Preliminary Open-Labeled Study to Examine the Effect of Cilastatin on the Pharmacokinetics of Cisplatin in Patients with Lung Cancer Undergoing Cisplatin-Based Chemotherapy

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Background: In animal studies, the nephrotoxicity of cisplatin (CDDP) is reduced by cilastatin (CS), which is thought to be related to the function of the endocytosis receptor megalin in proximal tubular cells, and CS may antagonize megalin and reduce the nephrotoxicity of CDDP. CS is approved as a combination drug (Thienam®, imipenem-cilastatin sodium), not as a single agent, and its effects on the pharmacokinetics of CDDP in humans have not been examined. To evaluate the pharmacokinetics and safety of CDDP when Thienam® is administered during chemotherapy including CDDP in patients with non-small cell lung cancer (NSCLC). Methods: Patients, aged >20 years but not >70 years with advanced stage NSCLC not amenable to surgery or radical irradiation, who had not previously received chemotherapy and had an eGFR of 60 mL/min/1.73 m2 or higher, were included. Patients were administered pembrolizumab (200 mg/body) and pemetrexed (500 mg/m2) followed by intravenous Thienam® and then CDDP (75 mg/m2). The primary endpoint was the pharmacokinetics of CDDP in combination with CS, which was evaluated with serum platinum concentrations. Results: Patients were sequentially administered 0, 0.5, and 1.0 g of Thienam®, and a total of nine patients, three in each group, were enrolled in the study. The median age was 65 (range, 47-70) years and eight (89%) patients were men. The stages were unresectable stage III in one, stage IVA in four, and stage IVB in four patients. The Cmax was 2.44±0.09, 2.61±0.34, and 2.43±0.26 μg/mL, T1/2 was 114.9±14.5, 114.6±31.7, 76.8±3.4 h, and area under the curve (AUC) was 8574±1418, 8184±2480, and 7764±1217 μg/mL min in the 0, 0.5, and 1 g thienam groups, respectively. No serious adverse events occurred; only one case of grade 3 or higher adverse event (leukopenia) occurred, which was thought to be due to chemotherapy. Conclusions: In chemotherapy, including CDDP administered to chemotherapy-naive patients with advanced NSCLC, the T1/2 and AUC of serum platinum concentration were decreased, particularly in the high-dose thienam group. It might be due to the suppression of megalin-mediated renal uptake and retrieval of CDDP by CS (Trial registration: jRCTs031180329). Funding: Clinical Revenue Support

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