Using the LeiCNS-PK3.0 Physiologically-Based Pharmacokinetic Model to Predict Brain Extracellular Fluid Pharmacokinetics in Mice
Pharmaceutical Research, vol. 40, pp. 2555–2566
Abstract
Abstract Introduction The unbound brain extracelullar fluid (brainECF) to plasma steady state partition coefficient, Kp,uu,BBB, values provide steady-state information on the extent of blood-brain barrier (BBB) transport equilibration, but not on pharmacokinetic (PK) profiles seen by the brain targets. Mouse models are frequently used to study brain PK, but this information cannot directly be used to inform on human brain PK, given the different CNS physiology of mouse and human. Physiologically based PK (PBPK) models are useful to translate PK information across species. Aim Use the LeiCNS-PK3.0 PBPK model, to predict brain extracellular fluid PK in mice. Methods Information on mouse brain physiology was collected from literature. All available connected data on unbound plasma, brainECF PK of 10 drugs (cyclophosphamide, quinidine, erlotonib, phenobarbital, colchicine, ribociclib, topotecan, cefradroxil, prexasertib, and methotrexate) from different mouse strains were used. Dosing regimen dependent plasma PK was modelled, and Kpuu,BBB values were estimated, and provided as input into the LeiCNS-PK3.0 model to result in prediction of PK profiles in brainECF. Results Overall, the model gave an adequate prediction of the brainECF PK profile for 7 out of the 10 drugs. For 7 drugs, the predicted versus observed brainECF data was within two-fold error limit and the other 2 drugs were within five-fold error limit. Conclusion The current version of the mouse LeiCNS-PK3.0 model seems to reasonably predict available information on brainECF from healthy mice for most drugs. This brings the translation between mouse and human brain PK one step further.
Authors 6
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Mohammed A. A. Saleh Aachen Division of Systems Pharmacology and Pharmacy Leiden Academic Centre for Drug Research
Affiliation as printed
Division of Systems Pharmacology and Pharmacy, Leiden Academic Center for Drug Research, Leiden University, Gorlaeus laboratorium, Einsteinweg 55, 2333 CC, Leiden, The Netherlands
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Berfin Gülave Aachen Division of Systems Pharmacology and Pharmacy Leiden Academic Centre for Drug Research
Affiliation as printed
Division of Systems Pharmacology and Pharmacy, Leiden Academic Center for Drug Research, Leiden University, Gorlaeus laboratorium, Einsteinweg 55, 2333 CC, Leiden, The Netherlands
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St. Jude Children's Research Hospital
Affiliation as printed
Department of Pharmacy and Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, USA
Department of Pharmacy and Pharmaceutical Sciences, St Jude Children’s Research Hospital, Memphis, USA
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St. Jude Children's Research Hospital
Affiliation as printed
Department of Pharmacy and Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, USA
Department of Pharmacy and Pharmaceutical Sciences, St Jude Children’s Research Hospital, Memphis, USA
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Affiliation as printed
PD-value B.V., Utrecht, The Netherlands
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Elizabeth C. M. de Lange corresponding Aachen Division of Systems Pharmacology and Pharmacy Leiden Academic Centre for Drug Research
Affiliation as printed
Division of Systems Pharmacology and Pharmacy, Leiden Academic Center for Drug Research, Leiden University, Gorlaeus laboratorium, Einsteinweg 55, 2333 CC, Leiden, The Netherlands. ecmdelange@lacdr.leidenuniv.nl
Division of Systems Pharmacology and Pharmacy, Leiden Academic Center for Drug Research, Leiden University, Gorlaeus laboratorium, Einsteinweg 55, 2333 CC, Leiden, The Netherlands
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