Therapeutic Drug Monitoring of Posaconazole: an Update

Bart G J Dekkers, Martijn Bakker, Kim C M van der Elst, Marieke G G Sturkenboom, Anette Veringa, Lambert F R Span, Jan-Willem C Alffenaar, Bart G J Dekkers, Martijn Bakker, Kim C M van der Elst, Marieke G G Sturkenboom, Anette Veringa, Lambert F R Span, Jan-Willem C Alffenaar

Abstract

Posaconazole is a second-generation triazole agent with a potent and broad antifungal activity. In addition to the oral suspension, a delayed-release tablet and intravenous formulation with improved pharmacokinetic properties have been introduced recently. Due to the large interindividual and intraindividual variation in bioavailability and drug-drug interactions, therapeutic drug monitoring (TDM) is advised to ensure adequate exposure and improve clinical response for posaconazole. Here, we highlight and discuss the most recent findings on pharmacokinetics and pharmacodynamics of posaconazole in the setting of prophylaxis and treatment of fungal infections and refer to the challenges associated with TDM of posaconazole.

Keywords: Dried blood spot; Fusarium infections; Invasive aspergillosis; Invasive fungal infection; Mucormycosis; Pharmacodynamics; Pharmacokinetics; Posaconazole; Prophylaxis; Scedosporium infections; Therapeutic drug monitoring.

Figures

Fig. 1
Fig. 1
Therapeutic drug monitoring (TDM) of posaconazole. TDM is recommended after 7 days of treatment for posaconazole in case of the salvage treatment of invasive fungal infections, interacting drugs (P-gp inhibitors), of use of the posaconazole oral suspension and in case of specific clinical circumstances. In case of salvage treatment, TDM is also required when a pathogen with reduced susceptibility (>0.12 mg/l) to posaconazole is isolated or when the pathogen is localized at a difficult to reach site. If the trough level is above 0.7 (0.9) mg/l (AUC/MIC > 100) for prophylaxis or above 1.25 (1.8) mg/l (AUC/MIC > 200) for salvage treatment, the dose should be maintained. In case of a trough level below these target concentrations, effort should be done to increase the concentration to target levels. IFD invasive fungal disease, MIC minimum fungicidal inhibitory concentration, and P-gp P-glycoprotein

References

    1. Drew RH, Townsend ML, Pound MW, Johnson SW, Perfect JR. Recent advances in the treatment of life-threatening, invasive fungal infections. Expert Opin Pharmacother. 2013;14:2361–74. doi: 10.1517/14656566.2013.838217.
    1. Torres HA, Hachem RY, Chemaly RF, Kontoyiannis DP, Raad II. Posaconazole: a broad-spectrum triazole antifungal. Lancet Infect Dis. 2005;5:775–85. doi: 10.1016/S1473-3099(05)70297-8.
    1. Seyedmousavi S, Mouton JW, Melchers WJG, Brüggemann RJM, Verweij PE. The role of azoles in the management of azole-resistant aspergillosis: from the bench to the bedside. Drug Resist Updat. 2014;17:37–50. A review providing an approach to link fungal genotype and phenotype, posaconazole pharmacokinetic and pharmacodynamic properties, and (pre)clinical treatment efficacy in (refractory) invasive fungal disease.
    1. Wiederhold N, Patterson T. Emergence of azole resistance in Aspergillus. Semin Respir Crit Care Med. 2015;36:673–80. doi: 10.1055/s-0035-1562894.
    1. Lipp H-P. Clinical pharmacodynamics and pharmacokinetics of the antifungal extended-spectrum triazole posaconazole: an overview. Br J Clin Pharmacol. 2010;70:471–80. doi: 10.1111/j.1365-2125.2010.03680.x.
    1. Li Y, Theuretzbacher U, Clancy CJ, Nguyen MH, Derendorf H. Pharmacokinetic/pharmacodynamic profile of posaconazole. Clin Pharmacokinet. 2010;49:379–96. doi: 10.2165/11319340-000000000-00000.
