Research project
24-hour rhythms in drug exposure and effect
Although rarely considered by the pharmaceutical industry or clinicians, 24-hour rhythms in physiology are a factor of potential influence on the pharmacokinetics and pharmacodynamics of drugs.
- Contact
- Elizabeth (Liesbeth) de Lange
- Partners
Project in collaboration with Prof. Dr. Joke Meijer
A thorough understanding of the underlying physiological processes that determine a drug’s exposure and effect is required to address the challenges encountered during the development or optimisation of new and existing drug therapies. Although rarely considered by the pharmaceutical industry or clinicians, 24-hour rhythms in physiology are a factor of potential influence on the pharmacokinetics and pharmacodynamics of drugs.
Although chronopharmacology has existed for decades, we identified several methodological issues in the current body of literature that often precludes implementation of chronopharmacological principles in clinical practice. In general, it was found that a systematic approach to analyse and integrate the data obtained within this field is currently lacking. Therefore, the aim of our research is to develop a more structured approach to study the effect of 24-hour variation on the exposure and effect of drugs. A few drugs were selected to probe 24-hour rhythms.
Midazolam is used to investigate CYP3A mediated metabolism, levofloxacin to study solubility- and permeability-independent absorption and passive renal elimination as well as QT elongation, quinidine to investigate P-glycoprotein mediated transport in the brain, and morphine to investigate P-glycoprotein as well as probenecid-sensitive transporters mediated transport in the brain.
Publications
- Kervezee et al. Levofloxacin-Induced QTc Prolongation Depends on the Time of Drug Administration. CPT Pharmacometrics Syst Pharmacol. 2016 Aug 1. doi: 10.1002/psp4.12085. [Epub ahead of print]
- Kervezee et al. Identifying 24 h variation in the pharmacokinetics of levofloxacin: a population pharmacokinetic approach. Br J Clin Pharmacol. 2016 Feb;81(2):256-68. doi: 10.1111/bcp.12783. Epub 2015 Nov 25.
- van Rongen A et al. Population Pharmacokinetic Model Characterizing 24-Hour Variation in the Pharmacokinetics of Oral and Intravenous Midazolam in Healthy Volunteers. CPT Pharmacometrics Syst Pharmacol. 2015 Aug;4(8):454-64. doi: 10.1002/psp4.12007. Epub 2015 Jul 24.
- Kervezee L, et al. Diurnal variation in P-glycoprotein-mediated transport and cerebrospinal fluid turnover in the brain. AAPS J. 2014 Sep;16(5):1029-37. doi: 10.1208/s12248-014-9625-4. Epub 2014 Jun 11.