Abstract
Intermittent drug dosing intervals are usually initially guided by the terminal pharmacokinetic half life and are dependent on drug formulation. For chronic multiple dosing and for extended release dosage forms, the terminal half life often does not predict the plasma drug accumulation or fluctuation observed. We define and advance applications for the operational multiple dosing half lives for drug accumulation and fluctuation after multiple oral dosing at steady-state. Using Monte Carlo simulation, our results predict a way to maximize the operational multiple dosing half lives relative to the terminal half life by using a first-order absorption rate constant close to the terminal elimination rate constant in the design of extended release dosage forms. In this way, drugs that may be eliminated early in the development pipeline due to a relatively short half life can be formulated to be dosed at intervals three times the terminal half life, maximizing compliance, while maintaining tight plasma concentration accumulation and fluctuation ranges. We also present situations in which the operational multiple dosing half lives will be especially relevant in the determination of dosing intervals, including for drugs that follow a direct PKPD model and have a narrow therapeutic index, as the rate of concentration decrease after chronic multiple dosing (that is not the terminal half life) can be determined via simulation. These principles are illustrated with case studies on valproic acid, diazepam, and anti-hypertensives.
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Acknowledgments
We thank the Center for Drug Development Sciences at the University of California, San Francisco for the annotated list of drugs approved from 1980 to 2007 that served as the basis for the anti-hypertensive case study. AG is funded in part by an American Foundation for Pharmaceutical Education Pre-Doctoral fellowship and by an Achievement Rewards for College Scientists fellowship.
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Grover, A., Benet, L.Z. Intermittent drug dosing intervals guided by the operational multiple dosing half lives for predictable plasma accumulation and fluctuation. J Pharmacokinet Pharmacodyn 38, 369–383 (2011). https://doi.org/10.1007/s10928-011-9198-0
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DOI: https://doi.org/10.1007/s10928-011-9198-0