Ibarra M (1), Suarez G (2), Salada S (2), MartÃnez I (2), Montero J (2), Vázquez M (1), Fagiolino P(1).
(1) Department of Pharmaceutical Sciences, Faculty of Chemistry, Universidad de la República. Uruguay. (2) Laboratory of Pharmacology, Faculty of Veterinary, Universidad de la República. Uruguay.
Objectives: Naphthalophos (NAF) is a widely used organophosphate for the control of sheep gastrointestinal nematode infection. In this work, a K-PD model [1] was developed to describe acetylcholinesterase activity after NAF oral administration in order to estimate absorption rate and residence time.
Methods: One hundred (100) Corriedale lambs were involved in the current experiment under regular field conditions (Uruguay). The animals were randomly allocated into five groups (n=20 each): an untreated control group and four groups treated with a single NAF oral dose of 10, 30, 50 and 70 mg/kg of Tritom NF ® (NAF 15%, Cibeles S.A.). Twenty-five animals (5 of each group) received the dose in fasting conditions. Five blood samples per animal were obtained over the 28 days post-dosing period. Samples were immediately stored and kept at -18°C until analysis. Acetylcholinesterase activity in red blood cells (AChE, μmol/mL/min) was determined using a modified Ellman assay. Population analysis was done in NONMEM 7.3 [2].
Results: A virtual two compartment model with first order absorption was used to predict NAF amount in blood after administration. Two routes were included for NAF elimination from central compartment: one involving AChE inhibition and a parallel first-order process. AChE activity versus time data was described by a turnover model with zero-order input and first-order elimination (kout). Stimulation of kout by NAF according to an indirect response model was included to describe its inhibitory effect of AChE activity. Interindividual variability was included for AChE baseline and NAF first-order absorption rate (ka). Typical estimates for AChE baseline and kout were 1.64 μmol/mL/min and 0.0129 h-1 respectively. NAF dose-proportionality on AChE inhibition was well captured by the model; estimates for maximum kout stimulation and NAF amount producing 50% of maximum effect were 20.3 and 0.709 mg/kg respectively. NAF oral absorption was independent of dose and food administration, with an estimated ka of 1.06 h-1. Simulated NAF pharmacokinetic model predicts a 14 day post-dosing period before complete washout of the drug.
Conclusions: The model described AChE typical tendency and captured interindividual variability. A pharmacokinetic profile for NAF was obtained, allowing estimation and population analysis of NAF input and disposition kinetics. This model could be further used to assess systemic NAF exposure produced after administration of the different formulations marketed in Uruguay.
References:
[1] Jacqmin P, Snoeck E, van Schaick EA, Gieschke R, Pillai P, Steimer JL, Girard P. Modelling response time profiles in the absence of drug concentrations: definition and performance evaluation of the K-PD model. J Pharmacokinet Pharmacodyn 2007;34(1): 57-85.
[2] Beal, S., Sheiner, L.B., Boeckmann, A., & Bauer, R.J. NONMEM User’s Guides 1989-2009; Icon Development Solutions, Ellicott City, MD, USA, 2009
Reference: PAGE 25 () Abstr 6013 [www.page-meeting.org/?abstract=6013]
Poster: Drug/Disease modeling - Other topics