Abstract
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 kawas 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 kavalues: kawas 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.
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References
S. L. Beal and L. B. Sheiner, (eds.).NONMEM Users Guides, NONMEM Project Group, University of California at San Francisco, San Francisco, 1989.
T. H. Grasela, E. J. Antal, R. J. Townsend, and R. B. Smith. An evaluation of population pharmacokinetics in therapeutic trials. Part I. Comparison of methodology.Clin. Pharmacol. Ther. 39:605–612 (1986).
J. Antal, T. H. Grasela, and R. B. Smith. An evaluation of population pharmacokinetics in therapeutic trials. Part III. Prospective data collection versus retrospective data assembly.Clin. Pharmacol. Ther. 46:552–559 (1989).
L. B. Sheiner, B. Rosenberg, and V. V. Marathe. Estimation of population characteristics of pharmacokinetic parameters from routine clinical data.J. Pharmacokin. Biopharm. 5:445–479 (1977).
E. S. Moore, R. G. Faix, R. C. Banagle, and T. H. Grasela. The population phar-macokinetics of theophylline in neonates and young infants.J. Pharmacokin. Biopharm. 17:47–66 (1989).
N. M. Graves, T. M. Ludden, G. B. Holmes, R. H. Fuerst, and I. E. Leppik. Pharmacokinetics of felbamate, a novel antiepileptic drug: Application of mixed-effect modelling to clinical trials.Pharmacotherapy 9:372–376 (1989).
D. M. Jermain, M. L. Crismon, and E. S. Martin III. Population pharmacokinetics of lithium.Clin. Pharm. 10:376–381 (1991).
E. S. Martin, III, M. L. Crismon, and P. J. Godley. Postinduction carbamazepine clearance in an adult psychiatric population.Pharmacotherapy 11:296–302 (1991).
C. N. Verme, T. M. Ludden, W. A. Clementi, and S. C. Harris. Pharmacokinetics of quinidine in male patients—A population analysis.Clin. Pharmacokin. 22:468–480 (1992).
L. Collart, T. F. Blaschke, F. Boucher, and C. G. Prober. Potential of population pharmacokinetics to reduce the frequency of blood sampling required for estiating kinetic parameters in neonates.Dev. Pharmacol. Ther. 1871–80 (1992).
P. J. Williams, J. Lane, W. Murray, M. A. Mergener, and M. Kamigaki. Pharmacokinetics of the digoxin-quinidine interaction via mixed-effect modelling.Clin. Pharmacokin. 22:66–74 (1992).
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J. R. Wade was supported by a grant from Syntex Research, Thames House, 1 Bell Street Maidenhead, Berkshire, SL6 1BU, United Kingdom.
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Wade, J.R., Kelman, A.W., Howie, C.A. et al. Effect of misspecification of the absorption process on subsequent parameter estimation in population analysis. Journal of Pharmacokinetics and Biopharmaceutics 21, 209–222 (1993). https://doi.org/10.1007/BF01059771
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DOI: https://doi.org/10.1007/BF01059771