E.C.M. de Lange

Population pharmacokinetic modelling of non-linear brain distribution of morphine: influence of active saturable influx and P-glycoprotein mediated efflux

Biophase equilibration must be considered to gain insight into the mechanisms underlying the pharmacokinetic‐pharmacodynamic (PK‐PD) correlations of opioids. The objective was to characterise in a quantitative manner the non‐linear distribution kinetics of morphine in brain.

Repeated microdialysis perfusions: periprobe tissue reactions and BBB permeability

In the present paper the time course of brain tissue changes as evoked by a microdialysis probe and repeated dialysis procedures was examined by semiquantitative histology. The reactions to the presence of the probe as such were minimal. However, after more than two repeated perfusion procedures, tissue scores of hypercellularity and infiltration of granulocytes increased. It is concluded that the frequent use of repeated dialysis procedures may give rise to tissue effects parallelled by changes in BBB permeability. This has to be taken into account when intracerebral microdialysis is applied repeatedly within the same animal.

The Use of Intracerebral Microdialysis for the Determination of Pharmacokinetic Profiles of Anticancer Drugs in Tumor-Bearing Rat Brain

AbstractPurpose. The use of intracerebral microdialysis as a tool to measure the penetration of anticancer agents in brain tumor was investigated. Methods. Following intravenous (iv) administration of 75 mg/kg. concentration-time profiles of methotrexate (MTX) were determined in brain cortical dialysate and in plasma. The individual ratio of the area under the curve of MTX in brain dialysate over that in plasma (MTX penetration) was determined in normal brain, in tumor-bearing brain and in brain after sham tumor implantation. Individual brains were examined histologically on the presence of tumor, as well as for other factors that might influence local MTX penetration. Histological scores were related to the individual data on penetration of MTX. Results. MTX penetration values were higher in cortical brain at the site of the tumor, as compared to the levels measured in normal or sham implanted brain (mean increase to 250 %). In the cortical brain contralateral to the tumor, MTX penetration values were found to be lower than in normal brain (mean reduction of 65 %). Furthermore, it appeared that in the absence of tumor tissue, the presence of exudate around the probe was independently associated with increased penetration of MTX into the brain. Conclusions. Tumor tissue appeared to be the most important parameter in changing local MTX penetration in brain after tumor implantation. In general, it is anticipated that intracerebral microdialysis combined with histological examination can be used to investigate effects of brain tumor presence on regional (periprobe) penetration of anticancer drugs into the brain.

Influence of biophase distribution and P‐glycoprotein interaction on pharmacokinetic‐pharmacodynamic modelling of the effects of morphine on the EEG

The aim was to investigate the influence of biophase distribution including P‐glycoprotein (Pgp) function on the pharmacokinetic‐pharmacodynamic correlations of morphines actions in rat brain.

Pharmacokinetic-pharmacodynamic modelling of S(-)-atenolol in rats: reduction of isoprenaline-induced tachycardia as a continuous pharmacodynamic endpoint.

For development of mechanism‐based pharmacokinetic‐pharmacodynamic (PK‐PD) models, continuous recording of drug effects is essential. We therefore explored the use of isoprenaline in the continuous measurement of the cardiovascular effects of antagonists of β‐adrenoceptors (β‐blockers). The aim was to validate heart rate as a pharmacodynamic endpoint under continuous isoprenaline‐induced tachycardia by means of PK‐PD modelling of S(−)‐atenolol.

Influence of Plasma Protein Binding on Pharmacodynamics: Estimation of In Vivo Receptor Affinities of β Blockers Using a New Mechanism-Based PK–PD Modelling Approach

The objective of this investigation was to examine in a systematic manner the influence of plasma protein binding on in vivo pharmacodynamics. Comparative pharmacokinetic-pharmacodynamic studies with four beta blockers were performed in conscious rats, using heart rate under isoprenaline-induced tachycardia as a pharmacodynamic endpoint. A recently proposed mechanism-based agonist-antagonist interaction model was used to obtain in vivo estimates of receptor affinities (K(B,vivo)). These values were compared with in vitro affinities (K(B,vitro)) on the basis of both total and free drug concentrations. For the total drug concentrations, the K(B,vivo) estimates were 26, 13, 6.5 and 0.89 nM for S(-)-atenolol, S(-)-propranolol, S(-)-metoprolol and timolol. The K(B,vivo) estimates on the basis of the free concentrations were 25, 2.0, 5.2 and 0.56 nM, respectively. The K(B,vivo)-K(B,vitro) correlation for total drug concentrations clearly deviated from the line of identity, especially for the most highly bound drug S(-)-propranolol (ratio K(B,vivo)/K(B,vitro) approximately 6.8). For the free drug, the correlation approximated the line of identity. Using this model, for beta-blockers the free plasma concentration appears to be the best predictor of in vivo pharmacodynamics.

