S. Aksenov (1), I. Demin (2), L. Ting (3), P. Tang (2)
(1)Novartis Pharmaceuticals, Department of Modeling and Simulation, Cambridge, MA, USA; (2)Novartis Pharma AG, Department of Modeling and Simulation, Basel, Switzerland; (3)Novartis Pharmaceuticals, Department of Metabolism and Pharmacokinetics, USA
Objectives: To assess similarity of tobramycin concentration-time profiles in serum of Phase III product (TIP-PhIII) and the marketed product (TIP-Mkt).
Methods: The population PK analysis was based on a two-compartment model with first-order absorption and first-order elimination and was implemented in NONMEM VI. Predictive simulations of the model were performed in R 2.10.1 software. Visual predictive check (VPC) plots were constructed to assess the overall agreement between simulated and observed concentration data. The NPDE tests were performed with R package npde version 1.2.1. All tests were performed at the pre-specified significance level of 0.05.
Results: Predictive simulations of serum concentration profiles using the population PK model for TIP-PhIII showed that the majority of observed concentrations for TIP-Mkt fall within the 90% predictive interval; proportion of data points outside the interval (13%) is close to expected 10% if the procedure was repeated on independent realizations of PK data with identical study design. Model adequately described the central tendency and variability of observed concentrations of the modified product. Diagnostic plots and results of tests for normality of the NPDE distribution showed that null hypothesis that the distribution is normal is not rejected at pre-specified level of 0.05.
Conclusions: Serum exposure profiles of tobramycin after inhalation of TIP-Mkt are not statistically significantly different from exposure after inhalation of TIP-PhIII expected based on the population PK model of TIP-PhIII. Statistical equivalence of exposures implies that estimates of PK model parameters and effect of covariates reported in the existing population PK model apply to TIP-Mkt as well.
References:
[1] Gelman, A., 2004. Bayesian data analysis 2nd ed., Boca Raton Fla.: Chapman & Hall/CRC.
[2] Yano, Y., Beal, S.L. & Sheiner, L.B., 2001. J Pharmacokinet Pharmacodyn, 28(2), p.171-192.
[3] Brendel, K. et al., 2006. Pharmaceutical research, 23(9), p.2036-49.
[4] Brendel, K., Comets, E. & Mentre, F., 2010. J Pharmacokinet Pharmacodyn, 37, p.49-65.
Reference: PAGE 21 (2012) Abstr 2501 [www.page-meeting.org/?abstract=2501]
Poster: New Modelling Approaches