Carlos Perez-Ruixo (1), Peter Rigaux (1), Stefaan Rossenu (1), Juan Jose Perez-Ruixo (1), David Lançois (2), Mark Ackermann (3) and Dymphy Huntjens (1)
(1) Janssen R&D, Beerse, Belgium, (2) Janssen-Cilag, Val de Reuil, France, (3) Iowa State University, Ames, USA
Objectives: To develop a population pharmacokinetic model in neonatal lambs to describe plasma and lung concentrations of a new compound in development and determine its impact in lung infection.
Methods: Three groups of five lambs were inoculated with virus and doses of 2, 10 and 50 mg/kg of compound x were administered respectively. Blood samples were collected just before the first dose, at 2 hours after the first and the last dose and at 24 hours following each dose until 6th day. Lung concentrations were measured at sacrifice (day 6). A total of 112 plasma and 11 lung concentrations were obtained from the study. Pharmacokinetic data were analyzed with non-linear mixed effect model using NONMEM 7.3 software and model evaluations were performed using predictive checks and non-parametric bootstrap analysis.
Results: A one compartmental model with first-order absorption, asymptotic exponential maturation-increase in clearance (kmat) [1] and enzyme auto-induction [2] drug effect was shown to adequately describe plasma pharmacokinetics. The auto-induction was described with an enzyme turn-over model in which the compound x plasma concentration increased the enzyme production rate (kenz) in a linear fashion, where α was the linear relationship between the auto-induction effect and plasma concentrations. Lung pharmacokinetics was described using a general PBPK linear distribution model where the lamb physiological parameters were derived from the literature [3,4]. The estimated half-lifes for kmat and kenz were 6.31 days and 3.29 days respectively, while α was 0.094 mL/ng. Both, the maturation and auto-induction drug effect lead to a 1.79-fold increase in metabolic clearance in 6 days. The partition coefficient (kp) [5] driving the drug uptake into the lung was estimated to be 0.68 identical to results reported in adult rats. Model-based simulations suggest that a 25 mg/kg can produce a 95% mean inhibition of lung infection after 6 days post inoculation of the virus in lambs.
Conclusion: The PK model developed in neonatal lambs, properly describes the concentration time course in plasma and lungs. Based on PK/PD modeling, compound x shows promising antiviral activity in lambs.
References:
[1] Anderson BJ, Holford NH. Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol. 2008; 48: 303-32.
[2] Clewe O, Goutelle S, Conte JE Jr, Simonsson US. A pharmacometric pulmonary model predicting the extent and rate of distribution from plasma to epithelial lining fluid and alveolar cells–using rifampicin as an example. Eur J Clin Pharmacol. 2015; 71: 313-9.
[3] Gratama JW, Dalinghaus M, Meuzelaar JJ, Gerding AM, Koers JH, Zijlstra WG, Kuipers JR. Blood volume and body fluid compartments in lambs with aortopulmonary left-to-right shunts. J Clin Invest. 1992; 90: 1745-52.
[4] Jani J, Breysem L, Maes F, Boulvain M, Roubliova X, Lewi L, Vaast P, Biard JM, Cannie M, Deprest J. Accuracy of magnetic resonance imaging for measuring fetal sheep lungs and other organs. Ultrasound Obstet Gynecol. 2005; 25: 270-6.
[5] Thompson MD, Beard DA, Wu F. Use of partition coefficients in flow-limited physiologically-based pharmacokinetic modeling. J Pharmacokinet Pharmacodyn. 2012; 39: 313-27.
Reference: PAGE 25 () Abstr 5710 [www.page-meeting.org/?abstract=5710]
Poster: Drug/Disease modeling - Infection