted in an increase in midazolam concentrations (3.0-fold Cmax (90% CI: 2.6, 3.4) and 5.7-fold AUC (90% CI: 5.0, 6.5)).
Co-administration of tucatinib with sensitive CYP3A substrates such as alfentanil, avanafil, buspirone, darifenacin, darunavir, ebastine, everolimus, ibrutinib, lomitapide, lovastatin, midazolam, naloxegol, saquinavir, simvastatin, sirolimus, tacrolimus, tipranavir, triazolam, and vardenafil may increase their systemic exposures which may increase the toxicity associated with a CYP3A substrate. Concomitant use of tucatinib with CYP3A substrates, when minimal concentration changes may lead to serious or life-threatening toxicities, should be avoided. If concomitant use is unavoidable, the CYP3A substrate dosage should be decreased in accordance with the concomitant medicinal product SmPC.


 P-gp substrates
A clinical drug interaction study found that co-administration of tucatinib with digoxin (a sensitive P-gp substrate) resulted in an increase in digoxin concentrations (2.4-fold Cmax (90% CI: 1.9, 2.9) and 1.5-fold AUC (90% CI: 1.3, 1.7)). Concomitant use of tucatinib with a P-gp substrate may increase the plasma concentrations of the P-gp substrate, which may increase the toxicity associated with the P-gp substrate. Dose reduction of P-gp substrates (including sensitive intestinal substrate such as dabigatran) should be considered in accordance with the concomitant medicine SmPC and P-gp substrates should be administered with caution when minimal concentration changes may lead to serious or life-threatening toxicities (see section 4.4).

CYP2C8 substrates
A clinical drug interaction study found that co-administration of tucatinib with repaglinide (a CYP2C8 substrate) resulted in an increase in repaglinide concentrations (1.7-fold Cmax (90% CI: 1.4, 2.1) and 1.7-fold AUC (90% CI: 1.5, 1.9)). No dose adjustment is required.

MATE1/2K substrates
A clinical drug interaction study found that co-administration of tucatinib with metformin (a MATE1/2-K substrate) resulted in an increase in metformin concentrations (1.1-fold Cmax (90% CI: 1.0, 1.2) and 1.4-fold AUC (90% CI: 1.2, 1.5)). Tucatinib reduced the renal clearance of metformin without any effect on glomerular filtration rate (GFR) as measured by iohexol clearance and serum cystatin C. No dose adjustment is required.

CYP2C9 substrates
Based on clinical drug interaction studies conducted with tucatinib, no drug interactions were observed when tucatinib is combined with tolbutamide (a sensitive CYP2C9 substrate). No dose adjustment is required.