Prognostic significance of pretreatment sodium levels in patients of nonsmall cell lung cancer treated with pemetrexed-platinum doublet chemotherapy.

BACKGROUND: Recent studies have shown pretreatment sodium level to be a predictive and prognostic marker in nonsmall cell lung cancer (NSCLC) patients treated with erlotinib. The objective of this study was to evaluate the prognostic significance of pretreatment sodium levels on progression-free survival (PFS) and overall survival (OS) in patients of NSCLC treated with pemetrexed-platinum doublet chemotherapy. PATIENTS AND METHODS: Stage IIIb/IV NSCLC patients aged ≥18 years for whom baseline serum sodium level was available were included in this retrospective study. All patients received standard pemetrexed-cisplatin/carboplatin doublet for six cycles followed by maintenance pemetrexed till progression. Electronic medical record database of our hospital was used to retrieve demographic data, pretreatment sodium levels, and survival data. Normal serum sodium (NSS) was defined as serum sodium ≥136 mEq/L, and low serum sodium (LSS) was defined as serum sodium <136 mEq/L. The impact of sodium levels on PFS and OS after adjusting other prognostic factors was estimated using Cox proportional hazard model. RESULTS: Data were available for 257 patients (male/female = 182/75) with median age of 55 (21-78) years. A total of 120 (46%) patients had LSS whereas 137 (54%) had NSS. Patients with NSS had significantly longer median PFS (7 months vs. 6 months; P < 0.05) and OS (16 months vs. 11 months; P < 0.05) compared to LSS group. Multivariate analysis showed LSS as an independent prognostic variable for poor survival (hazard ratio = 2.07, 95% confidence interval = 1.11-3.84). CONCLUSION: Pretreatment serum sodium level is an important prognostic marker in Stage IIIb/IV NSCLC patients. The simple possibility of testing coupled with low cost makes it an attractive biomarker.

Biodistribution and Pharmacokinetic Study of 3,3' Diseleno Dipropionic Acid (DSePA), A Synthetic Radioprotector, in Mice.

BACKGROUND AND OBJECTIVES: 3,3' Diseleno dipropionic acid (DSePA), a synthetic compound has been shown to have radioprotective activity, especially as a lung radioprotector. In this study, the pharmacokinetics and biodistribution of DSePA in MX-1 tumour bearing SCID mice were evaluated. METHODS: Twenty SCID mice were administered DSePA (50 mg/kg bodyweight) by oral gavage following which four animals each were sacrificed at 15, 30 min, 1, 2 and 4 h. Blood and tissue samples were collected for determination of DSePA concentration by graphite furnace atomic absorption spectrometry (GFAAS) method. The control group (n = 4) was administered sterile water and sacrificed at 4 h. RESULTS: Peak plasma concentration (C max) of 2.7 µg/ml was observed at 15 min which returned to near baseline (baseline = 0.6 µg/ml) at 1 h following drug administration. Biphasic pharmacokinetics characterized by rapid distribution phase and a slower elimination phase were observed. Highest maximal concentration (C max) of the drug was observed in lung (19.2 µg/g at 30 min) followed by intestine (14.64 µg/g at 15 min) and kidney (12.96 µg/g at 15 min). There was negligible uptake in tumor tissue and no uptake in brain. CONCLUSIONS: DSePA has a favorable pharmacokinetic profile which makes it a potentially good candidate for further development as a radioprotective agent.

High plasma exposure to pemetrexed leads to severe hyponatremia in patients with advanced non small cell lung cancer receiving pemetrexed-platinum doublet chemotherapy.

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.