Division of Systems Biomedicine and Pharmacology
Quantitative Clinical Pharmacology
The Quantitative Clinical Pharmacology group is led by Prof. Catherijne Knibbe. Her research group aims to define how to adjust a drug dose in special patient populations such as (prematurely born) neonates or children, obese individuals, the elderly or critically ill patients. Through combining the statistical power of the population approach with physiologically-based approaches and large datasets from (routine) clinical practice, computer models are developed that can predict the efficacy and safety of drugs in each individual pediatric or adult patient.
Knowledge on how to adjust a drug dose in special patient populations such as (prematurely born) neonates or children, obese individuals, the elderly or critically-ill patients, is not only crucial for novel compounds but also for existing drugs which are often used in an off-label manner.
Within the context of close collaborations with our clinical partners, we gather data in these special patient populations through clinical studies or routine clinical practice. Studies are performed in (prematurely born) neonates, children, severly obese patients, obese adolescents or the elderly. From these studies, predictors of variability (covariates) are identified that can subsequently be used to guide dosing in these groups. As covariates, bodyweight, severity of illness, age or a biomarker can for instance be identified. For this purpose, we use advanced statistical techniques, that are particularly needed to handle sparse data sets from neonates and children, as in those cases only limited clinical observations can be obtained because of small patient numbers and limited blood sampling possibilities.
While these studies lead to individualized dosing guidelines for specific drugs in these populations based on advanced pharmacokinetic and pharmacodynamics analyses, it would require tremendous efforts and budgets to study all drugs across all populations. Therefore beside models for specific drugs, we aim to develop system models in which we integrate physiological concepts, advanced data analysis approaches, and datasets from (routine) clinical practice that can provide general insight into how to predict dosages in special patient populations. The use of physiologically-based methods within this approach is crucial as it allows to predict how drug action changes for instance in case of changes in the human system as a result of ageing or obesity (system specific properties), or as a result of different drug properties (drug specific properties).
Ultimately, these efforts should lead to quantitative clinical pharmacology models that can predict patient the efficacy and safety of the drug studied, and potentially of other (related) drugs in each individual.
- Knibbe C.A., Brill M.J., van Rongen A., Diepstraten J., van der Graaf P.H. & Danhof M. (2015), Drug disposition in obesity: toward evidence-based dosing, Annual Review of Pharmacology and Toxicolog 55: 149-67.
- Calvier E.A.M., Krekels E.H.J., Yu H., Välitalo P.A.J., Johnson T.N., Rostami-Hodjegan A., Tibboel D., van der Graaf P.H., Danhof M., Knibbe C.A.J. (2018), Drugs Being Eliminated via the Same Pathway Will Not Always Require Similar Pediatric Dose Adjustments. CPT Pharmacometrics Syst Pharmacol.
- Calvier E.A.M., Krekels E.H.J., Välitalo P.A.J., Rostami-Hodjegan A., Tibboel D., Danhof M., Knibbe C.A.J. (2017), Allometric Scaling of Clearance in Paediatric Patients: When Does the Magic of 0.75 Fade?, Clinical Pharmacokinetics.
- van Rongen A., Brill M.J.E., Vaughns J.D., Välitalo P.A.J., van Dongen E.P.A., van Ramshorst B., Barrett J.S., van den Anker J.N., Knibbe C.A.J. (2017), Higher Midazolam Clearance in Obese Adolescents Compared with Morbidly Obese Adults. Clin Pharmacokinet.
- Krekels E.H.J., van Hasselt J.G.C., van den Anker J.N., Allegaert K., Tibboel D., Knibbe C.A.J. (2017), Evidence-based drug treatment for special patient populations through model-based approaches. Eur J Pharm Sci. 109S: S22-S26.
- Brill M.J., Välitalo P.A., Darwich A.S., van Ramshorst B., van Dongen H.P., Rostami-Hodjegan A., Danhof M., Knibbe C.A. (2016), Semiphysiologically based pharmacokinetic model for midazolam and CYP3A mediated metabolite 1-OH-midazolam in morbidly obese and weight loss surgery patients. CPT Pharmacometrics Syst Pharmacol. 5(1): 20-30.
- Välitalo P.A., Krekels E.H., van Dijk M., Simons S., Tibboel D., Knibbe C.A. (2017), Morphine Pharmacodynamics in Mechanically Ventilated Preterm Neonates Undergoing Endotracheal Suctioning. CPT Pharmacometrics Syst Pharmacol. 6(4): 239-248.
- Brill M.J., Houwink A.P., Schmidt S., van Dongen E.P., Hazebroek E.J., van Ramshorst B., Deneer V.H., Mouton J.W., Knibbe C.A. (2014), Reduced subcutaneous tissue distribution of cefazolin in morbidly obese versus non-obese patients determined using clinical microdialysis. J Antimicrob Chemother. 69(3): 715-23.
- Krekels E.H.J., Tibboel D., Wildt S.N. de, Ceelie I., Dahan A. Dijk M. van, Danhof M. & Knibbe C.A.J. (2014), Evidence-based morphine dosing for postoperative neonates and infants., Clinical Pharmacokinetics 53(6): 553-563.