title: High plasma exposure to pemetrexed leads to severe hyponatremia in patients with advanced non small cell lung cancer receiving pemetrexed-platinum doublet chemotherapy.
abstract: 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.
  
  
  CONCLUSIONS
  Higher exposure to pemetrexed is associated with grade ≥3 hyponatremia. The pharmacogenetic basis for higher exposure to pemetrexed in Indian patients needs further investigation.
authors.affiliation: Department of Clinical Pharmacology, Advanced Centre for Treatment Research and Education in Cancer, Mumbai, India.
authors.forename: Vikram
authors.initials: V
authors.lastname: Gota
authors.affiliation: Department of Clinical Pharmacology, Advanced Centre for Treatment Research and Education in Cancer, Mumbai, India.
authors.forename: Krunal
authors.initials: K
authors.lastname: Kavathiya
authors.affiliation: Department of Clinical Pharmacology, Advanced Centre for Treatment Research and Education in Cancer, Mumbai, India.
authors.forename: Kartik
authors.initials: K
authors.lastname: Doshi
authors.affiliation: Department of Clinical Pharmacology, Advanced Centre for Treatment Research and Education in Cancer, Mumbai, India.
authors.forename: Murari
authors.initials: M
authors.lastname: Gurjar
authors.affiliation: Department of Clinical Pharmacology, Advanced Centre for Treatment Research and Education in Cancer, Mumbai, India.
authors.forename: Solai E
authors.initials: SE
authors.lastname: Damodaran
authors.affiliation: Department of Medical Oncology, Tata Memorial Hospital, Mumbai, India.
authors.forename: Vanita
authors.initials: V
authors.lastname: Noronha
authors.affiliation: Department of Medical Oncology, Tata Memorial Hospital, Mumbai, India.
authors.forename: Amit
authors.initials: A
authors.lastname: Joshi
authors.affiliation: Department of Medical Oncology, Tata Memorial Hospital, Mumbai, India.
authors.forename: Kumar
authors.initials: K
authors.lastname: Prabhash
keywords: non small cell lung carcinoma; pharmacogenetics; pharmacokinetics; platinum compounds