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Vikram Gota,1 Krunal Kavathiya,1 Kartik Doshi,1 Murari Gurjar,1 Solai E Damodaran,1 Vanita Noronha,2 Amit Joshi,2 Kumar Prabhash2 1Department of Clinical Pharmacology, Advanced Centre for Treatment Research and Education in Cancer, 2Department of Medical Oncology, Tata Memorial Hospital, Mumbai, India Background: Pemetrexed-platinum doublet therapy is a standard treatment for stage IIIb/IV nonsquamous non small cell lung cancer (NSCLC). While the regimen is associated with several grade ≥3 toxicities, hyponatremia is not a commonly reported adverse effect. Here we report an unusually high incidence of grade ≥3 hyponatremia in Indian patients receiving pemetrexed-platinum doublet, and the pharmacological basis for this phenomenon. Methods: Forty-six patients with advanced NSCLC were enrolled for a bioequivalence study of two pemetrexed formulations. All patients received the pemetrexed-platinum doublet for six cycles followed by single-agent pemetrexed maintenance until progression. Pharmacokinetic blood samples were collected at predefined time points during the first cycle and the concentration-time profile of pemetrexed was investigated by noncompartmental analysis. Hyponatremic episodes were investigated with serum electrolytes, serum osmolality, urinary sodium, and urine osmolality. Results: Sixteen of 46 patients (35%) had at least one episode of grade ≥3 hyponatremia. Twenty-four episodes of grade ≥3 hyponatremia were observed in 200 cycles of doublet chemotherapy. Plasma exposure to pemetrexed was significantly higher in patients with high-grade hyponatremia than in those with low-grade or no hyponatremia (P=0.063 and P=0.001, respectively). Pemetrexed clearance in high-grade hyponatremia was quite low compared with normal and low-grade hyponatremia (P=0.001 and P=0.055, respectively). Median pemetrexed exposure in this cohort was much higher than that reported in the literature from Western studies. Conclusion: Higher exposure to pemetrexed is associated with grade ≥3 hyponatremia. The pharmacogenetic basis for higher exposure to pemetrexed in Indian patients needs further investigation. Keywords: non small cell lung carcinoma, platinum compounds, pharmacokinetics, pharmacogenetics

The study aimed to compare the pharmacokinetics of 2 pemetrexed formulations (Pemgem, Dr. Reddy's Laboratories w.r.t; Alimta, Eli Lilly) in adult chemonaive subjects with adenocarcinoma stage III/IV non-small cell lung cancer. All patients received 500 mg/m 2 pemetrexed (Alimta or Pemgem) as a 10-minute infusion on day 1 of a 21-day cycle. Plasma pemetrexed concentrations were determined on day 1 of cycle 1. Area under the concentration-time curve (AUC 0-inf ) and the maximum plasma concentration (C max ) were estimated using noncompartment analysis and compared between the 2 arms. Forty-eight patients were enrolled in the study, 24 in each arm. Patient demographics were comparable in both arms. Mean AUC 0-inf for the generic and innovator formulations was 218.2 ± 19.18 and 223.6 ± 34.24 μg·h/mL, respectively, and mean C max was 119 ± 13.44 and 113 ± 7.26 μg/mL, respectively. Volume of distribution of pemetrexed was 17.5 and 27.6 L, clearance was 4.2 versus 4.72 L/h, and half-life was 4.3 and 4.83 h in the 2 arms respectively. Both formulations showed comparable response rates (objective response of 45% versus 50% in the Pemgem and Alimta arms, respectively) and similar safety profiles. To conclude, Pemgem showed pharmacokinetic and safety profiles similar to Alimta. Substitution of Alimta with Pemgem will be cost-effective and likely to yield comparable efficacy., (© 2017, The American College of Clinical Pharmacology.)