Votrient Drug Interactions

Effects of other medicinal products on pazopanib: In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib.
CYP3A4, P-gp, BCRP Inhibitors: Pazopanib is a substrate for CYP3A4, P-gp and BCRP.
Concurrent administration of pazopanib (400 mg once daily) with the strong CYP3A4 and P-gp inhibitor, ketoconazole (400 mg once daily) for 5 consecutive days, resulted in a 66% and 45% increase in mean pazopanib AUC_(0-24) and C_max, respectively, relative to administration of pazopanib alone (400 mg once daily for 7 days). Pharmacokinetic parameter comparisons of pazopanib C_max (range of means 27.5 to 58.1 μg/mL) and AUC_(0-24) (range of means 48.7 to 1040 μg*h/mL) after administration of pazopanib 800 mg alone and after administration of pazopanib 400 mg plus ketoconazole 400 mg (mean C_max 59.2 μg/mL, mean AUC_(0-24) 1300 μg*h/mL) indicated that, in the presence of a strong CYP3A4 and P-gp inhibitor a dose reduction to pazopanib 400 mg once daily will, in the majority of patients, result in systemic exposure similar to that observed after administration of 800 mg pazopanib once daily alone. Some patients however may have systemic pazopanib exposure greater than what has been observed after administration of 800 mg pazopanib alone.
Co-administration of pazopanib with other strong inhibitors of the CYP3A4 family (e.g. itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase pazopanib concentrations. Grapefruit juice contains an inhibitor of CYP3A4 and may also increase plasma concentrations of pazopanib.
Administration of 1500 mg lapatinib (a substrate for and weak inhibitor of CYP3A4 and P-gp and a potent inhibitor of BCRP) with 800 mg pazopanib resulted in an approximately 50% to 60% increase in mean pazopanib AUC_(0-24) and C_max compared to administration of 800 mg pazopanib alone. Inhibition of P-gp and/or BCRP by lapatinib likely contributed to the increased exposure to pazopanib.
Co-administration of pazopanib with a CYP3A4, P-gp, and BCRP inhibitor, such as lapatinib, will result in an increase in plasma pazopanib concentrations. Co-administration with potent P-gp or BCRP inhibitors may also alter the exposure and distribution of pazopanib, including distribution into the central nervous system (CNS).
Concomitant use of pazopanib with a strong CYP3A4 inhibitor should be avoided (see Precautions). If no medically acceptable alternative to a strong CYP3A4 inhibitor is available, the dose of pazopanib should be reduced to 400 mg daily during concomitant administration. In such cases there should be close attention to adverse drug reaction, and further dose reduction may be considered if possible drug-related adverse events are observed.
Combination with strong P-gp or BCRP inhibitors should be avoided, or selection of an alternate concomitant medicinal product with no or minimal potential to inhibit P-gp or BCRP is recommended.
CYP3A4, P-gp, BCRP inducers: CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations. Co-administration of pazopanib with potent P-gp or BCRP inducers may alter the exposure and distribution of pazopanib, including distribution into the CNS. Selection of an alternative concomitant medication with no or minimal enzyme or transporter induction potential is recommended.
Effects of pazopanib on other medicinal products: In vitro studies with human liver microsomes showed that pazopanib inhibited CYP enzymes 1A2, 3A4, 2B6, 2C8, 2C9, 2C19, and 2E1. Potential induction of human CYP3A4 was demonstrated in an in vitro human PXR assay. Clinical pharmacology studies, using pazopanib 800 mg once daily, have demonstrated that pazopanib does not have a clinically relevant effect on the pharmacokinetics of caffeine (CYP1A2 probe substrate), warfarin (CYP2C9 probe substrate), or omeprazole (CYP2C19 probe substrate) in cancer patients. Pazopanib resulted in an increase of approximately 30% in the mean AUC and C_max of midazolam (CYP3A4 probe substrate) and increases of 33% to 64% in the ratio of dextromethorphan to dextrorphan concentrations in the urine after oral administration of dextromethorphan (CYP2D6 probe substrate). Co-administration of pazopanib 800 mg once daily and paclitaxel 80 mg/m² (CYP3A4 and CYP2C8 substrate) once weekly resulted in a mean increase of 26% and 31% in paclitaxel AUC and C_max, respectively.
Based on in vitro IC₅₀ and in vivo plasma C_max values, pazopanib metabolites GSK1268992 and GSK1268997 may contribute to the net inhibitory effect of pazopanib towards BCRP. Furthermore, inhibition of BCRP and P-gp by pazopanib in the gastrointestinal tract cannot be excluded. Care should be taken when pazopanib is co-administered with other oral BCRP and P-gp substrates.
In vitro, pazopanib inhibited human organic anion transporting polypeptide (OATP1B1). It cannot be excluded that pazopanib will affect the pharmacokinetics of substrates of OATP1B1 (e.g. statins, see "Effect of concomitant use of pazopanib and simvastatin" as follows).
Pazopanib is an inhibitor of the uridine diphosphoglucuronosyl-transferase 1A1 (UGT1A1) enzyme in vitro. The active metabolite of irinotecan, SN-38, is a substrate for OATP1B1 and UGT1A1. Co-administration of pazopanib 400 mg once daily with cetuximab 250 mg/m² and irinotecan 150 mg/m² resulted in an approximately 20% increase in systemic exposure to SN-38. Pazopanib may have a greater impact on SN-38 disposition in subjects with the UGT1A1*28 polymorphism relative to subjects with the wild-type allele. However, the UGT1A1 genotype was not always predictive of the effect of pazopanib on SN-38 disposition. Care should be taken when pazopanib is co-administered with substrates of UGT1A1.
Effect of concomitant use of pazopanib and simvastatin: Concomitant use of pazopanib and simvastatin increases the incidence of ALT elevations. Results from a meta-analysis using pooled data from clinical studies with pazopanib show that ALT >3 x ULN was reported in 126/895 (14%) of patients who did not use statins, compared with 11/41 (27%) of patients who had concomitant use of simvastatin (p=0.038). If a patient receiving concomitant simvastatin develops ALT elevations, follow guidelines for pazopanib posology and discontinue simvastatin (see Precautions). In addition, concomitant use of pazopanib and other statins should be undertaken with caution as there are insufficient data available to assess their impact on ALT levels. It cannot be excluded that pazopanib will affect the pharmacokinetics of other statins (e.g., atorvastatin, fluvastatin, pravastatin, rosuvastatin).
Effect of food on pazopanib: Administration of pazopanib with a high-fat or low-fat meal results in an approximately 2-fold increase in AUC and C_max. Therefore, pazopanib should be administered at least 1 hour before or 2 hours after a meal.
Medicines that raise gastric pH: Concomitant administration of pazopanib with esomeprazole decreases the bioavailability of pazopanib by approximately 40% (AUC and C_max), and co-administration of pazopanib with medicines that increase gastric pH should be avoided. If the concomitant use of a proton-pump inhibitor (PPI) is medically necessary, it is recommended that the dose of pazopanib be taken without food once daily in the evening concomitantly with the PPI. If the concomitant administration of an H2-receptor antagonist is medically necessary, pazopanib should be taken without food at least 2 hours before or at least 10 hours after a dose of an H2-receptor antagonist. Pazopanib should be administered at least 1 hour before or 2 hours after administration of short-acting antacids. The recommendations for how PPIs and H2-receptor antagonists are co-administered are based on physiological considerations.