Pazopanib and Statin-Induced Rhabdomyolysis

Abstract

Background: The VEGF inhibitor pazopanib is a widely used first-line therapy for the treatment of advanced renal cell carcinoma. Potential drug-drug interactions and toxicities may be underrecognized. Case Presentation: A 73-year-old woman with metastatic renal cell carcinoma on treatment with pazopanib presented with progressive inability to ambulate. The initial concern was for metastasis to the spine. However, MRI of the spine revealed diffuse muscle edema with no metastatic deposits or lytic lesions. Upon further evaluation, creatine kinase was significantly elevated and the diagnosis of rhabdomyolysis was made. With aggressive hydration and discontinuation of both pazopanib and rosuvastatin, the patient made a full recovery. Conclusion: This case of drug-induced rhabdomyolysis demonstrates an unexpected toxicity resulting from concomitant pazopanib and rosuvastatin therapy. This combination is predicted to be safe due to different, nonoverlapping effects on the cytochrome p450 enzymes. Discontinuation of statin therapy in patients with metastatic cancer should be considered when the risk of cancer-related death exceeds the risk of cardiovascular-related death.

Differences in discontinuation of statin treatment in women and men with advanced cancer disease

“…All lipid-soluble statins, e.g., simvastatin and atorvastatin, are metabolized by hepatic cytochrome P450 (CYP) enzymes, while the water-soluble pravastatin is mainly eliminated in the urine. In cancer patients with concomitant drugs that inhibit CYP3A4, e.g., fluconazole, there is a risk of drug-drug interactions with increased concentrations of lipid-soluble statins and subsequently increased risk of adverse events and myotoxicity [ 34 , 35 ].…”

Influence of Tyrosine Kinase Inhibition on Organic Anion Transporting Polypeptide 1B3-Mediated Uptake

“…1). These findings imply that TKImediated DDIs involving OATP1B substrates may be more devastating than originally anticipated, as absence of both OATP1B1 and OATP1B3, which often compensate for one another, would significantly increase the systemic concentrations and risk of adverse events for a variety of drugs (Kendra et al, 2015;Martin et al, 2016;Strumberg et al, 2016;Logue et al, 2017; https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/ 202806s002lbl.pdf).…”

“…Recently, there have been reports of DDIs involving OATP1B substrates and tyrosine kinase inhibitors (TKIs) (Kendra et al, 2015;Martin et al, 2016;Logue et al, 2017;Strumberg et al, 2016; https://www.accessdata.fda.gov/ drugsatfda_docs/label/2014/202806s002lbl.pdf), and some TKIs have been identified as OATP1B inhibitors in vitro (Pahwa et al, 2017;Leblanc et al, 2018;Kayesh et al, 2021) . TKIs are a class of drugs used to treat a variety of diseases including cancer, rheumatoid arthritis, and neurologic disorders (Gomez-Puerta and M ocsai, 2013;Ga ˛gało et al, 2015;Pottier et al, 2020).…”

Electrolytes disturbances in cancer patients

“…First, transcellular shift; during cells breakdown, the tumour cells and myocytes release their intracellular potassium content into the blood, contributing to the sudden rise in potassium concentration in patients with TLS and rhabdomyolysis, respectively. Rhabdomyolysis is a rare complication in cancer and is described in case reports as a paraneoplastic syndrome or in association with cancer therapy, including immune checkpoint inhibitor (CPI, nivolumab and pembrolizumab), alkylating agents (ifosfamide and cyclophosphamide), antimetabolite (pemetrexed, cytarabine, azacytidine) tyrosine kinase inhibitors (pazopanib and sunitinib), hormonal therapy (abiraterone), and others (lenalidomide and bortezomib) [47][48][49][50][51][52][53][54][55][56].…”