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.