    1. Krishna G, Moton A, Ma L, Medlock MM, McLeod J. Pharmacokinetics and absorption of posaconazole oral suspension under various gastric conditions in healthy volunteers. Antimicrob Agents Chemother. 2009;53:958–66. doi: 10.1128/AAC.01034-08.
    1. van der Elst KCM, Brouwers CHS, van den Heuvel ER, van Wanrooy MJP, Uges DRA, van der Werf TS, et al. Subtherapeutic posaconazole exposure and treatment outcome in patients with invasive fungal disease. Ther Drug Monit. 2015;1.
    1. Dolton MJ, Brüggemann RJM, Burger DM, McLachlan AJ. Understanding variability in posaconazole exposure using an integrated population pharmacokinetic analysis. Antimicrob. Agents Chemother. 2014;58:6879–85. A population pharmacokinetic study identifying a number of variables explaining the variable pharmacokinetics of the posaconazole suspension.
    1. Chae H, Cho S-Y, Yu H, Cha K, Lee S, Kim M, et al. Determination of posaconazole concentration with LC–MS/MS in adult patients with hematologic malignancy. Clin Chim Acta. 2015;450:220–6. doi: 10.1016/j.cca.2015.08.023.
    1. Cojutti P, Candoni A, Simeone E, Franceschi L, Fanin R, Pea F. Antifungal prophylaxis with posaconazole in patients with acute myeloid leukemia: dose intensification coupled with avoidance of proton pump inhibitors is beneficial in shortening time to effective concentrations. Antimicrob Agents Chemother. 2013;57:6081–4. doi: 10.1128/AAC.01586-13.
    1. Alffenaar J-WC, van Assen S, van der Werf TS, Kosterink JGW, Uges DRA. Omeprazole significantly reduces posaconazole serum trough level. Clin Infect Dis. 2009;48:839. doi: 10.1086/597110.
    1. Dolton MJ, Ray JE, Marriott D, McLachlan AJ. Posaconazole exposure-response relationship: evaluating the utility of therapeutic drug monitoring. Antimicrob Agents Chemother. 2012;56:2806–13. doi: 10.1128/AAC.05900-11.
    1. Kraft WK, Chang PS, van Iersel MLPS, Waskin H, Krishna G, Kersemaekers WM. Posaconazole tablet pharmacokinetics: lack of effect of concomitant medications altering gastric pH and gastric motility in healthy subjects. Antimicrob Agents Chemother. 2014;58:4020–5. doi: 10.1128/AAC.02448-13.
    1. Maertens J, Cornely OA, Ullmann AJ, Heinz WJ, Krishna G, Patino H, et al. Phase 1B study of the pharmacokinetics and safety of posaconazole intravenous solution in patients at risk for invasive fungal disease. Antimicrob Agents Chemother. 2014;58:3610–7. A first study investigating the properties of the intravenous posaconazole formulation, including pharmacokinetic properties.
    1. European Medicines Agency, Committee for Medicinal Products for Human Use. Assessment report noxafil. EMA/159150/2014. Available from http//.
    1. Krishna G, Ma L, Martinho M, O’Mara E. Single-dose phase I study to evaluate the pharmacokinetics of posaconazole in new tablet and capsule formulations relative to oral suspension. Antimicrob Agents Chemother. 2012;56:4196–201. doi: 10.1128/AAC.00222-12.
    1. Kersemaekers WM, Dogterom P, Xu J, Marcantonio EE, de Greef R, Waskin H, et al. Effect of a high-fat meal on the pharmacokinetics of 300-milligram posaconazole in a solid oral tablet formulation. Antimicrob Agents Chemother. 2015;59:3385–9. doi: 10.1128/AAC.05000-14.
    1. McKeage K. Posaconazole: a review of the gastro-resistant tablet and intravenous solution in invasive fungal infections. Drugs. 2015;75:397–406. doi: 10.1007/s40265-015-0348-3.
    1. Krishna G, Ma L, Martinho M, Preston RA, O’Mara E. A new solid oral tablet formulation of posaconazole: a randomized clinical trial to investigate rising single- and multiple-dose pharmacokinetics and safety in healthy volunteers. J Antimicrob Chemother. 2012;67:2725–30. doi: 10.1093/jac/dks268.