White Paper: Landscape on Technical and Conceptual Requirements and Competence Framework in Drug/Disease Modeling and Simulation

Pharmaceutical sciences experts and regulators acknowledge that pharmaceutical development as well as drug usage requires more than scientific advancements to cope with current attrition rates/therapeutic failures. Drug disease modeling and simulation (DDM&S) creates a paradigm to enable an integrated and higher‐level understanding of drugs, (diseased)systems, and their interactions (systems pharmacology) through mathematical/statistical models (pharmacometrics) 1 —hence facilitating decision making during drug development and therapeutic usage of medicines. To identify gaps and challenges in DDM&S, an inventory of skills and competencies currently available in academia, industry, and clinical practice was obtained through survey. The survey outcomes revealed benefits, weaknesses, and hurdles for the implementation of DDM&S. In addition, the survey indicated that no consensus exists about the knowledge, skills, and attributes required to perform DDM&S activities effectively. Hence, a landscape of technical and conceptual requirements for DDM&S was identified and serves as a basis for developing a framework of competencies to guide future education and training in DDM&S.

Effect of altered AGP plasma binding on heart rate changes by S(−)‐propranolol in rats using mechanism‐based estimations of in vivo receptor affinity (KB,vivo)

In contrast to the impact of plasma protein binding on pharmacokinetics, no quantitative in vivo information is available on its impact on pharmacodynamics. The pharmacokinetic-pharmacodynamic relationship of the model drug S(-)-propranolol was evaluated using mechanism-based estimations of in vivo receptor affinity (K(B,vivo)), under conditions of altered plasma protein binding resulting from different levels of alpha-1-acid glycoprotein (AGP). Male Wistar Kyoto rats with isoprenaline-induced tachycardia received an intravenous infusion of S(-)-propranolol, on postsurgery day 2 (n = 7) and day 7 (n = 8) with elevated and normal plasma protein binding, respectively. Serial blood samples were taken in parallel to heart rate measurements. AGP concentrations at 2 and 7 days postsurgery were 708 +/- 274 and 176 +/- 111 microg/mL (mean +/- SE), respectively. Using nonlinear mixed effects modeling, AGP concentration was a covariate for intercompartmental clearance for the third compartment of the pharmacokinetic model of S(-)-propranolol. Individual values of AGP concentrations ranged between 110 and 1150 microg/mL, and were associated with K(B,vivo) values of S(-)-propranolol from 7.0 to 30 nM. Using the K(B,vivo) for S(-)-propranolol with correction for average values for normal and elevated plasma protein binding, nearly identical values were found. This confirms, strictly quantitative, earlier indications that plasma protein binding restricts the pharmacodynamics of S(-)-propranolol.

Drug transport to the brain: in vitro versus in vivo approaches

This paper summarizes the applicability of in vitro and in vivo methods to assess drug transport to the brain. In vitro methods: culture of confluent monolayers of bovine brain endothelial cells which represent the blood-brain barrier (BBB) and confocal laser scanning microscopy. In vivo methods: BBB-clearance model and microdialysis in rats. Ascertaining selectivity in BBB-transport in disease states is emphasized.

The influence of drug distribution and drug-target binding on target occupancy : The rate-limiting step approximation

Abstract The influence of drug‐target binding kinetics on target occupancy can be influenced by drug distribution and diffusion around the target, often referred to as “rebinding” or “diffusion‐limited binding”. This gives rise to a decreased decline of the drug‐target complex concentration as a result of a locally higher drug concentration that arises around the target, which leads to prolonged target exposure to the drug. This phenomenon has been approximated by the steady‐state approximation, assuming a steady‐state concentration around the target. Recently, a rate‐limiting step approximation of drug distribution and drug‐target binding has been published. However, a comparison between both approaches has not been made so far. In this study, the rate‐limiting step approximation has been rewritten into the same mathematical format as the steady‐state approximation in order to compare the performance of both approaches for the investigation of the influence of drug‐target binding kinetics on target occupancy. While both approximations clearly indicated the importance of kon and high target concentrations, it was shown that the rate‐limiting step approximation is more accurate than the steady‐state approximation, especially when dissociation is fast compared to association and distribution out of the binding compartment. It is therefore concluded that the new rate‐limiting step approximation is to be preferred for assessing the influence of binding kinetics on local target site concentrations and target occupancy. Graphical abstract No caption available.