Variability intraindividual

Both interindividual variations (responders and non-responders) and variable intraindividual temporal efficacy (short-term responders) for HbF expression may reflect the inherited differences in the metabolic pathways of the drug, in their targets, or in their adaptative mechanisms. These aspects remain to be clarified. 

Subject variability High intraindividual variability in QTc values (circadian and seasonal variation law of regression to the mean) High interindividual variability in QTc values (males versus females) Unknown prevalence in the general population of subjects carrying silent mutations in the ion channels responsible for cardiac repolarization (these subjects have normal QTc value but reduced repolarization reserve) Variability in the individual metabolic capacity for a given drug... 

Thummel, K.E., Shen, D.D., Podoll,T.D., Kunze, K.L., Trager, W.F., Bacchi, C.E., Marsh, C.L., McVicar, J.P., Barr, D.M., Perkins, J.D., Carithers, R.L. (1994) Use of midazolam as a human cytochrome P450 3A probe. II. Characterization of inter- and intraindividual hepatic CYP3A variability after liver transplantation. Journal of Pharmacology and Experimental Therapeutics, 271 (1), 557-566. 

Improved pharmacokinetic behavior was also seen with the microemulsion in many other studies. Inter- and intraindividual variabilities of cyclosporine primary pharmacokinetic parameters (Cmax, /max, AUC, and terminal half-life) were compared following the administration of the two formulations to 24 healthy volunteers. Both inter- and intraindividual variabilities were significantly reduced with the microemulsion intraindividual variability ranged between 9% and 22% for the microemulsion, compared with 19%-41% for the standard formulation, and the interindividual variability values were 3%-22% and 20%-34%, respectively [40],... 

Kovarik, J.M., et al. 1994. Reduced inter- and intraindividual variability in cyclosporine pharmacokinetics from a microemulsion formulation. J Pharm Sci 83 444. 

The potential sources of variability for gastric residence in the fed mode are the size of the pyloric opening versus the tablet size, the rate of reduction in the size of the tablet by dissolution and antral grinding by the stomach, and inter- and intraindividual variations in the duration of the fed mode, particularly as a function of caloric and fat content. The dominant limitation in the use of food for gastric retention is the minimal total fat content. 

The influence of pharmacokinetic factors—such as physical exercise, body build, diet, and polymorphisms—on interindividual and intraindividual variability in biomarker concentration depends on the physicochemical characteristics of the chemicals. The relationships are often difficult to describe with simple, general rules. It may be advantageous to use PBPK models to understand their influence. (These are described in Chapter 5 and Appendix B.)... 

J. M. Kovarik, E. A. Mueller, J. B. van Bree, W. Tetzloff, and K. Kutz, Reduced inter and intraindividual variability in cyclosporine pharmacokinetics form a microemulsion formulation, J. Pharm. Sci. 83 444-446 (1994). 

The interoccasion variability (IOV) or intraindividual variability [11] arises when a parameter of the model, e.g. CL, varies within a subject between study occasions. The term occasion can be defined arbitrarily, usually logical intervals for an occasion are chosen, e.g. each dosing interval in multiple dose studies or each treatment period of a cross-over study can be defined as an occasion. To assess the IOV of a specific parameter more than one measurement per individual has to be available per occasion. The IOV can be implemented in the random effect model as described in the following ... 

Madsen, B., Shao, Z.Z., and Vollrath, F. "Variability in the mechanical properties of spider silks on three levels Interspecific, intraspecific and intraindividual". Int. J. Biol. Macromol. 24(2-3), 301-306 (1999). 

Thus, the notions of intraindividual variability and uncertainty are distinct concepts, because they arise for different reasons. Variability is an inherent property of the system being modelled. In contrast, uncertainty can be conceptualized as dependent on the current state of knowledge regarding the system being modelled. From this perspective, uncertainty is more a... 

Heterogeneity of values over time, space or different members of a population, including stochastic variability and controllable variability. Variability implies real differences among members of that population. For example, different individual persons have different intake and susceptibility. In relation to human exposure assessment, differences over time for a given individual are referred to as intraindividual variability differences over members of a population at a given time are referred to as interindividual variability. 

One may immediately imagine further subdividing the last type of variability. For example, one might wish to distinguish intraindividual variability due to different aspects of kinetics and separate all such variability from that due to measurement error. The problem with so doing is only that most data are insufficiently detailed and complete to allow these components of variance to be estimated separately. The two-way division we have proposed appears to suffice for most applications and data sets. 

According to the population approach, the analysis of collected data requires an explicit mathematical model, including parameters quantifying population mean profiles, interindividual variability, and residual variability including intraindividual variability and measurement error [460]. 

Nonlinear mixed-effects modeling methods as applied to pharmacokinetic-dynamic data are operational tools able to perform population analyses [461]. In the basic formulation of the model, it is recognized that the overall variability in the measured response in a sample of individuals, which cannot be explained by the pharmacokinetic-dynamic model, reflects both interindividual dispersion in kinetics and residual variation, the latter including intraindividual variability and measurement error. The observed response of an individual within the framework of a population nonlinear mixed-effects regression model can be described as... 

Although intraindividual kinetic variability has only been regarded as a nuisance, the typical degree of intraindividual kinetic variability from all causes can be used to fix rational limits on the increments for tablet dosage, and on permissible tablet-to-tablet and lot-to-lot variability. 

A Dynamic Perspective of Variability The model under study here offers an opportunity to refer to some implications of the existence of nonlinear dynamics. Apart from the jagged cortisol concentration profile, elements such as the sensitive dependence from the initial conditions (expressed by the positive Lyapunov exponent), as well as the system s parameters, play an important role and may explain the inter- and intraindividual variability observed in the secretion of cortisol. These implications, together with other features absent from classical models, are demonstrated in Figure 11.12. 

Finally, experimental evidence indicates that fluctuations in cortisol secretion are not produced by random processes. In fact, the large inter- and intraindividual variability observed in studies dealing with the effect of fluticasone propionate on cortisol levels [526] may be partly explained with the erratic behavior of the system of (11.12) to (11.15). 

Xie HG, Prasad HC, Kim RB, Stein CM (2002) CYP2C9 allelic variants ethnic distribution and functional significance. Adv. Drug Delivery Review 54 1257-1270 Yasar U, Dahl ML, Christensen M, Eliasson E (2002) Intraindividual variability in urinary losartan oxidation ratio, an in vivo marker of CYP2C9 activity. Br J Clin Pharmacol 54 183-185... 

Kashuba ADM, Bertino JS, Kearns GL et al. (1998) Quantitation of three-month intraindividual variability and influence of sex and menstrual cycle phase on CYP1A2, N-acetyltransferase-2, and xanthine oxidase activity determined with caffeine phenotyping. Clin Pharmacol Ther 63 540-551... 

Grahnen A, Wennerlund P, Dahlstrom B, Eckernas SA. Inter- and intraindividual variability in the concentration-effect (sedation) relationship of flunitrazepam. Br J Clin Pharmacol 1991 31(l) 89-92. 

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