    1. Kersemaekers WM, van Iersel T, Nassander U, O’Mara E, Waskin H, Caceres M, et al. Pharmacokinetics and safety study of posaconazole intravenous solution administered peripherally to healthy subjects. Antimicrob Agents Chemother. 2015;59:1246–51. doi: 10.1128/AAC.04223-14.
    1. Luke DR, Tomaszewski K, Damle B, Schlamm HT. Review of the basic and clinical pharmacology of sulfobutylether-beta-cyclodextrin (SBECD) J Pharm Sci. 2010;99:3291–301. doi: 10.1002/jps.22109.
    1. Merck S & DL. Merck, Sharp & Dohme Ltd. Noxafil (posaconazole)—summary of product characteristics. Available from http// [Last accessed 14 Oct. 2015]. 2015;1–102.
    1. Dolton MJ, McLachlan AJ. Optimizing azole antifungal therapy in the prophylaxis and treatment of fungal infections. Curr Opin Infect Dis. 2014;27:493–500. doi: 10.1097/QCO.0000000000000103.
    1. Veringa A, Sturkenboom MGG, Dekkers BGJ, Koster RA, Roberts JA, Peloquin CA, et al. LC-MS/MS for therapeutic drug monitoring of anti-infective drugs. Trends Anal. Chem. 2016. doi:10.1016/j.trac.2015.11.026.
    1. Lewis RE, Albert ND, Kontoyiannis DP. Comparative pharmacodynamics of posaconazole in neutropenic murine models of invasive pulmonary aspergillosis and mucormycosis. Antimicrob Agents Chemother. 2014;58:6767–72. doi: 10.1128/AAC.03569-14.
    1. Seyedmousavi S, Mouton JW, Melchers WJG, Verweij PE. Posaconazole prophylaxis in experimental azole-resistant invasive pulmonary aspergillosis. Antimicrob Agents Chemother. 2015;59:1487–94. doi: 10.1128/AAC.03850-14.
    1. Dolton MJ, Ray JE, Chen SC-A, Ng K, Pont L, McLachlan AJ. Multicenter study of posaconazole therapeutic drug monitoring: exposure-response relationship and factors affecting concentration. Antimicrob Agents Chemother. 2012;56:5503–10. doi: 10.1128/AAC.00802-12.
    1. Seyedmousavi S, Mouton JW, Verweij PE, Brüggemann RJ. Therapeutic drug monitoring of voriconazole and posaconazole for invasive aspergillosis. Expert Rev Anti Infect Ther. 2013;11:931–41. doi: 10.1586/14787210.2013.826989.
    1. Ashbee HR, Barnes RA, Johnson EM, Richardson MD, Gorton R, Hope WW. Therapeutic drug monitoring (TDM) of antifungal agents: guidelines from the British Society for Medical Mycology. J. Antimicrob. Chemother. 2013;69:1162–76. doi: 10.1093/jac/dkt508.
    1. EUCAST. Posaconazole Aspergillus breakpoints. 2012;
    1. Jung DS, Tverdek FP, Kontoyiannis DP. Switching from posaconazole suspension to tablets increases serum drug levels in leukemia patients without clinically relevant hepatotoxicity. Antimicrob Agents Chemother. 2014;58:6993–5. doi: 10.1128/AAC.04035-14.
    1. Miceli MH, Perissinotti AJ, Kauffman CA, Couriel DR. Serum posaconazole levels among haematological cancer patients taking extended release tablets is affected by body weight and diarrhoea: single centre retrospective analysis. Mycoses. 2015;58:432–6. doi: 10.1111/myc.12339.
    1. Blennow O, Eliasson E, Pettersson T, Pohanka A, Szakos A, El-Serafi I, et al. Posaconazole concentrations in human tissues after allogeneic stem cell transplantation. Antimicrob Agents Chemother. 2014;58:4941–3. doi: 10.1128/AAC.03252-14.
    1. Rüping MJGT, Albermann N, Ebinger F, Burckhardt I, Beisel C, Müller C, et al. Posaconazole concentrations in the central nervous system. J Antimicrob Chemother. 2008;62:1468–70. doi: 10.1093/jac/dkn409.
