Population pharmacokinetic-pharmacodynamic modeling of subcutaneous and pulmonary insulin in rats

Abstract

Purpose: To develop a population pharmacokinetic-pharmacodynamic (PKPD) model for insulin in rats. Methods: Rats were administered insulin either subcutaneously (s.c) (0.26,1.3,2.6 U/kg) or by pulmonary route (spray-instillation (s.i)) (0.26,1.3,2.6,13,26 U/kg). Insulin (0.26,1.3,2.6 U/kg) combined with different combinations of hydroxy methyl amino propionic acid (HMAP: 5,10,16,25 mg/kg) was also administered by spray-instillation. Plasma insulin and glucose concentrations at pre-determined time points were measured. Population pharmacokinetic-pharmacodynamic modeling was performed using NONMEM. Results: Insulin exhibited dose-disproportional PK across formulations and routes of administration. The kinetic model suggested monoexponential disposition with simultaneous first order (64%-dimeric form of insulin) - zero order (36%-hexameric form of insulin) absorption. Maximum relative bioavailability (relative to s.c - 0.26 U/kg) of spray-instilled insulin was 46%. Addition of HMAP increased the relative bioavailability of insulin administered via spray-instilled route by 40%. The insulin-glucose relationship was characterized using an indirect response model, wherein, insulin stimulation of glucose uptake into muscle cells was assumed. The basal zero order production rate of glucose (k(G, prod)) was estimated as 0.98 mg/dl/min. The SC50 was fixed at 80 mu U/ml based on literature reports and the S-max was estimated to be 6. Conclusions: The proposed PKPD model satisfactorily describes insulin disposition and glucose concentrations across range of doses with and without HMAP