Pharmacogenomics Guided Dosing of Tyrosine Kinase Inhibitors in a Patient with Renal Cell Carcinoma

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Cytochrome P450 (CYP) enzymes play a crucial role in the human body. These enzymes are responsible for the synthesis of steroid hormones and cholesterol, as well as the metabolism of external substances such as medications. While more than 50 CYP enzymes have been identified, just 6 are credited with metabolizing most drugs. Of note is CYP 3A4, which metabolizes ~34% of medications that use the CYP enzyme system. CYP enzymes are polymorphic, meaning there are different versions of the same enzyme; therefore there is variability from individual to individual in their ability to metabolize medications. In the oncology field tyrosine kinase has been identified as an important target controlling cell regulatory functions and proliferation. Thus, tyrosine kinase inhibitors have become widely used for a variety of malignancies. Many of these tyrosine kinase inhibitors rely on CYP 3A4 for metabolism and are subject to variable toxicities based on an individual patient’s genome.

A 62-year-old female was diagnosed with Renal Cell Carcinoma (RCC). After undergoing a left nephrectomy, a surveillance scan 21 months after diagnosis was concerning for metastatic disease, which was then confirmed through biopsy. The patient was started on sunitinib 50 mg on days 1-28 of a six-week cycle for metastatic RCC. The patient suffered from Grade 3 myelosupression/mucositis within two weeks of the initiation of therapy. The early onset and severity of the toxicity lead to CYP 3A4 pharmacogenetic testing. She was subsequently found to have a 3A4 polymorphism (*1/*28). The dose of sunitinib was reduced to 25 mg followed by a further reduction to 12.5 mg due to toxicity. Eighteen months after starting sunitinib, a CT scan showed disease progression and therapy was changed to pazopanib. Due to her 3A4 polymorphism, the starting pazopanib dose was empirically reduced by 50% and was started at 400 mg/daily. Pazopanib was held for episodes of severe diarrhea and was further reduced to 200 mg/daily. Nine months after starting pazopanib, new imaging showed lesions in the patient’s liver, confirming disease progression. The patient was subsequently started on nivolumab but quickly progressed. She was then started on cabozantinib at a dose reduced 20 mg/daily. This initial dosing was tolerated well by the patient, so a decision was made to alternate between 20 and 40 mg/daily to increase to an average of 30 mg/daily. She is currently tolerating the 30 mg/daily and continues treatment for metastatic RCC.

As described above, CYP 3A4 polymorphisms can result in severe toxicities that present earlier in the treatment course than traditionally expected. Moving forward there may be a role in testing for these polymorphisms to determine an individual’s optimal dose before initiating therapy with tyrosine kinase inhibitors. The advantage of performing such testing would be to limit the severity of toxicities experienced by this patient population, while retaining the overall benefit of these medications.


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