Pharmacokinetic-pharmacodynamic model routes

What are the strengths and weaknesses of these approaches The use of intrinsic clearance in vitro permits predictions between species for the particular enzyme/route of metabolism concerned. If humans have qualitatively different routes of metabolism for any particular compound, then this will weaken the predictive value of the in vitro observation. Similarly, allometric scaling works best for compounds with a high component of non-enzymatic elimination, such as our model compound with approximately 90% excretion as unchanged drug. This prediction weakens as variations in rates of enzymatic reactions become more important. The pharmacokinetic-pharmacodynamic modelling approaches use existing in vivo data to calculate constants which can be applied to other in vivo data, but does not, in its present form, link in vitro and in vivo data. 

Teeguarden JG, Housand CJ, Smith JN, Hinderliter PM, Gunawan R, Timchalk CA. A multi-route model of nicotine-cotinine pharmacokinetics, pharmacodynamics and brain nicotinic acetylcholine receptor binding in humans. Regal Toxicol Pharmacol 2013 65(l) 12-28. 

Model refinement and validation for both the chltnpyrifos and the diazinon PBPK/PD models wa.s accomplished by conducting a scries of in vivo pharmacokinetic and pharmacodynamic studies in the rat and by evaluating the capability of the model to accurately simulate in vivo data published in the literature. The experimental details are fully described in Timchalk et ai (2002b) and Poet et at. (2004). In brief, these studies involved an acute oral exposure to chlorpyrifos or diazinon and the blood time course of the parent compounds and metabolites was determined, as well as the time course for the cholinesterase inhibition in several tissues. Representative results and model simulations are presented in Fig. 12 and 13 for the pharmacokinetic and pharmacodynamic response in rats following comparable oral doses (50 and 100 mg/kg) of chlorpyrifos and diazinon, respectively, The overall response was fairly comparable for these two insecticides, and the models reasonably simulated both dosimetry and the dose-dependent cholinesterase inhibition. These results arc very consistent with a fairly rapid oral absorption for both insecticides and subsequent metabolism and distribution of the active oxon metabolites. Figure 14 illustrates the capability of the diazinon PBPK/PD model to simulate rodent dosimetry data from the open literature and the capability of the model to accommodate alternative exposure routes (Poet et ai, 2004). In these examples, the time course of diazinon in plasma and cholinesterase inhibition in tissues (i.e.. blood,... 

---