Prolactin (Prl) is an anterior pituitary peptide hormone which is found in women and men. Prl serum levels in women are substantially higher than in men, and more markedly so during pregnancy. In women, Prl functions in the initiation and maintenance of lactation. Prl is also synthesized at extrapituitary sites where it mediates local function; for example, by lymphocytes where it demonstrates immune system effects much like a cytokine. Prl has potential for therapeutic value in the areas of cancer, human immunodeficiency virus, and as a vaccine adjuvant in the elderly. Currently, there is no information on the effects of administration of rhPrl to humans. This investigation explored the pharmacokinetics, dose proportionality, and relative bioavailability of intravenously and subcutaneoously administered rhPrl in normal young women and men. Subjects were monitored for potential adverse effects of acute short-term rhPrl administration. Finally, preliminary assessments of rhPrl effects on the immune system were conducted. This investigation was a fixed-dose, single blind, dose escalation, Phase I crossover study performed to detect common dose-related adverse effects. We recruited healthy women and men between the ages of twenty-one and thirty-four to participate in the study. Each subject received her/his assigned dose level both intravenously and subcutaneously one week apart and in random order. Twenty-four hours after the study drug administration, routine laboratory tests were performed for safety monitoring and immune function. Subjects were observed for adverse effects during and for twenty- four hours after treatment and discharged after a brief exit history and physical. Each subject was readmitted six days after discharge for a second visit in order to receive their assigned doses of rhPrl by the alternate route. A follow-up history and physical examination along with laboratory testing was performed at no less than 21 days after their second dose. Measurements of serum Prl after treatment were used to derive pharmacokinetic parameters including areas under the concentration time curve from 0 to 12 hours, area under the concentration time curve from zero to infinity, peak Prl concentration (Cmax), time to peak concentration (Tmax), elimination rate (the elimination half-life [t1/2]), volume distribution (Vd), and clearance (Cl). Genzyme Corporation laboratories performed the pK and hrPrl anitbody testing. Immune function testing will consist of delayed hypersensitivity skin tests in vivo and evaluation of immune cell function in vitro performed within the Laboratory of Immunology, Gerontology Research Center(GRC)/NIA. Endocrine studies were performed by the GCRC Core Laboratory and by the Endocrine Section, GRC/NIA laboratory, and routine lab testing for screening and safety data were performed by Quest Diagnostics. All testing of statistical significance will be two-sided, and treatment differences resulting in a p- value <0.05 will be considered significant. Should this study reveal beneficial effects with a low adverse effect profile, we anticipate conducting pK and pD investigations in an aging population, as well as pursuing investigations of the potential immune adjuvant effects of rhPrl.
Showing the most recent 10 out of 406 publications
