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

Abstract

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 I_max were 6.8 ng/mL and 63.5%, respectively, based on inhibitory E_max model. The PK parameters, such as clearance (CL), volume of distribution at steady state (Vd_ss), and the absorption rates (k_a), were then scaled to human’s. The scaled human CL and Vd_ss 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).

Keywords:

• PYY(3–36)
• PK/PD
• pulmonary drug delivery
• modeling and simulation
• inhaled peptide

Disclosure statement

No potential conflict of interest was reported by the authors.