Although posaconazole tablets show relatively low variability in pharmacokinetics (PK), the proportion of patients achieving the PK/PD target at the approved uniform dose for both prophylaxis and therapy is not satisfactory. The aim of this study was to develop a posaconazole population PK model in lung-transplant recipients and to propose a covariate-based dosing optimization for both prophylaxis and therapy. In this prospective study, 80 posaconazole concentrations obtained from 32 lung-transplant patients during therapeutic drug monitoring were analyzed using nonlinear mixed-effects modelling, and a Monte Carlo simulation was used to describe the theoretical distribution of posaconazole PK profiles at various dosing regimens. A one-compartment model with both linear absorption and elimination best fit the concentration-time data. The population apparent volume of distribution was 386.4 L, while an apparent clearance of 8.8 L/h decreased by 0.009 L/h with each year of the patient's age. Based on the covariate model, a dosing regimen of 200 mg/day for prophylaxis in patients ˃60 years, 300 mg/day for prophylaxis in patients ˂60 years and for therapy in patients ˃60 years, and 400 mg/day for therapy in patients ˂60 years has been proposed. At this dosing regimen, the PK/PD target for prophylaxis and therapy is reached in 95% and 90% of population, respectively, representing significantly improved outcomes in comparison with the uniform dose.

Department of Medical Chemistry and Clinical Biochemistry 2nd Faculty of Medicine Charles University Prague and Motol University Hospital 150 06 Prague Czech Republic

Department of Pharmacology 1st Faculty of Medicine Charles University and General University Hospital Prague 128 00 Prague Czech Republic

Prague Lung Transplant Program 3rd Department of Surgery 1st Faculty of Medicine Charles University Prague and Motol University Hospital 150 06 Prague Czech Republic

Prague Lung Transplant Program Department of Pneumology 2nd Faculty of Medicine Charles University Prague and Motol University Hospital 150 06 Prague Czech Republic

Zobrazit více v PubMed

Pappas P.G., Alexander B.D., Andes D.R., Hadley S., Kauffman C.A., Freifeld A., Anaissie E.J., Brumble L.M., Herwaldt L., Ito J., et al. Invasive fungal infections among organ transplant recipients: Results of the Transplant-Associated Infection Surveillance Network (TRANSNET) Clin. Infect. Dis. 2010;50:1101–1111. doi: 10.1086/651262. PubMed DOI

Aguilar C.A., Hamandi B., Fegbeutel C., Silveira F.P., Verschuuren E.A., Ussetti P., Chin-Hong P.V., Sole A., Holmes-Liew C., Billaud E.M., et al. Clinical risk factors for invasive aspergillosis in lung transplant recipients: Results of an international cohort study. J. Heart Lung Transplant. 2018;37:1226–1234. doi: 10.1016/j.healun.2018.06.008. PubMed DOI

Doligalski C.T., Benedict K., Cleveland A.A., Park B., Derado G., Pappas P.G., Baddley J.W., Zaas D.W., Harris M.T., Alexander B.D. Epidemiology of invasive mold infections in lung transplant recipients. Am. J. Transplant. 2014;14:1328–1333. doi: 10.1111/ajt.12691. PubMed DOI PMC

Husain S., Sole A., Alexander B.D., Aslam S., Avery R., Benden C., Billaud E.M., Chambers D., Danziger-Isakov L., Fedson S., et al. The 2015 International Society for Heart and Lung Transplantation Guidelines for the management of fungal infections in mechanical circulatory support and cardiothoracic organ transplant recipients: Executive summary. J. Heart Lung Transplant. 2016;35:261–282. doi: 10.1016/j.healun.2016.01.007. PubMed DOI

Patterson T.F., Thompson G.R., 3rd, Denning D.W., Fishman J.A., Hadley S., Herbrecht R., Kontoyiannis D.P., Marr K.A., Morrison V.A., Nguyen M.H., et al. Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clin. Infect. Dis. 2016;63:e1–e60. doi: 10.1093/cid/ciw326. PubMed DOI PMC

Husain S., Camargo J.F. Invasive Aspergillosis in solid-organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin. Transplant. 2019;33:e13544. doi: 10.1111/ctr.13544. PubMed DOI

Pennington K.M., Yost K.J., Escalante P., Razonable R.R., Kennedy C.C. Antifungal prophylaxis in lung transplant: A survey of United States’ transplant centers. Clin. Transplant. 2019;33:e13630. doi: 10.1111/ctr.13630. PubMed DOI PMC

Dekkers B.G.J., Bakker M., van der Elst K.C.M., Sturkenboom M.G.G., Veringa A., Span L.F.R., Alffenaar J.C. Therapeutic Drug Monitoring of Posaconazole: An Update. Curr. Fungal Infect. Rep. 2016;10:51–61. doi: 10.1007/s12281-016-0255-4. PubMed DOI PMC

Summary of Product Characteristics (Posaconazole), State Institute for Drug Control of Czech Repuplic. [(accessed on 5 April 2023)]. Available online: https://www.ema.europa.eu/en/documents/product-information/noxafil-epar-product-information_cs.pdf.

