Pharmacokinetic and pharmacodynamic modeling of gut hormone peptide YY(3–36) after pulmonary delivery

Peptide YY(3-36) (PYY(3-36)) is an endogenous appetite suppressing peptide. The present research was to perform pharmacokinetic/pharmacodynamic (PK/PD) analysis for predicting the concentration- and response-time profiles of PYY(3-36) after systemic and pulmonary delivery in mice, with the goal of suggesting a potential pulmonary dosing regimen in humans. A PK/PD model was developed to describe PYY(3-36) plasma concentration - and relative food intake rate ratio (as % of control) - time profiles after intraperitoneal and subcutaneous administration, and inhalation in mice. The absorption of inhaled PYY(3-36) from the lungs of mice could only be described with a combined slow (absorption rate of 0.147 L/h) and fast (absorption rate of 104.4 L/h) absorption process, presumably related to absorption from the central and peripheral regions of the lungs. The estimates for IC50 and Imax were 6.8 ng/mL and 63.5%, respectively, based on inhibitory Emax model. The PK parameters, such as clearance (CL), volume of distribution at steady state (Vdss), and the absorption rates (ka), were then scaled to human's. The scaled human CL and Vdss for obese subjects were 24.8 L/h and 9.0 L, respectively. The model predicted human plasma PYY(3-36) concentrations agreed reasonably well with placebo-normalized plasma PYY(3-36) concentrations after short-term infusion and SC injection in literature. An inhalation dose of PYY(3-36) of about 100 µg was proposed for obese subjects based on simulations. This PK/PD analysis satisfactorily described PYY(3-36) concentration-time and relative food intake rate ratio- time profiles at all doses and routes. The developed model might facilitate the inhalation dose selection of PYY(3-36).