Leiden University Scholarly Publications

Your Search

Enabled Filters

  • (-) = Bellanti, F.

Refine Results

Resource Type

Availability

Creation Date

Faculty

Collection

Author

Language

Search results

  • RSS Feed
(1 - 5 of 5)
P-glycoprotein protein expression versus functionality at the blood-brain barrier using immunohistochemistry, microdialysis and mathematical modeling
Lange, E.C.M. de; Berg, D.J. van den; Bellanti, F.; Voskuyl, R.A.; Syvänen, S. 2018
P-glycoprotein protein expression versus functionality at the blood-brain barrier using immunohistochemistry, microdialysis and mathematical modeling
Article / Letter to editor
open access
A proper understanding of P-gp mediated transport (functionality) at the blood-brain barrier (BBB) and beyond is needed to interpret, understand and predict pharmacokinetic (PK)- pharmacodynamic ... Show moreA proper understanding of P-gp mediated transport (functionality) at the blood-brain barrier (BBB) and beyond is needed to interpret, understand and predict pharmacokinetic (PK)- pharmacodynamic (PD) relationships of CNS drugs that are substrates of P-gp, especially since P-gp functionality may be different in different conditions. Often, P-gp expression is taken as a biomarker of transporter functionality. The aim of our study was to investigate whether brain capillary protein expression of P-gp is associated with changes in P-gp mediated drug efflux at the BBB. Status Epilepticus (SE) was induced by kainate in male rats. During 3-5 weeks post SE, hippocampal P-gp expression was determined using immunohistochemistry, while BBB P-gp functionality was assessed by microdialysis of quinidine, in absence and presence of the P-gp blocker tariquidar. The data were analyzed using Non-linear Mixed Effect Modeling implemented in NONMEM. Following SE, changes in brain capillary P-gp expression were observed. However, no relation between BBB P-gp protein expression and BBB P-gp mediated drug efflux was found. This warrants a critical view on the interpretation of reported changes in BBB P-gp expression as a biomarker of BBB P-gp functionality. Show less
Target-Site Investigation for the Plasma Prolactin Response: Mechanism-Based Pharmacokinetic-Pharmacodynamic Analysis of Risperidone and Paliperidone in the Rat
Shimizu, S.; Hoedt, S.M. den; Mangas-Sanjuan, V.; Cristea, S.; Geuer, J.K.; Berg, D.-J. van den; ... ; Lange, E.C.M. de 2017
Target-Site Investigation for the Plasma Prolactin Response: Mechanism-Based Pharmacokinetic-Pharmacodynamic Analysis of Risperidone and Paliperidone in the Rat
Article / Letter to editor
metadata only
To understand the drivers in the biological system response to dopamine D2 receptor antagonists, a mechanistic semiphysiologically based (PB) pharmacokinetic-pharmacodymanic (PKPD) model was... Show moreTo understand the drivers in the biological system response to dopamine D2 receptor antagonists, a mechanistic semiphysiologically based (PB) pharmacokinetic-pharmacodymanic (PKPD) model was developed to describe prolactin responses to risperidone (RIS) and its active metabolite paliperidone (PAL). We performed a microdialysis study in rats to obtain detailed plasma, brain extracellular fluid (ECF), and cerebrospinal fluid (CSF) concentrations of PAL and RIS. To assess the impact of P-glycoprotein (P-gp) functioning on brain distribution, we performed experiments in the absence or presence of the P-gp inhibitor tariquidar (TQD). PK and PKPD modeling was performed by nonlinear mixed-effect modeling. Plasma, brain ECF, and CSF PK values of RIS and PAL were well described by a 12-compartmental semi-PBPK model, including metabolic conversion of RIS to PAL. P-gp efflux functionality was identified on brain ECF for RIS and PAL and on CSF only for PAL. In the PKPD analysis, the plasma drug concentrations were more relevant than brain ECF or CSF concentrations to explain the prolactin response; the estimated EC50 was in accordance with reports in the literature for both RIS and PAL. We conclude that for RIS and PAL, the plasma concentrations better explain the prolactin response than do brain ECF or CSF concentrations. This research shows that PKPD modeling is of high value to delineate the target site of drugs. Show less
From data to models : reducing uncertainty in benefit risk assessment : application to chronic iron overload in children
Bellanti, F. 2015
From data to models : reducing uncertainty in benefit risk assessment : application to chronic iron overload in children
Doctoral Thesis
open access
2017-09-24T00:00:00Z; 2016-07-29T00:00:00Z; 2015-11-21T00:00:00Z; 2017-03-24T00:00:00Z; 2017-03-24T00:00:00Z; 2017-03-24T00:00:00Z; 2017-09-24T00:00:00Z; 2017-03-24T00:00:00Z; 2017-03-24T00:00:00Z
Growing awareness about the relevance of formal evaluation of the efficacy and safety in children has resulted into important changes in the requirements for the approval of medicines for children.... Show moreGrowing awareness about the relevance of formal evaluation of the efficacy and safety in children has resulted into important changes in the requirements for the approval of medicines for children. In this thesis a model-based approach is proposed to ensure more efficient use of the evidence available from historical data. The work presented provides a quantitative framework for the assessment of the benefit-risk balance prior to drug approval. Three central questions are addressed, which refer to the need to ensure that accurate inferences are made about the safety and efficacy of a therapeutic intervention, especially when considering long-term outcome. In brief, we demonstrate how modelling and simulations can be applied together with multi-criteria decision analysis to address essential clinical, scientific and regulatory questions. Focus is given to the opportunity for optimising experimental protocol design (evidence generation) and integrating existing knowledge about the drug and the disease in the target population (evidence synthesis). These concepts are illustrated by real-life examples on the treatment of transfusion-dependent haemoglobinopathies, but the proposed framework can be extrapolated to a broader range of diseases and conditions. We anticipate that some of the meta-analytical elements presented here will become embedded into daily practice in pharmaceutical R&D. Show less
Integration of PKPD relationships into benefit-risk analysis
Bellanti, F.; Wijk, R.C. van; Danhof, M.; Della Pasqua, O.E. 2015
Integration of PKPD relationships into benefit-risk analysis
Article / Letter to editor
metadata only
AimDespite the continuous endeavour to achieve high standards in medical care through effectiveness measures, a quantitative framework for the assessment of the benefit–risk balance of new... Show more