    1. Aigner M, Lass-Flörl C. Treatment of drug-resistant Aspergillus infection. Expert Opin Pharmacother. 2015;1–4.
    1. Cornely OA, Duarte RF, Haider S, Chandrasekar P, Helfgott D, Jiménez JL, et al. Phase 3 pharmacokinetics and safety study of a posaconazole tablet formulation in patients at risk for invasive fungal disease. J Antimicrob Chemother. 2016;71(3):718-26. A first study investigating the posaconazole tablets formulation in patients at high risk for invasive fungal disease in relation to pharmacokinetics and efficacy.
    1. Ponath PD, Qin S, Ringler DJ, Clark-Lewis I, Wang J, Kassam N, et al. Cloning of the human eosinophil chemoattractant, eotaxin. Expression, receptor binding, and functional properties suggest a mechanism for the selective recruitment of eosinophils. J. Clin. Invest. LeukoSite, Inc., Cambridge, Massachusetts 02142, USA; PM:8609214; 1996;97:604–12.
    1. Moore JN, Healy JR, Kraft WK. Pharmacologic and clinical evaluation of posaconazole. Expert Rev. Clin. Pharmacol. 2015;8:321–34. doi: 10.1586/17512433.2015.1034689.
    1. van der Elst KCM, Span LFR, van Hateren K, Vermeulen KM, van der Werf TS, Greijdanus B, et al. Dried blood spot analysis suitable for therapeutic drug monitoring of voriconazole, fluconazole, and posaconazole. Antimicrob. Agents Chemother. 2013;57:4999–5004. doi: 10.1128/AAC.00707-13.
    1. Reddy TM, Tama CI, Hayes RN. A dried blood spots technique based LC–MS/MS method for the analysis of posaconazole in human whole blood samples. J Chromatogr B. 2011;879:3626–38. doi: 10.1016/j.jchromb.2011.10.008.
    1. Clinical validation of a dried blood spot method for analysis of immunosuppressives and antifungals in pediatrics (PROTECT). https// [Last accessed 26 Oct. 2015].
    1. Brüggemann RJM, Aarnoutse RE. Fundament and prerequisites for the application of an antifungal TDM service. Curr Fungal Infect Rep. 2015;9:122–9. doi: 10.1007/s12281-015-0224-3.
    1. Heinz WJ, Egerer G, Lellek H, Boehme A, Greiner J. Posaconazole after previous antifungal therapy with voriconazole for therapy of invasive Aspergillus disease, a retrospective analysis. Mycoses. 2013;56:304–10. doi: 10.1111/myc.12023.
    1. Bassetti M, Pecori D, Della Siega P, Corcione S, De Rosa FG. Current and future therapies for invasive aspergillosis. Pulm Pharmacol Ther. 2015;32:155–65. doi: 10.1016/j.pupt.2014.06.002.
    1. Walsh TJ, Raad I, Patterson TF, Chandrasekar P, Donowitz GR, Graybill R, et al. Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: an externally controlled trial. Clin Infect Dis. 2007;44:2–12. doi: 10.1086/508774.
    1. A study of the safety and efficacy of posaconazole versus voriconazole for the treatment of invasive aspergillosis (MK-5592-069/P06200). https//. Accessed 26 Oct 2015.
    1. Valsecchi I, Mellado E, Beau R, Raj S, Latgé J-P. Fitness studies of azole-resistant strains of Aspergillus fumigatus. Antimicrob Agents Chemother. 2015;59:7866–9. doi: 10.1128/AAC.01594-15.
    1. Howard SJ, Cerar D, Anderson MJ, Albarrag A, Fisher MC, Pasqualotto AC, et al. Frequency and evolution of azole resistance in Aspergillus fumigatus associated with treatment failure. Emerg Infect Dis. 2009;15:1068–76. doi: 10.3201/eid1507.090043.
    1. EUCAST. Posaconazole Candida breakpoints. 2012. Available from. Accessed 26 Oct 2015.
    1. Conant MM, Sha BE, Proia LA. Use of posaconazole delayed-release tablets for treatment of invasive aspergillosis. Mycoses. 2015;58:313–4. doi: 10.1111/myc.12309.
