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United States Department of Agriculture

Agricultural Research Service

Title: PHARMACOKINETICS OF RECOMBINANT METHIONYL HUMAN LEPTIN (RL) IN LEAN AND OBESE SUBJECTS FOLLOWING SINGLE SUBCUTANEOUS ADMINISTRATION)

Author
item Lau, David
item Dixon, Russell
item Greenberg, Andrew
item Heymsfield, Steven
item Fujiola, Ken
item Kushner, Robert
item Hunt, Thomas
item Patane, Janet
item Staten, Myrlene
item Mccamish, Mark

Submitted to: Diabetes
Publication Type: Abstract Only
Publication Acceptance Date: 5/1/1998
Publication Date: N/A
Citation: LAU, D., DIXON, R., GREENBERG, A.S., HEYMSFIELD, S.B., FUJIOLA, K., KUSHNER, R., HUNT, T., PATANE, J., STATEN, M., MCCAMISH, M. PHARMACOKINETICS OF RECOMBINANT METHIONYL HUMAN LEPTIN (RL) IN LEAN AND OBESE SUBJECTS FOLLOWING SINGLE SUBCUTANEOUS ADMINISTRATION. DIABETES. 1998.

Interpretive Summary:

Technical Abstract: The pharmacokinetic properties of rL (Amgen Inc.) were examined following the first bolus subcutaneous dose in 54 lean (BMI 20.0-27.4 kg/m2) and 73 obese (BMI 27.5-36.0kg/m2) subjects in a randomized, double-blind, placebo-controlled, escalating dose cohort trial. A total of 89 subjects received rL (at 0.01, 0.03, 0.2, or 0.3 mg/kg) and 38 subjects received placebo. Serum concentrations were determined by an immunoassay that detected both endogenous leptin and rL. Endogenous leptin profiles within the 24-hour sampling period were examined in the placebo subjects. The baseline leptin levels varied substantially among these subjects (0.22-109 ng/mL). A diurnal rhythm, characterized by a nocturnal peak, was observed. In rL-treated subjects, estimates of rL serum concentrations were made by subtracting projected endogenous leptin concentrations derived from matched placebo subjects. Pharmacokinetic parameters were calculated from the baseline-subtracted rL concentrations using noncompartmental methods. Average serum rL concentrations peaked between 3-4 hours following the subcutaneous dose. Peak serum concentrations and the area-under-the-serum- concentration-curve (AUC) increased linearly with dose. The terminal half-life of rL averaged approximately 4 hours. Estimated bioavailability of rL was 90%. These data showed that: 1) rL was rapidly and extensively absorbed following subcutaneous administration, 2) the half-like of rL was similar to the half-lives of other small proteins (<20 kd in MW), and 3) rL exhibited linear pharmacokinetics over the dose-range tested, suggesting that rL-treated subjects received dose-proportional exposure to rL in this study. Based on these results, daily or twice-daily SC administration of rL appears appropriate for further study.

Last Modified: 8/24/2016
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