Pharmacokinetics of Subcutaneous Recombinant Methionyl Human Leptin Administration in Healthy Subjects in the Fed and Fasting States

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.