    1. Green MR, Woolery JE. Posaconazole serum level on day 2 predicts steady state posaconazole serum level. Ther Drug Monit. 2012;34:118–9. doi: 10.1097/FTD.0b013e31823cef77.
    1. Goodman JL, Winston DJ, Greenfield RA, Chandrasekar PH, Fox B, Kaizer H, et al. A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation. N Engl J Med. 1992;326:845–51. doi: 10.1056/NEJM199203263261301.
    1. Cornely OA, Maertens J, Winston DJ, Perfect J, Ullmann AJ, Walsh TJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med. 2007;356:348–59. doi: 10.1056/NEJMoa061094.
    1. Ullmann AJ, Lipton JH, Vesole DH, Chandrasekar P, Langston A, Tarantolo SR, et al. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med. 2007;356:335–47. doi: 10.1056/NEJMoa061098.
    1. Hahn J, Stifel F, Reichle A, Holler E, Andreesen R. Clinical experience with posaconazole prophylaxis—a retrospective analysis in a haematological unit. Mycoses. 2011;54(Suppl 1):12–6. doi: 10.1111/j.1439-0507.2010.01980.x.
    1. Kung H-C, Johnson MD, Drew RH, Saha-Chaudhuri P, Perfect JR. Clinical effectiveness of posaconazole versus fluconazole as antifungal prophylaxis in hematology-oncology patients: a retrospective cohort study. Cancer Med. 2014;3:667–73. doi: 10.1002/cam4.225.
    1. Egerer G, Geist MJP. Posaconazole prophylaxis in patients with acute myelogenous leukaemia—results from an observational study. Mycoses. 2011;54(Suppl 1):7–11. doi: 10.1111/j.1439-0507.2010.01979.x.
    1. Girmenia C, Frustaci AM, Gentile G, Minotti C, Cartoni C, Capria S, et al. Posaconazole prophylaxis during front-line chemotherapy of acute myeloid leukemia: a single-center, real-life experience. Haematologica. 2012;97:560–7. doi: 10.3324/haematol.2011.053058.
    1. Vehreschild JJ, Rüping MJGT, Wisplinghoff H, Farowski F, Steinbach A, Sims R, et al. Clinical effectiveness of posaconazole prophylaxis in patients with acute myelogenous leukaemia (AML): a 6 year experience of the Cologne AML cohort. J Antimicrob Chemother. 2010;65:1466–71. doi: 10.1093/jac/dkq121.
    1. Pagano L, Caira M, Candoni A, Aversa F, Castagnola C, Caramatti C, et al. Evaluation of the practice of antifungal prophylaxis use in patients with newly diagnosed acute myeloid leukemia: results from the SEIFEM 2010-B registry. Clin Infect Dis. 2012;55:1515–21. doi: 10.1093/cid/cis773.
    1. Bertz H, Drognitz K, Lübbert M. No difference between posaconazole and fluconazole antifungal prophylaxis and mycological diagnostics except costs in patients undergoing AML chemotherapy: a 1-year “real-life” evaluation. Ann Hematol. 2014;93:165–7. doi: 10.1007/s00277-013-1854-6.
    1. Peterson L, Ostermann J, Rieger H, Ostermann H, Rieger CT. Posaconazole prophylaxis—impact on incidence of invasive fungal disease and antifungal treatment in haematological patients. Mycoses. 2013;56:651–8. doi: 10.1111/myc.12086.
    1. Ananda-Rajah MR, Grigg A, Downey MT, Bajel A, Spelman T, Cheng A, et al. Comparative clinical effectiveness of prophylactic voriconazole/posaconazole to fluconazole/itraconazole in patients with acute myeloid leukemia/myelodysplastic syndrome undergoing cytotoxic chemotherapy over a 12-year period. Haematologica. 2012;97:459–63. doi: 10.3324/haematol.2011.051995.
    1. Walsh TJ, Anaissie EJ, Denning DW, Herbrecht R, Kontoyiannis DP, Marr KA, et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2008;46:327–60. doi: 10.1086/525258.
