Application for Travel grants possible
The NVH awards Travel Grants to junior researchers (PhD students and postdocs). The financial resources come from the former NSFW foundation. The resources are limited, so only a limited number of Travel Grants of 500 euros can be given. To be eligible for this, the applicant must:
- be a member of the NVF
- have accepted an abstract for the Spring Meeting visit
- be prepared to also present during the FIGON Dutch Medicines Days.
Applications can be sent by e-mail AFTER 2 January 2020 to firstname.lastname@example.org.
The NVF board decides on the allocation of the Travel Grants.
The travel grant awardees of 2019
- Katja Jansen
- Bianca van Groen
- Laurens Verscheijden
(Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht, The Netherlands)
Meeting attended: 12th International ISSX Meeting in Portland, US
Testimonials: The opportunity to share research findings on an international/overseas conference is definitely one of the highlights of a PhD. The NFV travel grant took away some financial burden; at the same time, it gave me the feeling of being supported on my journey as member of the Dutch pharmacological society.
Title of the research abstract
A systematic meta-analysis on interspecies differences in renal clearance
Authors and affiliations
Katja Jansen1, Carla Pou Casellas2,3, Lucianne Groenink1, Kimberley E. Wever4, Rosalinde Masereeuw1
¹Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht, The Netherlands; ²Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands; ³Hubrecht Institute – Royal Netherlands Academy of Arts and Sciences, Utrecht, the Netherlands; ⁴Systematic Review Centre for Laboratory animal Experimentation (SYRCLE), Department for Health Evidence, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
Before new drugs are approved for human use, various animal models are applied to study drug efficacy and safety. Renal clearance (CLr) is a standard safety measure since a significant part of drugs is cleared by the kidneys. It is assumed that glomerular filtration rate and metabolic waste removal are determined by metabolic rate, which in turn scales linearly to body weight. Thus, human CLr should be predictable based on body weight. However, they are biological differences between species which could be reflected in pharmacokinetics. Our aim was to identify species-specific limitations in human CLr extrapolation. Using PubMed and EMBASE, we systematically reviewed human and animal studies that have reported CLr or related outcome measures for 20 renally excreted drugs with different physicochemical properties. Based on the human data and simple allometry, we assessed how much animal models deviate from the expected value, and correlated these differences to the properties of the drugs. In total, we included 264 studies with human or animal CLr data for the selected drugs. For each animal species, we calculated average fold errors per drug, as well as the mean differences with 95% confidence intervals compared to humans. These mean differences varied between -0.56 and 1.74 for mice, -0.24 and 2.86 for rats, -0.77 and 0.57 for rabbits, -0.78 and 2.33 for dogs, and -0.55 and 0.47 for monkeys. Subgroup analyses based on physicochemical drug properties revealed significant alterations between average mean differences, hinting towards critical physiological interspecies differences at play. This systematic meta-analysis presents a novel approach to quantify interspecies differences. We showed that rats tend to overestimate human CLr. In general, however, animals are good predictive models for renal drug excretion.
(Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands)
ASCPT annual meeting 2019, Washington, US
Testimonials: Grant was used to cover part of the travel and hotel expenses
Title of the research abstract
Development of a Paediatric Brain PBPK Model in Children with and Without Meningitis.
Authors and affiliations
Laurens F.M. Verscheijden1, Jan B. Koenderink1, Karel Allegaert2, 3, Saskia N. de Wildt1,2, Frans G.M. Russel1
1Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands, 2Intensive Care and Department of Paediatric Surgery, Erasmus MC-Sophia Children’s Hospital, Rotterdam, The Netherlands, 3Department of Development and Regeneration, KU Leuven, Leuven, Belgium
Several paediatric physiologically-based pharmacokinetic (PBPK) models have been developed that incorporate developmental changes affecting plasma drug concentrations. Disposition into cerebrospinal fluid (CSF) is also age-related and influenced by physiological factors, including CSF production rate, but also by brain diseases, such as meningitis, which are associated with impaired blood-brain barrier integrity. Our aim was to develop a paediatric brain PBPK model to predict CSF drug concentrations in children with and without meningitis.
A paediatric PBPK model was developed incorporating age-appropriate parameters and associated inter-individual variability. The model was validated for paracetamol, ibuprofen, flurbiprofen and naproxen, and for a paediatric meningitis population by estimating meropenem blood-brain barrier penetration using sensitivity analysis. Plasma and CSF drug concentrations derived from literature were used to perform visual predictive checks and to calculate ratios between simulated and observed AUCs in order to evaluate model performance.
Simulated data were comparable to observed over a broad age range (1 day – 15 y postnatal age), for all drugs investigated. The ratios between observed and simulated AUCs were within 2-fold difference both in plasma and in CSF, indicating acceptable model performance. Disposition of meropenem into the brain was slow and CSF concentrations were lower compared to plasma concentrations. In addition, several days were needed to achieve CSF steady-state concentration.
Our paediatric brain PBPK model provides a new tool to predict CSF concentrations in children with and without meningitis and can be used as a template model for other drugs acting in the CNS.