AimDespite the continuous endeavour to achieve high standards in medical care through effectiveness measures, a quantitative framework for the assessment of the benefit–risk balance of new medicines is lacking prior to regulatory approval. The aim of this short review is to summarise the approaches currently available for benefit–risk assessment. In addition, we propose the use of pharmacokinetic–pharmacodynamic (PKPD) modelling as the pharmacological basis for evidence synthesis and evaluation of novel therapeutic agents.MethodsA comprehensive literature search has been performed using MESH terms in PubMed, in which articles describing benefit–risk assessment and modelling and simulation were identified. In parallel, a critical review of multi-criteria decision analysis (MCDA) is presented as a tool for characterising a drug's safety and efficacy profile.ResultsA definition of benefits and risks has been proposed by the European Medicines Agency (EMA), in which qualitative and quantitative elements are included. However, in spite of the value of MCDA as a quantitative method, decisions about benefit–risk balance continue to rely on subjective expert opinion. By contrast, a model-informed approach offers the opportunity for a more comprehensive evaluation of benefit–risk balance before extensive evidence is generated in clinical practice.ConclusionsBenefit–risk balance should be an integral part of the risk management plan and as such considered before marketing authorisation. Modelling and simulation can be incorporated into MCDA to support the evidence synthesis as well evidence generation taking into account the underlying correlations between favourable and unfavourable effects. In addition, it represents a valuable tool for the optimization of protocol design in effectiveness trials.Keywords:

  • benefit–risk assessment;
  • European Medicines Agency;
  • multi criteria decision analysis;
  • not-in-trial simulations;
  • paediatric drug development;
  • pharmacokinetic–pharmacodynamic modelling
  •  
  •  

  

Show less
Model-Based Optimisation of Deferoxamine Chelation Therapy
Bellanti, F.; Vecchio, G.C. Del; Putti, M.C.; Cosmi, C.; Fotzi, I.; Bakshi, S.D.; ... ; Della, Pasqua O.E. 2015
Model-Based Optimisation of Deferoxamine Chelation Therapy
Article / Letter to editor
open access