Pharmacokinetic/pharmacodynamic modelling of the EEG effects of opioids: The role of complex biophase distribution kinetics

Groenendaal, Dorien; Freijer, Jan; Rosier, Andrea; Mik, D de; Nicholls, G. D.; Hersey, Anne; Ayrton, Andrew D.; Danhof, Meindert; Lange, Elizabeth C. M. de

doi:10.1016/j.ejps.2008.03.003

Cited by 27 publications

(20 citation statements)

References 27 publications

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“…• Studying series of chemically similar drugs with varying degrees of agonism for the specific receptor and simultaneous analysis of the PKPD relationships (Cox et al 1998;Groenendaal et al 2008). …”

Section: Operational Model Of Agonismmentioning

confidence: 99%

PKPD Aspects of Brain Drug Delivery in a Translational Perspective

Lange

2013

Drug Delivery to the Brain

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The development and optimization of CNS drug is hampered by the inaccessibility of the human brain and the difficulty to quantify human CNS drug effects. The use of serial CSF sampling in animals and mathematical modeling of plasma pharmacokinetics, in conjunction with CNS effects, provided only useful information for drugs that distribute to the brain target site by simple diffusion and having direct and reversible CNS effects. Active transport processes across bloodbrain barriers and brain cell membranes may be applicable for many drugs and should be taken into account. Also, context dependencies of the rates and extents of all transport processes should be included. This indicates the need for crosscompare designed preclinical experimental approaches and mathematical modeling to provide information on contributions of the (main) individual processes, in terms of rate and extent, as well as their interplay, to be able to predict human CNS drug effects. Abbreviations ARAgonist receptor complex density BBB Blood-brain barrier BCSFB Blood-cerebrospinal fluid barrier Ce Concentration of the drug in the effect compartment CNS Central nervous system CSF Cerebrospinal fluid E Effect

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Section: Operational Model Of Agonismmentioning

confidence: 99%

PKPD Aspects of Brain Drug Delivery in a Translational Perspective

Lange

2013

Drug Delivery to the Brain

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“…Depending on the PK, as well as the type of response (inhibition or stimulation), different PK-PD models can be used. With that, it is possible to learn more about factors that play a role in target activation and signal transduction to the ultimate effect or biomarker of the effect [57][58][59][60][61], interspecies differences in concentrationeffect relationships [62], tolerance and sensitization [63], and intra-and interindividual variability. Moreover, for studies with only PK and PD observations but not TO data, a delay between the PK and PD is often be explained by a biophase (or effect compartment) distribution model.…”

Section: Cns Drug Effectsmentioning

confidence: 99%

“…Currently, to link (neuro-)PK to the systems response, PK-PD modeling is often applied. These models can include target activation (receptor theory [65][66][67][68]), signal transduction [57][58][59][60][61], interspecies differences [62], tolerance and sensitization [63], and intra-and interindividual variability. Also here, it should be noted that parameter values of PK, PD, and disease processes should not be obtained in isolation, and in different systems, because in such manner interrelationships and systems dependencies of processes cannot be assessed.…”

Section: Expert Opinionmentioning

confidence: 99%

Novel CNS drug discovery and development approach: model-based integration to predict neuro-pharmacokinetics and pharmacodynamics

Lange

Brink

Yamamoto

et al. 2017

Expert Opinion on Drug Discovery

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Introduction: CNS drug development has been hampered by inadequate consideration of CNS pharmacokinetic (PK), pharmacodynamics (PD) and disease complexity (reductionist approach). Improvement is required via integrative model-based approaches. Areas covered: The authors summarize factors that have played a role in the high attrition rate of CNS compounds. Recent advances in CNS research and drug discovery are presented, especially with regard to assessment of relevant neuro-PK parameters. Suggestions for further improvements are also discussed. Expert opinion: Understanding time-and condition dependent interrelationships between neuro-PK and neuro-PD processes is key to predictions in different conditions. As a first screen, it is suggested to use in silico/in vitro derived molecular properties of candidate compounds and predict concentrationtime profiles of compounds in multiple compartments of the human CNS, using time-course based physiology-based (PB) PK models. Then, for selected compounds, one can include in vitro drug-target binding kinetics to predict target occupancy (TO)-time profiles in humans. This will improve neuro-PD prediction. Furthermore, a pharmaco-omics approach is suggested, providing multilevel and paralleled data on systems processes from individuals in a systems-wide manner. Thus, clinical trials will be better informed, using fewer animals, while also, needing fewer individuals and samples per individual for proof of concept in humans. ARTICLE HISTORY

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“…Previous investigations have shown that quantitative (spectral) analysis of the increase in delta frequency band of the resting EEG is a suitable biomarker for the PK-PD correlation of opioids [20,21] . In a study of biophase kinetics within the PK-PD analysis of a wide range of opioids, morphine showed profound hysteresis between the blood pharmacokinetics and EEG effect [22] . Groenendaal et al [22] have concluded that within the wide range of opioids used in their study, only morphine displayed complex biophase distribution kinetics, which can be explained by its relatively low permeability of the blood-brain barrier and its interaction with active transporters present at the barrier.…”

Section: Surgical Patient Studiesmentioning

confidence: 99%

“…In a study of biophase kinetics within the PK-PD analysis of a wide range of opioids, morphine showed profound hysteresis between the blood pharmacokinetics and EEG effect [22] . Groenendaal et al [22] have concluded that within the wide range of opioids used in their study, only morphine displayed complex biophase distribution kinetics, which can be explained by its relatively low permeability of the blood-brain barrier and its interaction with active transporters present at the barrier. Figure 1 Understanding the effect of analgesics.…”

Section: Surgical Patient Studiesmentioning

confidence: 99%