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Leptin Hormonal Kinetics in the Fed State: Effects of Adiposity, Age, and Gender on Endogenous Leptin Production and Clearance Rates

Departments of Pharmacokinetics and Drug Metabolism (S.L.W.) and Clinical Research (A.M.D.), Amgen Inc., Thousand Oaks, California 91320; and Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine (J.H.L., C.S.M.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215

Address all correspondence and requests for reprints to: Christos S. Mantzoros, M.D., D.Sc., Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Stoneman 816, Boston, Massachusetts 02215. E-mail: cmantzor{at}bidmc.harvard.edu.

Leptin is an adipocyte-secreted hormone that regulates energy homeostasis and neuroendocrine function. Replacement therapy with recombinant methionyl human leptin (r-metHuLeptin) improves obesity, insulin resistance, hyperlipidemia, and neuroendocrine dysfunction associated with low-leptin states. We administered three doses of r-metHuLeptin (0.1, 0.3, and 1.0 mg/kg) to healthy subjects to determine r-metHuLeptin pharmacokinetics in the fed state, to determine endogenous leptin production and clearance rates, and to study the effects of age, body mass index, gender, and race on r-metHuLeptin pharmacokinetics.

We detected no dose-dependent effects on elimination half-life (t_1/2), dose-normalized area under the curve (nAUC_0–), total body clearance (CL), or volume of distribution at steady state. The mean t_1/2, CL, and volume of distribution at steady state of r-metHuLeptin are 3.4 ± 1.5 h, 79 ± 16 ml/kg·h, and 150 ± 39 ml/kg, respectively. Older subjects have a higher nAUC_0– (P = 0.003) and tend to have a decreased leptin production rate (R_syn) and CL (P = 0.01). Increased body mass index is associated with higher baseline endogenous leptin levels (P < 0.0001), higher R_syn (P < 0.0001), and longer t_1/2 (P = 0.008). Females have significantly greater baseline endogenous leptin levels and R_syn than males (P < 0.0001).

In summary, the leptin production rate is increased in females and with increasing adiposity, whereas leptin clearance is decreased with increasing adiposity, and nAUC_0– is increased with age. Elucidation of leptin pharmacokinetic parameters allows the accurate calculation of exogenous leptin replacement doses for humans in the fed state.

This work was supported by Amgen Inc., National Institutes of Health (NIH) Grant RO1-58785 (to C.S.M.), NIH Training Grant 5T32DK07516-18 (to J.H.L.), and an Eli Lilly and Co. fellowship award.

S.L.W. and A.M.D. contributed equally to this work.

Abbreviations: ANCOVA, Analysis of covariance; BMI, body mass index; CL, total body clearance; CL_out, clearance of endogenous leptin; L₀, baseline serum concentration of endogenous leptin; nAUC_0–, dose-normalized area under the curve; r-metHuLeptin, recombinant methionyl human leptin; R_syn, endogenous production rate of leptin; t_1/2, elimination half-life; V_ss, volume of distribution at steady state.

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