    1. Jang SH, Colangelo PM, Gobburu JVS. Exposure-response of posaconazole used for prophylaxis against invasive fungal infections: evaluating the need to adjust doses based on drug concentrations in plasma. Clin Pharmacol Ther. 2010;88:115–9. doi: 10.1038/clpt.2010.64.
    1. Danion F, Aguilar C, Catherinot E, Alanio A, DeWolf S, Lortholary O, et al. Mucormycosis: new developments into a persistently devastating infection. Semin Respir Crit Care Med. 2015;36:692–705. doi: 10.1055/s-0035-1562896.
    1. Greenberg RN, Mullane K, van Burik J-AH, Raad I, Abzug MJ, Anstead G, et al. Posaconazole as salvage therapy for zygomycosis. Antimicrob Agents Chemother. 2006;50:126–33. doi: 10.1128/AAC.50.1.126-133.2006.
    1. Andes D. Optimizing antifungal choice and administration. Curr Med Res Opin. 2013;29(Suppl 4):13–8. doi: 10.1185/03007995.2012.761135.
    1. Cornely OA, Arikan-Akdagli S, Dannaoui E, Groll AH, Lagrou K, Chakrabarti A, et al. ESCMID† and ECMM‡ joint clinical guidelines for the diagnosis and management of mucormycosis 2013. Clin Microbiol Infect. 2014;20:5–26. doi: 10.1111/1469-0691.12371.
    1. Vehreschild JJ, Birtel A, Vehreschild MJGT, Liss B, Farowski F, Kochanek M, et al. Mucormycosis treated with posaconazole: review of 96 case reports. Crit Rev Microbiol. 2013;39:310–24. doi: 10.3109/1040841X.2012.711741.
    1. Araujo R, Oliveira M, Amorim A, Sampaio-Maia B. Unpredictable susceptibility of emerging clinical moulds to tri-azoles: review of the literature and upcoming challenges for mould identification. Eur J Clin Microbiol Infect Dis. 2015;34:1289–301. doi: 10.1007/s10096-015-2374-1.
    1. Tortorano AM, Richardson M, Roilides E, van Diepeningen A, Caira M, Munoz P, et al. ESCMID and ECMM joint guidelines on diagnosis and management of hyalohyphomycosis: Fusarium spp., Scedosporium spp. and others. Clin. Microbiol. Infect. 2014;20:27–46.
    1. Chau MM, Kong DCM, van Hal SJ, Urbancic K, Trubiano JA, Cassumbhoy M, et al. Consensus guidelines for optimising antifungal drug delivery and monitoring to avoid toxicity and improve outcomes in patients with haematological malignancy, 2014. Intern Med J. 2014;44:1364–88. doi: 10.1111/imj.12600.
    1. Horn DL, Freifeld AG, Schuster MG, Azie NE, Franks B, Kauffman CA. Treatment and outcomes of invasive fusariosis: review of 65 cases from the PATH Alliance(®) registry. Mycoses. 2014;57:652–8. doi: 10.1111/myc.12212.
    1. Tortorano AM, Prigitano A, Esposto MC, Arsic Arsenijevic V, Kolarovic J, Ivanovic D, et al. European Confederation of Medical Mycology (ECMM) epidemiological survey on invasive infections due to Fusarium species in Europe. Eur J Clin Microbiol Infect Dis. 2014;33:1623–30. doi: 10.1007/s10096-014-2111-1.
    1. Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2011;52:e56–93. doi: 10.1093/cid/cir073.
    1. Lempers VJ, Alffenaar JW, Touw DJ, Burger DM, Uges DR, Aarnoutse RE, et al. Five year results of an international proficiency testing programme for measurement of antifungal drug concentrations. J. Antimicrob. Chemother. Radboud University Medical Center, Department of Pharmacy, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.; Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Centre Groningen, Groning (TRUNCATED: Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy; 2014;69:2988–94.
    1. Phillips PPJ, Gillespie SH, Boeree M, Heinrich N, Aarnoutse R, McHugh T, et al. Innovative trial designs are practical solutions for improving the treatment of tuberculosis. J Infect Dis. 2012;205(Suppl):S250–7. doi: 10.1093/infdis/jis041.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi