High-throughput holistic preclinical screens are increasingly used in drug discovery, to assess both drug efficacy and drug safety.

The prevalence of obesity (BMI >40 kg/m2) has increased rapidly over the recent years, not only in adults, but also in children and adolescents.

Promotor: M. Danhof, Co-promotores: J. Freijer, A. Yassen

Promotores: C.A.J. Knibbe; J.N. van den Anker, Co-promotores: H.P.A. van Dongen; B. van Ramshorst

In this thesis population pharmacokinetic and physiologically-based pharmacokinetic (PBPK) approaches were applied to investigate the influence of glomerular filtration (GF) and active tubular secretion (ATS) on renal clearance in children.

The zebrafish is a promising vertebrate model organism in early drug discovery and development.

Promotor: C.A.J. Knibbe, Co-promotor: J.J. Boelens, R.G.M. Bredius

Clinical development of drugs for central nervous system (CNS) disorders has been particularly challenging and still suffers from high attrition rates.

Discovery and development of Central Nervous System (CNS) drugs is hampered by high attrition rates.

Currently, more than 80% of drugs are used in an off-label manner in critically ill neonates.

The aim of this thesis is to expedite and ensure the systematic accuracy of clearance scaling from adults to paediatric patients, with a special focus on drugs undergoing hepatic metabolism.

Growth and development affect the metabolism of drugs administered to neonates, infants, and children.

Promotor: Prof.dr. M. Danhof, Co-promotor: E.C.M. de Lange

Promotores: Prof.dr. C.A.J. Knibbe, Prof.dr. M. Danhof, Prof.dr. K. Allegaert (Leuven)

Promotor: Prof.dr. M. Danhof, Co-promotor: O.E. Della Pasqua

Course

Clearance is the most important pharmacokinetic parameter for drug dose selection. Pharmacokinetic information is typically first available in the adult population, and in general only limited pharmacokinetic data are available in children when drugs enter into the market. It is therefore of the utmost…

Growth hormone profiles are pulsatile and highly variable between individuals, limiting the implementation of mathemathical models to quantify an individual's secretion.

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.

Key publications of the Quantitative Clinical Pharmacology group

Key publications of the Predictive Pharmacology group.

Key publications of the Systems Pharmacology group

A next, general pharmacological problem to be tackled is how drug-target binding kinetics in vivo, affects target occupancy as an important indicator of the time-course of drug effects.

PhD Defence

Timely, adequate and optimal treatment of infectious diseases is essential for the survival of patients with bacterial infections (Surviving Sepsis campaign).

Prediction of human (CNS) target site concentrations in health and disease In the vision of Prof. de Lange we will only be able to predict human (central nervous system, CNS) target site concentrations and effects if we perform systematic, condition-dependent, integrative, and strictly quantitative…

Key publications of the Quantitative Pharmacology group

Knowledge on how to adjust a drug dose in special patient populations such as (prematurely born) neonates or children, obese individuals 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 in these special patient…

This research area is focused on the development and application of novel concepts and models in the emerging area of quantitative systems pharmacology (QSP).

After 41 years, Meindert Danhof, Professor of Pharmacology, is leaving the Leiden Academic Centre for Drug Research on 31 March. A symposium in his honour, prior to his farewell lecture, will show what has been achieved in this period. Danhof takes a look back on his career.

An overview of research projects at the Predictive Pharmacology group.

The overarching clinical aim of this thesis was to improve pharmacological pain management by characterizing the pharmacodynamics of analgesics.

M. Danhof, Co-promotor: O.E. Della Pasqua

A novel mathematical model describes spatial-temporal drug distribution within one or more brain units, which are cubic representations of a piece of brain tissue with brain capillaries at the edges.

PhD Defence

PhD Defence

In neonates and infants, body size, enzyme pathways, and expression and function of receptors and (target) proteins are still developing.

The list of substances prohibited by the World Anti-Doping Agency (WADA) is huge. PhD candidate Jules Heuberger looked at many of these, as well as at the methods used to detect them. He concluded that for very few of these substances is there is evidence that they actually do enhance performance. PhD…

The Leiden Academic Centre for Drug Research (LACDR) is a centre of excellence for multidisciplinary research on drug discovery and development.

The lack of success of new CNS drugs in clinical development is in part due to the complexity of the CNS, unexpected side effects, difficulties for drugs to penetrate the brain, but also by the lack of biomarkers.

Previous research has found important inter-individual differences in the pharmacokinetics (PK) of morphine in special populations such as children, the morbidly obese or the critically ill.

PhD Defence

In this thesis, mathematical modeling and simulation was applied as a tool to inform quantitative decision making in oncology drug discovery and development.

Oxidation is a common degradation pathway that affects therapeutic proteins and peptides during production, purification, formulation, transportation, storage and handling of solid and liquid preparations. In the present work we review the scientific literature about structural and biological consequences…

Can we develop a generic method for Quan/Qual analysis of small molecule drugs, their metabolites and endogenous metabolites in (pre-)clinical samples?

From descriptive to physiological models that can predict oral absorption and elimination of CYP3A substrates across the pediatric age range.