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Background It is still not certain whether it is worth using theophylline in

A prospective simulation study has been carried out to evaluate the effect of potential misspecification of the absorption rate constant (ka) in population pharmacokinetic analysis when few to no concentration-time data were available in the absorption phase and estimation of ka was not possible. Data were simulated for 100 subjects using a one-compartment model at steady state with first-order input. Data were generated over a range of ka values: ka was misspecified in the NONMEM analysis by factors of 0.25, 0.5, 1, 2, 3, and 4. In general, clearance (CL) was typically estimated with a small, constant underprediction, regardless of the range of misspecification of ka or whether data were present in the absorption phase. The same was not true for volume of distribution (V), values were biased and sensitive to the degree of misspecification, but only when the data contained even a little information about absorption. If studies are to be designed in which information absorption is either not required or is of no therapeutic use, then blood samples could be concentrated in the postabsorption phase and the absorption input fixed according to the best a priori information available.

The distinctive pharmacokinetic characteristics of amlodipine, particularly the long half-life, are presumed to translate directly to a prolonged duration of action, but the concentration-effect relationship for the antihypertensive response has not been clearly established. In this study of 12 patients with essential hypertension, treatment with 5 mg amlodipine once daily has been evaluated with use of an integrated pharmacokinetic-pharmacodynamic model to calculate individual patient responsiveness for the decrease in blood pressure per unit change in drug concentration. Amlodipine concentrations were well correlated with the placebo-corrected reductions in blood pressure in individual patients and responsiveness, for example, for erect systolic blood pressure was -3.1 +/- 0.9 mm Hg/ng/ml. By characterizing the concentration-effect relationships in individual patients, this study has confirmed that the plasma concentration-time profile is an appropriate index of the effect-time profile, as reflected by an antihypertensive response that is sustained throughout 24 hours with relatively little trough-to-peak variability.

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A simulation study was carried out to determine the impact of various design factors on the accuracy and precision with which population pharmacokinetic parameters are estimated in preclinical pharmacokinetic studies. A drug given by intravenous bolus injection and having mono-exponential disposition characteristics was assumed. The factors investigated were (i) number of animals sampled at specified times with one observation taken per animal, (ii) error in observed concentration measurements, and (iii) doubling the number of observations per animal while varying the number of animals. Data were analyzed with the NONMEM program, and the least number of animals per time point (where each animal supplied one concentration-time point) required for accurate and precise parameter estimation was determined. The one observation per animal design yielded biased and imprecise estimates of variability, and residual variability could not be estimated. Increasing the error in the concentration measurement led to a significant deterioration in the accuracy and precision with which variability was estimated. Obtaining a second sample from each animal practically eliminated bias and facilitated the partitioning of interanimal variability and residual intraanimal variability, by introducing information about the latter. Doubling the total number of observations per animal required using half (i.e., 50) the total number of animals required for accurate and precise parameter estimation with the one sample per animal design.