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Double Peaking Phenomena in Pharmacokinetic Disposition Revisited
Malaz Yousef1, Dion R Brocks1, Raimar Löbenberg1
1Faculty of Pharmacy and Pharmaceutical Sciences, Katz Centre for Pharmacy and Health Research, University of Alberta, Edmonton, AB, T6G 2E1, Canada.
Clinical Pharmacokinetics
|August 13, 2025
Summary
Multiple peaking, or observing multiple drug concentration peaks after one dose, complicates drug efficacy and bioequivalence. This review identifies new causes and explores advanced modeling for better drug development.
Area of Science:
- Pharmacokinetics and Drug Metabolism
- Pharmaceutical Sciences
- Drug Delivery Systems
Background:
- Multiple peaking in pharmacokinetics, characterized by two or more peaks in drug plasma concentrations after a single dose, complicates pharmacokinetic parameter interpretation.
- This phenomenon significantly impacts clinical decisions regarding drug efficacy, bioequivalence, and therapeutic drug monitoring.
Purpose of the Study:
- To re-examine and expand upon the known physicochemical, formulation-related, and physiological causes of multiple peaking.
- To explore the role of specialized formulations, such as pulsatile drug delivery systems (PDDS), in managing this complex pharmacokinetic behavior.
- To highlight advanced modeling tools and bioequivalence considerations for drugs exhibiting multiple peaks.
Main Methods:
- Comprehensive literature review of existing and novel mechanisms contributing to multiple peaking.
- Exploration of specialized drug delivery systems and their influence on absorption profiles.
- Discussion of advanced modeling techniques, including physiologically based pharmacokinetic (PBPK) modeling.
- Analysis of bioequivalence assessment strategies, such as partial area under the curve (pAUC), for multiple-peak drug products.
Main Results:
- Identified novel contributing factors to multiple peaking, including lymphatic uptake, enterogastric and hepatoenteric recycling, dual absorption pathways, overdose, and pharmacobezoars.
- Demonstrated the potential of pulsatile drug delivery systems (PDDS) to influence and potentially mitigate multiple peaking.
- Highlighted the utility of PBPK modeling in elucidating complex absorption profiles and guiding drug development.
- Emphasized the importance of specific bioequivalence metrics like pAUC for products exhibiting multiple peaks.
Conclusions:
- Understanding and accurately modeling multiple peaking is crucial for optimizing drug development processes.
- Advanced modeling and formulation strategies can help manage the complexities of multiple peaking.
- Improved characterization of this phenomenon supports precision dosing, therapeutic monitoring, and informed regulatory decision-making.
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