Population Pharmacokinetic–Pharmacodynamic Modeling of Subcutaneous and Pulmonary Insulin in Rats

Author： Gopalakrishnan Mathangi Suarez Sandra Hickey Anthony Gobburu Jogarao

ISSN： 1567-567X

Source： Journal of Pharmacokinetics and Pharmacodynamics, Vol.32, Iss.3-4, 2005-08, pp. : 485-500

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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 μ 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.