Inter- and Intraindividual Variability

The population approach is a new point of view in clinical drug evaluation and therapy. It emphasizes the estimation of parameters describing the dose-concentration-response relationship both between and within patients (including average behavior and variability). The population approach recognizes vari- 

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]. 

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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. 

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). 

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). 

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. 

R.P. Scherersol system Liquid formulations for softgels, which incorporates the drug in a microemulsion preconcentrate or microemulsion form. Oral delivery of proteins and peptides enhanced oral bioavailability with reduced inter- and intraindividual variability in pharmacokinetics of certain drugs. Sandimmune Neoral (cyclosporine). 

Mentre, F. Escolano, S. Diquet, B. GoUnard, J.L. Mallet, A. Clinical pharmacokinetics of zidovudine inter and intraindividual variability and relationship to long-term efficacy and toxicity. Eur. J. Clin. Pharmacol 1993,45 (5), 397-407. 

This undesirable result can likely be attributed to the magnitudes of inter- and intraindividual variability used during the simulation step. 

Among others, individual susceptibility may be affected by host factors such as age, gender, disease state, and social influences. Together with dietary factors, related to the food matrix, these are the major cause of the observed overall high inter- and intraindividual variabilities. 

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. 

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. 

Although clearance of S-warfarin by CYP2C9 is an important determinant of interindividual dosing variability, many other factors have been implicated in maintenance dose. Clearly, the amount of vitamin K in the diet has a substantial impact on both inter- and intraindividual dosing [30]. Diet may also account for clearance differences observed in different ethnic groups. Although the factors resulting in the observed differences have not been elucidated, clearance of warfarin was seen to be different between... 

Keller TM, Rake A, Michel SCA, Seifert B, Efe G, Treiber K, Huch R, Marincek B, Kubik-Huch R (2003) Obstetric MR pelvimetry reference values and evaluation of inter- and intraobserver error and intraindividual variability. Radiology 227 37-43... 

Individual-related variables Extreme ages infant, adult, elderly Anatomical site Menstrual cycle periods Inter- and intraindividual variations Sweating thermal, emotional, physical, pharmacological Skin surface temperature Pharmacology e.g., drugs with vascular effects... 

Understand the mechanisms of drug incorporation into hair, and the reasons for its inter-/intraindividual variability ... 

The software NONMEM (17) with first-order conditional estimation (FOCE + INTER) was used throughout the analysis. The proportional error model was used for intraindividual variability, and interindividual variability was assumed lognormally distributed. Interindividual variabilities were assumed independent that is, diagonal matrices for OMEGA were used throughout for model development. These details were not explicitly stated in the plan but were maintained as... 

Disadvantages arise mainly from the complexity of the statistical algorithms and the fact that fitting models to data is time consuming. The first-order (EO) method used in NONMEM also results in biased estimates of parameters, especially when the distribution of inter individual variability is specified incorrectly. The first-order conditional estimation (EOCE) procedure is more accurate but is even more time consuming. The objective function and adequacy of the model are based in part on the residuals, which for NONMEM are determined based on the predicted concentrations for the mean pharmacokinetic parameters rather than on the predicted concentrations for each individual. Therefore, the residuals are confounded by intraindividual, inter individual, and linearization errors. 

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