Pazopanib - Drug-Drug Interactions

The main drug-drug interactions associated with pazopanib include

CYP3A4 Inhibitors/Inducers

CYP3A4 Inhibitors^1,2

Co-administration of strong CYP3A4 inhibitors increases pazopanib concentrations. Concomitant ketoconazole increased the mean pazopanib AUC(0-24) and C_max by 66% and 45%, respectively, relative to pazopanib alone.²

QT prolongators

QTc Interval-Prolonging Drugs

QT prolongation and Torsade de Pointes has been reported with pazopanib; use with caution in patients taking anti-arrhythmic drugs or other drugs that may prolong the QT interval.²

Other Drug-drug Interactions

P-glycoprotein and BCRP Inhibitors^1,2

Strong inhibitors of P-gp and BCRP may increase exposure to pazopanib.¹ Co-administration of 1500 mg lapatinib (a weak inhibitor of CYP3A4 and P-gp and a potent BCRP inhibitor) with 800 mg pazopanib increased the mean pazopanib AUC_(0-24) and Cmax by 50-60% compared to pazopanib alone.^1,2 Co-administration with potent P-gp or BCRP inhibitors may alter the distribution of pazopanib, including distribution into the central nervous systems (CNS).²

CYP3A4, P-gp, and BCRP Inducers^1,2

CYP3A4 inducers such as rifampicin may decrease plasma pazopanib concentrations. Co-administration of pazopanib with strong P-gp or BCRP inducers may alter the exposure and distribution of pazopanib, including distribution into the CNS.²

CYP3A4, CYP2D6, and CYP2C8 Substrates

Co-administration of pazopanib led to an increase of ~30% in the mean AUC and C_max of midazolam (CYP3A4 substrate); increases of 33-64% in the ratio of dextrometrophan to dextrophan in the urine after oral administration of dextromethorphan (CYP2D6 substrate); and increases of 25%-31% in the AUC and C_max of paclitaxel (CYP3A4 and CYP2C8 substrate).^1,2

UGT1A1 and OATP1B1 Substrates

Pazopanib may increase concentrations of drugs eliminated by UGT1A1 (uridine diphosphoglucuronosyl-transferase 1A1) and OATP1B1 (organic anion transporting polypeptide).^1,2

Co-administration of pazopanib 400 mg/day with cetuximab 250 mg/m² and irinotecan 150 mg/m² resulted in an increase of ~20% in systemic exposure to SN-38 (the active metabolite of irinotecan, and a substrate for UGT1A1 and OATP1B1).²

In a meta-analysis, ALT > 3x ULN was reported in 27% of patients given concomitant pazopanib and simvastatin, compared with 14% of those who did not use statins (p = 0.038). Statins are OATP1B1 substrates.^1,2

Medicines that Raise Gastric pH

Pazopanib exhibits pH-dependent solubility.¹ Co-administration of pazopanib and esomeprazole decreased the bioavailability of pazopanib by approximately 40% (AUC and C_max).^1,2

References

1. Food and Drug Administration. Pazopanib (VOTRIENT) Prescribing information. 2015.
2. European Medicines Agency. Pazopanib (VOTRIENT) Summary of Product Characteristics. 2015.