Pharmacokinetic and pharmacodynamic modeling of gut hormone peptide YY(3–36) after pulmonary delivery. (3rd July 2019)

• Record Type: Journal Article
• Authors: Shao, Jie; Chen, Mong-Jen; Kuehl, Philip J.; Hochhaus, Guenther
• Is Part Of: Drug development and industrial pharmacy. Volume 45:Number 7(2019)
• Page Start: 1101
• Page End: 1110
• Publication Date: 2019-07-03
• Subjects: PYY(3–36) -- PK/PD -- pulmonary drug delivery -- modeling and simulation -- inhaled peptide; Pharmaceutical chemistry -- Periodicals; Pharmaceutical industry -- Periodicals; Drug Industry -- Periodicals; Technology, Pharmaceutical -- Periodicals; 615.05
• DOI: 10.1080/03639045.2019.1593443
• Languages: English
• ISSNs: 0363-9045

Abstract

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 (Vdss ), and the absorption rates ( k a ), 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) .