Authors: Chan, Jean L.¹; Wong, Shekman L.²; Mantzoros, Christos S.¹

Source: Clinical Pharmacokinetics, Volume 47, Number 11, 2008 , pp. 753-764(12)

Publisher: Adis International

Abstract:

Background: Recombinant methionyl human leptin (r-metHuLeptin) has demonstrated efficacy in improving hormonal and metabolic parameters in leptin-deficient states, and it has been suggested that leptin replacement may reverse metabolic adaptations during weight loss interventions. The pharmacokinetics of subcutaneously administered r-metHuLeptin have been recently published, but whether pharmacokinetic parameters are altered by short-term fasting, adiposity and/or gender has not yet been evaluated.

Objective: The objective of this study was to characterize pharmacokinetic parameters following subcutaneous r-metHuLeptin administration at doses in the physiological to supra-physiological to pharmacological range in the fed state and during 3-day complete fasting in lean and obese subjects, including both men and women.

Methods: We analysed pharmacokinetic profiles in five lean men, five obese men and five lean women following subcutaneous administration of physiological (0.01 mg/kg), supra-physiological (0.1 mg/kg) and pharmacological (0.3 mg/kg) doses of r-metHuLeptin given once in the fed state and once daily during 3-day complete caloric deprivation (fasting).

Results: With r-metHuLeptin administration at 0.01 mg/kg, leptin concentrations ranged up to ~7 ng/mL in lean men, ~20 ng/mL in obese men and ~30 ng/mL in lean women in the fed state. There was a significant effect of 3-day fasting: it decreased baseline leptin concentrations, peak serum concentration (C_max) and area under the serum concentration-time curve from time zero to infinity (AUC_∞) [all p < 0.0001] and increased clearance (p < 0.001), most prominently in lean men (p < 0.0001 across the groups). Administration of r-metHuLeptin at 0.1 mg/kg resulted in leptin concentrations up to ~70 ng/mL in lean men, ~100 ng/mL in obese men and ~150 ng/mL in lean women in the fed state. At this dose, there was a similar effect of fasting on the pharmacokinetic parameters as well as a decrease in the terminal-phase elimination half-life (p = 0.02), consistent with increased clearance, but the effect of fasting was less pronounced overall than with the 0.01 mg/kg dose. With r-metHuLeptin administration at 0.3 mg/kg, leptin concentrations ranged up to ~150 ng/mL in lean men, ~300 ng/mL in obese men and ~400 ng/mL in lean women in the fed state. At this dose, fasting increased clearance to a lesser degree (p = 0.046), mainly in lean men, suggesting that the fasting-induced increase in leptin clearance by the kidneys can plateau. Within each group, the subjects lost ~3-4 kg of bodyweight after 3 days of fasting (all p < 0.0001), but the amount and time course of weight loss did not differ according to the dose of r-metHuLeptin administered or the circulating leptin concentrations achieved.

Conclusions: Short-term fasting in healthy individuals results in increased clearance of leptin; this contributes to hypoleptinaemia, which may serve as a signal to increase energy intake in the setting of caloric restriction. Obese individuals with greater energy stores at baseline have a blunted response to the fasting-induced increase in leptin clearance. Also, women have a differential response to fasting, with primarily decreased leptin production rather than increased clearance. These findings and the resulting formulas for calculating doses for r-metHuLeptin administration have important implications for future therapeutic use of r-metHuLeptin in conjunction with hypocaloric diets for the treatment of obesity.

Keywords: Adipokines; Fasting; Gender differences; Metreleptin; Research and development; Weight loss

Document Type: Research article

Affiliations: 1: 1 Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA 2: 2 Theravance, Inc., South San Francisco, California, USA

Publication date: 2008-01-01

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