Abstract
Sensitivity analysis is commonly used to characterize the effects of parameter perturbations on model output. One use for the approach is the optimization of an experimental design enabling estimation of model parameters with improved accuracy. The primary objective of this study is to conduct a sensitivity analysis of selected target-mediated pharmacokinetic models, ascertain the effect of parameter variations on model predictions, and identify influential model parameters. One linear model (Model 1, control) and 2 target-mediated models (Models 2 and 3) were evaluated over a range of dose levels. Simulations were conducted with model parameters being perturbed at the higher and lower ends from literature mean values. Profiles of free plasma drug concentrations and their partial derivatives with respect to each parameter vs time were analyzed. Perturbations resulted in altered outputs, the extent of which reflected parmater influence. The model outputs were highly sensitive to perturbations of linear disposition parameters in all 3 models. The equilibrium dissociation constant (KD) was less influential in Model 2 but was influential in the terminal phase in Model 3, highlighting the role ofKD in this region. An equation for Model 3 in support of the result forKD was derived. Changes in the initial receptor concentration [Rtot(0)] paralleled the observed effects of initial plasma volume (Vc) perturbations, with increased influence at higher values. Model 3 was also sensitive to the rates of receptor degradation and internalization. These results suggest that informed sampling may be essential to accurately estimate influential parameters of target-mediated models.
Keywords: Nonlinear pharmacokinetics, quasiequilibrium models, equilibrium dissociation constant, receptor internalization
Full Text
The Full Text of this article is available as a PDF (1.4 MB).
References
- 1.Levy G. Pharmacologic target-mediated drug disposition. Clin Pharmacol Ther. 1994;56:248–252. doi: 10.1038/clpt.1994.134. [DOI] [PubMed] [Google Scholar]
- 2.Mager DE, Jusko WJ. General pharmacokinetic model for drugs exhibiting target-mediated drug disposition. J Pharmacokinet Pharmacodyn. 2001;28:507–532. doi: 10.1023/A:1014414520282. [DOI] [PubMed] [Google Scholar]
- 3.Mager DE. Target-mediated drug disposition and dynamics. Biochem Pharmacol. 2006;72:1–10. doi: 10.1016/j.bcp.2005.12.041. [DOI] [PubMed] [Google Scholar]
- 4.Mager D, Krzyzanski W. Quasi-equilibrium pharmacolinetic model for drugs exhibiting target-mediated drug disposition. Pharm Res. 2005;22:1589–1596. doi: 10.1007/s11095-005-6650-0. [DOI] [PubMed] [Google Scholar]
- 5.Segrave AM, Mager DE, Charman SA, Edwards GA, Porter CJ. Pharmacokinetics of recombinant human leukemia inhibitory factor in sheep. J Pharmacol Exp Ther. 2004;309:1085–1092. doi: 10.1124/jpet.103.063289. [DOI] [PubMed] [Google Scholar]
- 6.Varkonyi P, Bruckner JV, Gallo JM. Effect of parameter variability on physiologically-based pharmacokinetic model predicted drug, concentrations. J Pharm Sci. 1995;84:381–384. doi: 10.1002/jps.2600840322. [DOI] [PubMed] [Google Scholar]
- 7.Hamby DM. A review of techniques for parameter sensitivity analysis of environmental models. Environ Monit Assess. 1994;32:135–154. doi: 10.1007/BF00547132. [DOI] [PubMed] [Google Scholar]
- 8.Wu G. Sensitivity analysis of pharmacokinetic parameters in one-compartment models. Pharmacol Res. 2000;41:445–453. doi: 10.1006/phrs.1999.0602. [DOI] [PubMed] [Google Scholar]
- 9.Nestorov IA. Sensitivity analysis of pharmacokinetic and pharmacodynamic systems, I: a structural approach to sensitivity analysis of physiologically based pharmacokinetic models. J Pharmacokinet Biopharm. 1999;27:577–596. doi: 10.1023/A:1020926525495. [DOI] [PubMed] [Google Scholar]
- 10.Nestorov IA, Aarons LJ, Rowland M. Physiologically based pharmacokinetic modeling of a homologous series of barbiturates in the rat: a sensitivity analysis. J Pharmacokinet Biopharm. 1997;25:413–447. doi: 10.1023/A:1025740909016. [DOI] [PubMed] [Google Scholar]
- 11.Hetrick DM, Jarabek AM, Travis CC. Sensitivity analysis for physiologically based pharmacokinetic models. J Pharmacokinet Biopharm. 1991;19:1–20. doi: 10.1007/BF01062190. [DOI] [PubMed] [Google Scholar]
- 12.Wagner JG. A new generalized nonlinear pharmacokinetic model and its implications. In: Wagner JG, editor. Biopharmaceutics and Relevant Pharmacokinetics. Hamilton, IL: Drug Intelligence Publications; 1971. pp. 302–317. [Google Scholar]
- 13.Hamby DM. A comparison of sensitivity analysis techniques. Health Phys. 1995;68:195–204. doi: 10.1097/00004032-199502000-00005. [DOI] [PubMed] [Google Scholar]
- 14.Saltelli A, Tarantola S, Chan KPS. A quantitative model-independent method for global sensitivity analysis of model output. Technometrics. 1999;41:39–56. doi: 10.2307/1270993. [DOI] [Google Scholar]