Importance of Therapeutic Drug Monitoring to Detect Drug Interaction between Pazopanib and Warfarin: A Case Report

Abstract

Pazopanib is an orally available multi-tyrosine kinase inhibitor and has been used to treat renal cell carcinoma (RCC). Here, we report the case of a patient with RCC with an increased prothrombin time-international normalized ratio (PT-INR) due to pazopanib therapy. In addition, we have reported the change in the blood levels of pazopanib. A 75-year-old man underwent a left nephrectomy for RCC. Four years later, his cancer recurred and pazopanib therapy was initiated. He was also taking warfarin for atrial fibrillation and his PT-INR was constant at approximately 2. His warfarin dose was reduced from 3.5 mg/day to 3.0 mg/day on day 10 because his PT-INR increased from 2.19 to 3.07 compared to that before starting pazopanib. On day 28, his PT-INR further increased to 4.34, and his aspartate aminotransferase, alanine transaminase, and alkaline phosphatase levels increased. The target concentration of pazopanib was 20.5 to 50.3 µg/mL, but his blood concentrations were 92.1 µg/mL on day 6 and 93.7 µg/mL on day 13. Therefore, both pazopanib and warfarin were discontinued. One week later, his laboratory tests recovered, and hence, warfarin treatment was resumed. However, pazopanib therapy was terminated due to concerns about liver dysfunction. His hepatic dysfunction and increased PT-INR were considered to be due to pazopanib treatment. Pazopanib has been reported to have no effect on the pharmacokinetics of warfarin in clinical patients. In this case, blood levels of pazopanib were abnormally high, possibly causing liver dysfunction and drug interactions, leading to his PT-INR prolongation. TDM monitoring, in addition to the recommended monitoring for pazopanib hepatotoxicity, may help identify patients at risk for drug interactions. For patients receiving concomitant pazopanib and warfarin, close monitoring of PT-INR is warranted.

Clinical Importance of Plasma Drug Concentration of Oral Molecular Targeted Drugs for Renal Cell Carcinoma

“…Compared with other drugs, there were fewer dose regulation interventions for pazopanib, which could be because its starting dose was lower than the usual 800 mg and the incidence of adverse events was low. In addition, one case that was useful in discovering the drug interaction confirmed in this study has already been previously reported (47). Recently, Noda et al (34) reported that the effective plasma concentration of pazopanib was in the range of 20.5 to 50.3 µg/mL, and they recommended a dose adjustment to this target range in the future.…”

Combination Therapy of Pembrolizumab plus Axitinib for a Patient on Hemodialysis with Metastatic Renal Cell Carcinoma: A Case Report

“…Conversely, long-term administration of sorafenib and sunitinib for >2 years in patients on HD could be safe and effective without major problems [ 8 ]. Since our TKI clearance findings strongly depended on the individuals from our study, therapeutic drug monitoring for TKIs could be reported to contribute to minimizing AEs [ 9 , 10 ].…”

Therapeutic Drug Monitoring of Pazopanib in Renal Cell Carcinoma and Soft Tissue Sarcoma: A Systematic Review

“…[17][18][19] Pazopanib weakly inhibits the OATP1B1 transport protein, but this inhibition was characterized as having only a low potential for clinically relevant OATP1B1-mediated interactions. 20 Although pazopanib is not capable of inhibiting CYP2C9, warfarin levels may be increased secondary to pazopanib-induced hepatotoxicity, as reported by Takasaki et al 21 This hepatotoxicity is likely caused by the aldehyde metabolite of pazopanib, which reduces the integrity and viability of hepatocytes. [22][23][24] Vanishing bile duct syndrome during pazopanib treatment has also been described.…”