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.
Similar content being viewed by others
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
References
Maertens J, Raad I, Petrikkos G, Boogaerts M, Selleslag D, Petersen FB, et al. Efficacy and safety of caspofungin for treatment of invasive aspergillosis in patients refractory to or intolerant of conventional antifungal therapy. Clin Infect Dis. 2004;39(11):1563–71.
Mora-Duarte J, Betts R, Rotstein C, Colombo AL, Thompson-Moya L, Smietana J, et al. Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med. 2002;347(25):2020–9.
Villanueva A, Arathoon EG, Gotuzzo E, Berman RS, DiNubile MJ, Sable CA. A randomized double-blind study of caspofungin versus amphotericin for the treatment of candidal esophagitis. Clin Infect Dis. 2001;33(9):1529–35.
Villanueva A, Gotuzzo E, Arathoon EG, Noriega LM, Kartsonis NA, Lupinacci RJ, et al. A randomized double-blind study of caspofungin versus fluconazole for the treatment of esophageal candidiasis. Am J Med. 2002;113(4):294–9.
Arathoon EG, Gotuzzo E, Noriega LM, Berman RS, DiNubile MJ, Sable CA. Randomized, double-blind, multicenter study of caspofungin versus amphotericin B for treatment of oropharyngeal and esophageal candidiases. Antimicrob Agents Chemother. 2002;46(2):451–7.
Sable C, Nguyen B, Chodakewitz J, DiNubile M. Safety and tolerability of caspofungin acetate in the treatment of fungal infections. Transpl Infect Dis. 2002;4(1):25–30.
Sawistowska-Schroeder ET, Kerridge D, Perry H. Echinocandin inhibition of 1, 3-β-D-glucan synthase from Candida albicans. FEBS Lett. 1984;173(1):134–8.
Shematek EM, Braatz JA, Cabib E. Biosynthesis of the yeast cell wall. I. Preparation and properties of beta-(1 leads to 3) glucan synthetase. J Biol Chem. 1980;255(3):888–94.
Kurtz M, Heath I, Marrinan J, Dreikorn S, Onishi J, Douglas C. Morphological effects of lipopeptides against Aspergillus fumigatus correlate with activities against (1, 3)-beta-D-glucan synthase. Antimicrob Agents Chemother. 1994;38(7):1480–9.
MSD. Package insert of Caspofungin. 2011.
Walsh TJ, Adamson PC, Seibel NL, Flynn PM, Neely MN, Schwartz C, et al. Pharmacokinetics, safety, and tolerability of caspofungin in children and adolescents. Antimicrob Agents Chemother. 2005;49(11):4536–45.
Hajdu R, Thompson R, Sundelof JG, Pelak BA, Bouffard FA, Dropinski JF, et al. Preliminary animal pharmacokinetics of the parenteral antifungal agent MK-0991 (L-743,872). Antimicrob Agents Chemother. 1997;41(11):2339–44.
Stone JA, Xu X, Winchell GA, Deutsch PJ, Pearson PG, Migoya EM, et al. Disposition of caspofungin: role of distribution in determining pharmacokinetics in plasma. Antimicrob Agents Chemother. 2004;48(3):815–23.
Stone EA, Fung HB, Kirschenbaum HL. Caspofungin: an echinocandin antifungal agent. Clin Ther. 2002;24(3):351–77.
Migoya EM, Mistry GC, Stone JA, Comisar W, Sun P, Norcross A, et al. Safety and pharmacokinetics of higher doses of caspofungin in healthy adult participants. J Clin Pharmacol. 2011;51(2):202–11.
Sandhu P, Lee W, Xu X, Leake BF, Yamazaki M, Stone JA, et al. Hepatic uptake of the novel antifungal agent caspofungin. Drug Metab Dispos. 2005;33(5):676–82.
Balani SK, Xu X, Arison BH, Silva MV, Gries A, DeLuna FA, et al. Metabolites of caspofungin acetate, a potent antifungal agent, in human plasma and urine. Drug Metab Dispos. 2000;28(11):1274–8.
Stone JA, Holland SD, Wickersham PJ, Sterrett A, Schwartz M, Bonfiglio C, et al. Single- and multiple-dose pharmacokinetics of caspofungin in healthy men. Antimicrob Agents Chemother. 2002;46(3):739–45.
Wuerthwein G, Cornely OA, Trame MN, Vehreschild JJ, Vehreschild MJ, Farowski F, et al. Population pharmacokinetics of escalating doses of caspofungin in a phase II study of patients with invasive aspergillosis. Antimicrob Agents Chemother. 2013;57(4):1664–71.
Ullmann AJ. Review of the safety, tolerability, and drug interactions of the new antifungal agents caspofungin and voriconazole. Curr Med Res Opin. 2003;19(4):263–71.
Schmitt W, Willmann S. Physiology-based pharmacokinetic modeling: ready to be used. Drug Discov Today : Technol. 2004;1(4):449–56.
Khalil F, Laer S. Physiologically based pharmacokinetic modeling: methodology, applications, and limitations with a focus on its role in pediatric drug development. J Biomed Biotechnol. 2011;2011:1–13.
Edginton AN, Theil F-P, Schmitt W, Willmann S. Whole body physiologically-based pharmacokinetic models: their use in clinical drug development. Expert Opin Drug Metab Toxicol. 2008;4(9):1143–52.
