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.

Accurate prediction of the unbound drug concentration-time profile at the CNS target site is crucial for the assessment of the right drug concentration-effect relationship. PBPK models have supported the PK prediction of the CNS target sites and the translation of PK data between species and between…

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.

Obesity may alter how a person absorbs, distributes, metabolizes or excretes medication. This thesis describes how obesity affects drug levels in the blood for antimicrobial agents, such as ciprofloxacin and fluconazole.

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

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.

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

This thesis focuses on enhancing predictions of central nervous system drug exposure using the LeiCNS-PK3.0, a physiologically based pharmacokinetic model.

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

Prematurely born neonates require, amongst others, pharmaceutical therapy. Dosing guidelines for these therapies are often based on data from term born neonates or older infants, while these are not necessarily similar to prematurely born 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.

The last decades it is increasingly recognized that acute as well as chronic postoperative pain is an important problem. Treatment and prevention of postoperative pain is a challenge, especially in special patient populations where there is only limited guidance on how to optimally use opioids.

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

Sepsis is a life-threatening condition caused by a dysregulated host response to infection, it is associated with significant morbidity, mortality, and with a high financial burden on global healthcare systems. Bacterial infections are the primary cause of sepsis, but the growing prevalence of antimicrobial…

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

Fungal infections pose a significant threat to individuals with compromised immune systems and despite advancements in diagnosis and treatment, they continue to jeopardize patient’s health.

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

Antimicrobial drugs constitute a fundamental part of modern medicine. The global rise in antimicrobial resistance poses a major threat to global health.

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 Predictive Pharmacology group.

Key publications of the Quantitative Clinical 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.

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…

Tuberculosis causes 1.5 million deaths yearly and anti-tuberculosis therapies are threatened by emergence of drug resistance. Development of innovative drug combinations should be accelerated with the use of translational pharmacological models. Moreover, host-directed therapies (HDT), which stimulate…

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).

An overview of research projects at the Predictive Pharmacology group.

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

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.

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.

Are you looking for a research project? We have projects available for motivated 6–9-month internship students with particular interest in organic/polymer synthesis, formulation development, gene delivery, protein delivery, and the preliminairy in vitro screening of drug delivery platforms. Students…

The Pharmacy research group focusses on the development of predictive models to improve clinical drug efficacy and safety. We work on clinical problems that require further mechanistic understanding and strive for ultimate benefit to patients.

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

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…

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.

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…

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

The research of the Biotherapeutic Delivery group led by Joachim Van Guyse focuses on developing novel polymer-based formulations for therapeutic nucleic acid and protein delivery. The research revolves around developing structure-activity relationships between the chemical structure of polymers, the…

The kidneys play a major role in the elimination of drugs. In children, the exact age-related physiological changes underlying kidney function remain largely unknown.

Prof. Elizabeth de Lange is concerned with the allocation of resources for the conduct of science towards the goal of best serving the public interest. Also, while she underscores that there is still the need for using animals in drug research, she is concerned about this use, and advocates the use…

Key publications of the Quantitative Pharmacology group