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Physiology-Based Pharmacokinetics of Caspofungin for Adults and Paediatrics

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Abstract

Purpose

Caspofungin (CAS) is an antifungal agent for intravenous application in adults and children. Our aim was the development and validation of a physiology-based pharmacokinetic (PBPK) model in order to predict the pharmacokinetics in different patient populations, particularly in paediatrics.

Methods

A PBPK model for adults was built and validated with raw data of the two clinical trials CASLAMB and CASMTD. Afterwards, the model was scaled for paediatric patients under the consideration of known biochemical differences between adults and paediatrics.

Results

The simulated results of the PBPK model were in good agreement with the observed values of the CASLAMB and CASMTD trial. Patients of the CASLAMB trial received CAS in combination with cyclosporine A (CsA), which leads to an increased AUC0–24h of CAS hypothetically due to an inhibition of the hepatic transport protein OATP1B1 by CsA. However, there was no difference in the transport rate of OATP1B1 between CASLAMB and CASMTD patients in the PBPK model, suggesting that CsA might not influence OATP1B1. Furthermore, the model was able to sufficiently predict the pharmacokinetics of paediatric patients compared to published data.

Conclusion

The final PBPK model of CAS without individualized parameter is able to predict the pharmacokinetics in different patient populations correctly. Thus, the model provides a basis for investigators to choose doses and sampling times for special populations such as infants and small children.

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Abbreviations

AUC:

Area under the curve

CAS:

Caspofungin

CI:

Confidence interval

CLH :

Hepatic clearance

CLint :

Hepatic intrinsic clearance

fu:

Fraction unbound

GEOM:

Geometric mean

GOF:

Goodness of fit

HTK:

Haematocrit

i.v.:

Intravenous

Krbc, u :

Partition coefficient of the unbound fraction into the red blood cells

LAMB:

Liposomal Amphotericin B

OATP:

Organic anion transporting polypeptide

PBPK:

Physiology based pharmacokinetic

PE:

Prediction error

POP-PK:

Population pharmacokinetic

QH :

Hepatic blood flow

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ACKNOWLEDGMENTS AND DISCLOSURES

This work was supported by a free software licence of PK-Sim® provided by Bayer Technology Services GmbH, Leverkusen, Germany. AHG has received grants from Gilead and Merck, Sharp & Dohme, is a consultant to Astellas, Gilead, Merck, Sharp & Dohme and Schering-Plough and has served on the speakers’ bureaus of Astellas, Gliead, Merck, Sharpe & Dohme, Pfizer, Schering-Plough and Zeneus/Cephalon. JJV is supported by the German Federal Ministry of Research and Education (BMBF grant 01KI0771) and the German Centre for Infection Research. JJV has received research grants from Astellas, Gilead Sciences, Infectopharm, Merck, Pfizer, and Essex/Schering-Plough; and served on the speakers’ bureau of Astellas, Merck Sharp Dohme/Merck, Gilead Sciences, Pfizer, and Essex/Schering-Plough. OAC is supported by the German Federal Ministry of Research and Education (BMBF grant 01KN1106), has received research grants from 3 M, Actelion, Astellas, Basilea, Bayer, Celgene, Cubist, Genzyme, Gilead, GSK, Merck/MSD, Miltenyi, Optimer, Pfizer, Quintiles, and Viropharma, is a consultant to 3 M, Astellas, Basilea, Cubist, Da Volterra, Daiichi Sankyo, F2G, Gilead, GSK, Merck/MSD, Optimer, Pfizer, Sanofi Pasteur and Summit/Vifor, and received lecture honoraria from Astellas, Gilead, Merck/MSD, and Pfizer. GH receives research grants from Bayer Technology Services GmbH, Leverkusen, Germany.

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Author notes

  1. Felix Stader

    Present address: Simcyp Limited (a Certara Company), Blades Enterprise Centre, John Street, S2 4SU, Sheffield, UK

Authors and Affiliations

  1. Institute of Pharmaceutical and Medical Chemistry - Department of Clinical Pharmacy, Westfaelische Wilhelms-University Muenster, Corrensstraße 48, 48149, Muenster, Germany

    Felix Stader & Georg Hempel

  2. Centre for Clinical Trials (ZKS, BMBF 01KN1105), Muenster, University Hospital Muenster, Von-Esmarch-Straße 62, 48149, Muenster, Germany

    Gudrun Wuerthwein

  3. Centre for Bone Marrow Transplantation and Department of Paediatric Haematology / Oncology, University Hospital Muenster, Albert-Schweitzer-Campus 1, 48149, Muenster, Germany

    Andreas H. Groll

  4. Department I of Internal Medicine, German Centre for Infection Research, partner site Bonn-Cologne, University of Cologne, Kerpener Straße 62, 50937, Cologne, Germany

    Joerg-Janne Vehreschild

  5. Department I of Internal Medicine, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Clinical Trials Centre Cologne, ZKS Köln, BMBF 01KN1106, Center for Integrated Oncology CIO KölnBonn, German Centre for Infection Research, University of Cologne, Kerpener Straße 62, 50937, Cologne, Germany

    Oliver A. Cornely

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  1. Felix Stader
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Correspondence to Georg Hempel.

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Stader, F., Wuerthwein, G., Groll, A.H. et al. Physiology-Based Pharmacokinetics of Caspofungin for Adults and Paediatrics. Pharm Res 32, 2029–2037 (2015). https://doi.org/10.1007/s11095-014-1595-9

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  • DOI: https://doi.org/10.1007/s11095-014-1595-9

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