Pharmacodynamics indirect response models

An instructive example is the physiological variable serum creatinine. Creatinine is an endogenous metabolite formed from, and thus reflecting, muscle mass. Total body muscle mass is sufficiently constant to render measurement of serum creatinine useful for assessing actual renal function. The serum value of creatinine (R) is namely dependent on the continuous (zero-order) input of creatinine into the blood (A in) and its renal elimination rate, which is a first-order rate process (A out x ) In case of an extensive muscle breakdown, kin will temporarily increase. It may also be permanently low, for example in old age when muscle mass is reduced. Likewise, creatinine clearance may decrease for various reasons, described by a decrease in A out- An increase in creatinine clearance may occur as well, for example following recovery from renal disease. According to pharmacodynamic indirect response models. 

W. Krzyzanski and W. J. Jusko, Note Caution in the use of empirical equations for pharmacodynamic indirect response models. J Pharmacokinet Biopharm 26 735-741 (1998). 

W. Krzyzanski, A. Chakraborty, and W. J. Jusko, Algorithm for apphcation of Fourier analysis for biorhythmic baselines of pharmacodynamic indirect response models. Chro-nobiol Int 17 77-93 (2000). 

Pharmacokinetic/pharmacodynamic evaluated using indirect response modeling with inhibition of input... 

Jusko, W.J. and Ko, H.C., Physiologic indirect response models characterize diverse types of pharmacodynamic effects, Clin. Pharmacol. Ther., 56, 406-419,1994. 

Although indirect response models can be applied to characterize the pharmacodynamics of numerous drugs, some practical limitations exist in their applications ... 

Y. Matsnmoto, T. Fnjita, Y. Ishida, M. Shimizn, H. Kakno, K. Yamashita, M. Majima, and Y. Knmagai, Popirlation pharmacokinetic-pharmacodynamic modeling of TF-505 rising extension of indirect response model by incorporating a circadian rhythm in healthy volimteers. Biol Pharm Bull 28 1455-1461 (2005). 

Odeberg J M, Callreus T, Lundin S, et al. (2004). A pharmacokinetics and pharmacodynamics study of desmopressin Evaluationg sex differences and the effect of pretreatment with piroxicam, and further validation of an indirect response model. J. Pharm. Pharmacol. 56 1389-1398. 

An extension of indirect response models are precursor pool-dependent indirect response models that include the lihera-tion of an endogenous compound from a storage pool. These models possess the unique ability to characterize hoth tolerance and rebound phenomena [90]. Such a model was, for example, used to describe the effect of interferon- Sla on neopterin, an endogenous marker for cell-mediated immunity, in humans and monkeys (Fig. 8) [91, 92]. The primary elimination mechanism of interferon- 8 la was modeled as receptor-mediated endo-cytosis, and the pharmacodynamic model was driven by the amount of internalized drug-receptor complex DR ... 

Flores-Murrieta, F. J. et al.. Pharmacokinetic-pharmacodynamic modeling of tolmetin antinociceptive effect in the rat using an indirect response model a population approach, J. Pharmacokinet. Biopharm., 26(5) 547-557, 1998. 

Zheng, N. X. et al., Pharmacokinetic-pharmacodynamic modehng of DP-1904, a novel thromboxane synthetase inhibitor in rabbits, based on an indirect response model, Eur. J. Drug Metab. Pharmacokinet., 21(4) 285-293, 1996. 

Fig. 14. Schematic description of pharmacokinetic and pharmacodynamic determinants of drug action. Distribution from the measurement site (Cp) to the biophase (Ce), determined by a distribution rate constant is followed by drug-induced inhibition or stimulation of the production (k ) or removal (A out) of a mediator (R), transduction of the response R and further transformation of R to the measured effect E, if the measured effect variable is not R. (Modified from Jusko WJ, Ko HC, Ebling WF. Convergence of direct and indirect pharmacodynamic response models. J Pharmacokinet Biopharm 1995 23 5-6.)...

Jusko WJ, Ko HC, Ebling WF. Convergence of direct and indirect pharmacodynamic response models. J Pharmacokinet Biopharm 1995 23 5-6. 

From a modeling point of view, the last equilibrium assumption that can be relaxed, for the processes depicted in Figure 10.1, is H4, between the activated receptors (v variable in the occupancy model) and the response E. Instead of the activated receptors directly producing the response, they interfere with some other process, which in turn produces the response E. This mechanism is usually described mathematically with a transducer function T which is no longer linear (cf. Section 10.4.1). This type of pharmacodynamic model is called indirect response and includes modeling of the response process usually through a linear differential equation of the form... 

Sharma, A., Ebling, W., and Jusko, W., Precursor-dependent indirect pharmacodynamic response model for tolerance and rebound phenomena, Journal of Pharmaceutical Sciences, Vol. 87, No. 12, 1998, pp. 1577-1584. 

Sharma, A. Ebling, W.F. Jusko, W.J. Precursor-dependent indirect pharmacodynamic response model for tolerance... 

FIGURE 17.2 Schematic representation of the indirect pharmacodynamic response model for dichloroacetate (with permission from Ref. 19). 

Piotrovsky, V. K., Indirect pharmacodynamic response model do not require any parametric pharmacokinetic model to be fitted to effect-time data. Methods Find. Exp. Clin. Pharmacol, 19(10) 723-729, 1997. 

Sharma, A. and Jusko, W.J., Characterization of four basic models of indirect pharmacodynamic responses, /. Pharmacokinet. Biopharm., 24,611-635,1996. 

Lin, S. and Ghien, Y.W., Pharmacokinetic-pharmacodynamic modeling of insulin comparison of indirect pharmacodjmamic response with effect-compartment link models, J. Pharm. Pharmacol, 54, 791-800, 2002. 

Sharma, A. and W.J. Jusko. 1998. Characteristics of indirect pharmacodynamic models and applications to clinical drug responses. Br.J. Clin. Pharmacol. 45 229-239. 

Dayneka, N., Garg, V., and Jusko, W., Comparison of four basic models of indirect pharmacodynamic response, Journal of Pharmacokinetics and Biopharmaceutics, Vol. 21, No. 4, 1993, pp. 457-478. 

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