Espie P, Tytgat D, Sargentini-Maier ML, Poggesi I, Watelet JB. Physiologically based pharmacokinetics (PBPK). Drug Metab Rev. 2009;41(3):391–407.
von Kleist M, Huisinga W. Physiologically based pharmacokinetic modelling: a sub-compartmentalized model of tissue distribution. J Pharmacokinet Pharmacodyn. 2007;34(6):789–806.
Jones HM, Parrott N, Jorga K, Lavé T. A novel strategy for physiologically based predictions of human pharmacokinetics. Clin Pharmacokinet. 2006;45(5):511–42.
Edginton AN, Schmitt W, Voith B, Willmann S. A mechanistic approach for the scaling of clearance in children. Clin Pharmacokinet. 2006;45(7):683–704.
Groll AH, Silling G, Young C, Schwerdtfeger R, Ostermann H, Heinz WJ, et al. Randomized comparison of safety and pharmacokinetics of caspofungin, liposomal amphotericin B, and the combination of both in allogeneic hematopoietic stem cell recipients. Antimicrob Agents Chemother. 2010;54(10):4143–9.
Cornely OA, Vehreschild JJ, Vehreschild MJ, Wuerthwein G, Arenz D, Schwartz S, et al. Phase II dose escalation study of caspofungin for invasive aspergillosis. Antimicrob Agents Chemother. 2011;55(12):5798–803.
MSD. http://www.cancias.de. 07.09.2013.
Nishimura M, Naito S. Tissue-specific mRNA expression profiles of human ATP-binding cassette and solute carrier transporter superfamilies. Drug Metab Pharmacokinet. 2005;20(6):452–77.
Morrissey K, Wen C, Johns S, Zhang L, Huang S, Giacomini K. The UCSF-FDA TransPortal: a public drug transporter database. Clin Pharmacol Ther. 2012;92(5):545–6.
Nakanishi T, Tamai I. Genetic polymorphisms of OATP transporters and their impact on intestinal absorption and hepatic disposition of drugs. Drug Metab Pharmacokinet. 2012;27(1):106–21.
Niemi M, Pasanen MK, Neuvonen PJ. Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake. Pharmacol Rev. 2011;63(1):157–81.
Krauss M, Burghaus R, Lippert J, Niemi M, Neuvonen P, Schuppert A, et al. Using bayesian-PBPK modeling for assessment of inter-individual variability and subgroup stratification. In Silico Pharmacol. 2013;1(1):1–11.
Rodgers T, Leahy D, Rowland M. Physiologically based pharmacokinetic modeling 1: predicting the tissue distribution of moderate‐to‐strong bases. J Pharm Sci. 2005;94(6):1259–76.
Rodgers T, Rowland M. Physiologically based pharmacokinetic modelling 2: predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions. J Pharm Sci. 2006;95(6):1238–57.
Valentin J. Basic anatomical and physiological data for use in radiological protection: reference values: ICRP Publication 89. Ann ICRP. 2002;32(3):1–277.
McNamara PJ, Alcorn J. Protein binding predictions in infants. AAPS Pharm Sci. 2002;4(1):19–26.
Rubin MI, Bruck E, Rapoport M, Snively M, McKay H, Baumler A. Maturation of renal function in childhood: clearance studies. J Clin Investig. 1949;28(5):1144–62.
Gertz M, Cartwright CM, Hobbs MJ, Kenworthy KE, Rowland M, Houston JB, et al. Cyclosporine inhibition of hepatic and intestinal CYP3A4, uptake and efflux transporters: application of PBPK modeling in the assessment of drug-drug interaction potential. Pharm Res. 2013;30(3):761–80.
Amundsen R, Christensen H, Zabihyan B, Asberg A. Cyclosporine A, but not tacrolimus, shows relevant inhibition of organic anion-transporting protein 1B1-mediated transport of atorvastatin. Drug Metab Dispos. 2010;38(9):1499–504.
Hornik K. The R, project. 2014.
Saez-Llorens X, Macias M, Maiya P, Pineros J, Jafri HS, Chatterjee A, et al. Pharmacokinetics and safety of caspofungin in neonates and infants less than 3 months of age. Antimicrob Agents Chemother. 2009;53(3):869–75.
Neely M, Jafri HS, Seibel N, Knapp K, Adamson PC, Bradshaw SK, et al. Pharmacokinetics and safety of caspofungin in older infants and toddlers. Antimicrob Agents Chemother. 2009;53(4):1450–6.
Wuerthwein G, Young C, Lanvers-Kaminsky C, Hempel G, Trame MN, Schwerdtfeger R, et al. Population pharmacokinetics of liposomal amphotericin B and caspofungin in allogeneic hematopoietic stem cell recipients. Antimicrob Agents Chemother. 2012;56(1):536–43.
Nguyen TH, Hoppe-Tichy T, Geiss HK, Rastall AC, Swoboda S, Schmidt J, et al. Factors influencing caspofungin plasma concentrations in patients of a surgical intensive care unit. J Antimicrob Chemother. 2007;60(1):100–6.
Li CC, Sun P, Dong Y, Bi S, Desai R, Dockendorf MF, et al. Population pharmacokinetics and pharmacodynamics of caspofungin in pediatric patients. Antimicrob Agents Chemother. 2011;55(5):2098–105.
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.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11095-014-1595-9