ISSN:
1573-8744
Keywords:
pharmacokinetics
;
variability
;
parameter estimation
;
modeling
;
nonlinear regression
;
Wagner-Nelson method
;
mixed effects models
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
Notes:
Abstract The impact of assay variability on pharmacokinetic modeling was investigated. Simulated replications (150) of three “individuals” resulted in 450 data sets. A one-compartment model with first-order absorption was simulated. Random assay errors of 10, 20, or 30% were introduced and the ratio of absorption rate (K a )to elimination rate (K e )constants was 2, 10, or 20. The analyst was blinded as to the rate constants chosen for the simulations. Parameter estimates from the sequential method (K e )estimated with log-linear regression followed by estimation of K a and nonlinear regression with various weighting schemes were compared. NONMEM was run on the 9 data sets as well. Assay error caused a sizable number of curves to have apparent multicompartmental distribution or complex absorption kinetic characteristics. Routinely tabulated parameters (maximum concentration, area under the curve, and, to a lesser extent, mean residence time) were consistently overestimated as assay error increased. When K a /K e =2,all methods except NONMEM underestimated K e ,overestimated K a ,and overestimated apparent volume of distribution. These significant biases increased with the magnitude of assay error. With improper weighting, nonlinear regression significantly overestimated K e when K a /K e ,=20. In general, however, the sequential approach was most biased and least precise. Although no interindividual variability was included in the simulations, estimation error caused large standard deviations to be associated with derived parameters, which would be interpreted as interindividual error in a nonsimulation environment. NONMEM, however, acceptably estimated all parameters and variabilities. Routinely applied pharmacokinetic estimation methods do not consistently provide unbiased answers. In the specific case of extended-release drug formulations, there is clearly a possibility that certain estimation methods yield K a and relative bioavailability estimates that would be imprecise and biased.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF01071350
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