Contribution of Trough Concentration Data in the Evaluation of Multiple-Dose Pharmacokinetics for Drugs with Delayed Distributional Equilibrium and Long Half-Life

Drug Design, Development and Therapy
Suein ChoiSeunghoon Han

Abstract

The performance of "trough sampling before reaching steady-state" and "serial sampling beyond the interval between steady-state" in a multiple-dose pharmacokinetic evaluation was compared. Drugs with long half-lives, following multi-compartment pharmacokinetics, and whose distribution-related characteristics are less likely to be assessed within one dosing interval are focused. Amlodipine pharmacokinetic data were collected from a human pharmacology study performed in Seoul St. Mary's Hospital (Seoul, Korea). Plasma concentration data until 144 hrs after a single administration was used. Nonlinear mixed-effects modeling was conducted to obtain the "true" model structure and pharmacokinetic parameter estimates. Then, stochastic simulation and estimation were performed using multiple-dose scenarios in various sampling strategies. Parameter accuracy and precision from each scenario were evaluated. A two-compartment model with first-order absorption followed by zero-order absorption with a lag time then first-order elimination was chosen as the final model and used in the stochastic simulation and estimation. In terms of parameter precision, the scenario incorporating data only within one dosing interval showed the worst results (V...Continue Reading

References

Jul 7, 2007·Pharmaceutical Research·Andrew C HookerMats O Karlsson
Aug 4, 2009·The AAPS Journal·Radojka M Savic, Mats O Karlsson
Dec 24, 2011·International Journal of Clinical Pharmacology and Therapeutics·Jingli DuanGangadhar Sunkara
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Aug 24, 2018·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Yi Rang HanK Sandy Pang

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Citations

Feb 28, 2021·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·Prakash KhadkaShyamal C Das
Oct 13, 2020·The American Journal of Emergency Medicine·Lisandra E de Castro BrásWilliam J Meggs
Oct 27, 2021·The Korean Journal of Physiology & Pharmacology : Official Journal of the Korean Physiological Society and the Korean Society of Pharmacology·Yunjung HongSeunghoon Han

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Clinical Trials Mentioned

NCT02205151

Software Mentioned

Perl
NONMEM ( PsN )
speaks
R Foundation for Statistical Computing
NONMEM

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