Ding Q., Huang S., Sun Z., Chen K., Li X., Pei Q. A Review of Population Pharmacokinetic Models of Posaconazole. Drug Des. Devel. Ther. 2022;16:3691–3709. doi: 10.2147/DDDT.S384637. PubMed DOI PMC

Dolton M.J., Ray J.E., Marriott D., McLachlan A.J. Posaconazole exposure-response relationship: Evaluating the utility of therapeutic drug monitoring. Antimicrob. Agents Chemother. 2012;56:2806–2813. doi: 10.1128/AAC.05900-11. PubMed DOI PMC

Zhang H., Nguyen M.H., Clancy C.J., Joshi R., Zhao W., Ensor C., Venkataramanan R., Shields R.K. Pharmacokinetics of Posaconazole Suspension in Lung Transplant Patients with and without Cystic Fibrosis. Antimicrob. Agents Chemother. 2016;60:3558–3562. doi: 10.1128/AAC.00424-16. PubMed DOI PMC

European Committee on Antimicrobial Susceptibility Testing Breakpoint Tables for Interpretation of MICs for Antifungal Agents. Version 10.0, valid from 4 February 2020. [(accessed on 4 April 2023)]. Available online: https://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/AFST/Clinical_breakpoints/AFST_BP_v10.0_200204_updatd_links_200924.pdf.

Stelzer D., Weber A., Ihle F., Matthes S., Ceelen F., Zimmermann G., Kneidinger N., Schramm R., Winter H., Zoller M., et al. Comparing Azole Plasma Trough Levels in Lung Transplant Recipients: Percentage of Therapeutic Levels and Intrapatient Variability. Ther. Drug Monit. 2017;39:93–101. doi: 10.1097/FTD.0000000000000371. PubMed DOI PMC

Petitcollin A., Boglione-Kerrien C., Tron C., Nimubona S., Lalanne S., Lemaitre F., Bellissant E., Verdier M.C. Population Pharmacokinetics of Posaconazole Tablets and Monte Carlo Simulations To Determine whether All Patients Should Receive the Same Dose. Antimicrob. Agents Chemother. 2017;61:e01166-17. doi: 10.1128/AAC.01166-17. PubMed DOI PMC

Mangoni A.A., Jackson S.H. Age-related changes in pharmacokinetics and pharmacodynamics: Basic principles and practical applications. Br. J. Clin. Pharmacol. 2004;57:6–14. doi: 10.1046/j.1365-2125.2003.02007.x. PubMed DOI PMC

De Sutter P.J., Gasthuys E., Van Braeckel E., Schelstraete P., Van Biervliet S., Van Bocxlaer J., Vermeulen A. Pharmacokinetics in Patients with Cystic Fibrosis: A Systematic Review of Data Published Between 1999 and 2019. Clin. Pharmacokinet. 2020;59:1551–1573. doi: 10.1007/s40262-020-00932-9. PubMed DOI

Dvorackova E., Sima M., Petrus J., Klapkova E., Hubacek P., Pozniak J., Havlin J., Lischke R., Slanar O. Ganciclovir Pharmacokinetics and Individualized Dosing Based on Covariate in Lung Transplant Recipients. Pharmaceutics. 2022;14:408. doi: 10.3390/pharmaceutics14020408. PubMed DOI PMC

Lignell A., Lowdin E., Cars O., Chryssanthou E., Sjolin J. Posaconazole in human serum: A greater pharmacodynamic effect than predicted by the non-protein-bound serum concentration. Antimicrob. Agents Chemother. 2011;55:3099–3104. doi: 10.1128/AAC.01671-10. PubMed DOI PMC

European Medicines Agency Guideline on Bioanalytical Method Validation. EMEA/CHMP/EWP/192217/2009 Rev. 1 Corr. 2**. Published: 21 July 2011. [(accessed on 5 April 2023)]. Available online: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-bioanalytical-method-validation_en.pdf.

Sima M., Pokorna P., Hronova K., Slanar O. Effect of co-medication on the pharmacokinetic parameters of phenobarbital in asphyxiated newborns. Physiol. Res. 2015;64:S513–S519. doi: 10.33549/physiolres.933213. PubMed DOI