Silber HE (1), Steffan J (2), Peyrou M (3), King S (4), Pigeolet E (1)
(1) Modeling & Simulation, Novartis Pharma AG, Basel, Switzerland. (2) Novartis Animal Health Inc., Basel, Switzerland. (3) Novartis Animal Health, Centre de Recherche Sante Animale SA, Saint-Aubin, Switzerland. (4) Novartis Animal Health US Inc., Greensboro, USA.
Objectives: To evaluate the pharmacokinetics of cyclosporine A (CsA) in healthy cats following single dose administration and to explore the effect of food on the resulting blood concentration time profile.
Methods: The dataset was based on a four-way cross over study in 12 healthy cats. Each cat was given 1 intravenous (i.v.) dose and 3 oral doses. The i.v. dose was 2 mg/kg and the oral dose was 7 mg/kg. The i.v. dose was given to fasted cats and the oral dose was given to fasted or fed cats, or mixed with food. Blood concentrations were measured up to 72 hours following each dose. A 2-week wash out period separated each dose from the previous. A population pharmacokinetic model was developed using non-linear mixed effects modeling in NONMEM VI [1]. Different structural models for disposition and absorption were evaluated to obtain the best description of the data. The effect of food on rate and extent of absorption was investigated. Goodness-of-fit was assessed using the objective function value for comparison of competing models in combination with graphical assessment. Standard errors of the model parameters were derived using a bootstrap (n=100). The predictive properties were assessed by a VPC (n=1000).
Results: A linear 3-compartment model was found to describe the blood concentrations of CsA following single dose administration. The absorption was described using a transit compartment model [2]. The absorption rate was about 4 fold lower when CsA was mixed in food and more than 10-fold lower when administered to fed compared to fasted cats. Bioavailability was reduced from 26% to 20% when CsA was given to fed cats compared to when CsA was given to fasted cats or mixed with food. These results were in line with previous results from the non compartment analysis. Precision of parameter estimates was obtained using a bootstrap and most parameters were found to be estimated with high certainty (RSE<30%). Some of the absorption parameters as well as the inter-individual parameter estimates had a higher standard error estimate (RSE ~ 50%). The VPC showed that the simulation properties of the model were satisfactory.
Conclusions: A 3-compartment linear disposition model was found to satisfactorily describe the data following single dose administration of CsA and the effect of food on rate and extent of absorption could be quantified.
References:
[1] Beal S.L. et. al. (1989-2006). Incon Development Solutions, Ellicot City, Maryland, USA. NONMEM Users Guides.
[2] Savic RM et. al. Implementation of a transit compartment model for describing drug absorption in pharmacokinetic studies. J Pharmacokin Pharmacodyn. 34(5):711-26. 2007.
Reference: PAGE 21 (2012) Abstr 2325 [www.page-meeting.org/?abstract=2325]
Poster: Other Drug/Disease Modelling