Pharmacokinetics of Intravenous Posaconazole in Critically Ill Patients

Fekade B Sime, Janine Stuart, Jenie Butler, Therese Starr, Steven C Wallis, Saurabh Pandey, Jeffrey Lipman, Jason A Roberts, Fekade B Sime, Janine Stuart, Jenie Butler, Therese Starr, Steven C Wallis, Saurabh Pandey, Jeffrey Lipman, Jason A Roberts

Abstract

To date, there is no information on the intravenous (i.v.) posaconazole pharmacokinetics for intensive care unit (ICU) patients. This prospective observational study aimed to describe the pharmacokinetics of a single dose of i.v. posaconazole in critically ill patients. Patients with no history of allergy to triazole antifungals and requiring systemic antifungal therapy were enrolled if they were aged ≥18 years, central venous access was available, they were not pregnant, and they had not received prior posaconazole or drugs interacting with posaconazole. A single dose of 300 mg posaconazole was administered over 90 min. Total plasma concentrations were measured from serial plasma samples collected over 48 h, using a validated chromatographic method. The pharmacokinetic data set was analyzed by noncompartmental methods. Eight patients (7 male) were enrolled with the following characteristics: median age, 46 years (interquartile range [IQR], 40 to 51 years); median weight, 68 kg (IQR, 65 to 82 kg); and median albumin concentration, 20 g/liter (IQR, 18 to 24 g/liter). Median (IQR) pharmacokinetic parameter estimates were as follows: observed maximum concentration during sampling period (Cmax), 1,702 ng/ml (1,352 to 2,141 ng/ml); area under the concentration-time curve from zero to infinity (AUC0-∞), 17,932 ng · h/ml (13,823 to 27,905 ng · h/ml); clearance (CL), 16.8 liters/h (11.1 to 21.7 liters/h); and volume of distribution (V), 529.1 liters (352.2 to 720.6 liters). The V and CL were greater than 2-fold and the AUC0-∞ was 39% of the values reported for heathy volunteers. The AUC0-∞ was only 52% of the steady-state AUC0-24 reported for hematology patients. The median of estimated average steady-state concentrations was 747 ng/ml (IQR, 576 to 1,163 ng/ml), which is within but close to the lower end of the previously recommended therapeutic range of 500 to 2,500 ng/ml. In conclusion, we observed different pharmacokinetics of i.v. posaconazole in this cohort of critically ill patients compared to those in healthy volunteers and hematology patients.

Keywords: antifungal; dosing; intensive care unit; pharmacodynamics; triazole antifungal.

Copyright © 2018 Sime et al.

Figures

FIG 1
FIG 1
Median (IQR) posaconazole concentration versus time data from eight critically ill patients administered a single i.v. dose of 300 mg.

References

    1. Montagna MT, Caggiano G, Lovero G, De Giglio O, Coretti C, Cuna T, Iatta R, Giglio M, Dalfino L, Bruno F, Puntillo F. 2013. Epidemiology of invasive fungal infections in the intensive care unit: results of a multicenter Italian survey (AURORA Project). Infection 41:645–653. doi:10.1007/s15010-013-0432-0.
    1. Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, Raad II, Rolston KV, Young JA, Wingard JR, Infectious Diseases Society of America. 2011. 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 52:e56–e93. doi:10.1093/cid/cir073.
    1. Chau MM, Kong DC, van Hal SJ, Urbancic K, Trubiano JA, Cassumbhoy M, Wilkes J, Cooper CM, Roberts JA, Marriott DJ, Worth LJ. 2014. Consensus guidelines for optimising antifungal drug delivery and monitoring to avoid toxicity and improve outcomes in patients with haematological malignancy, 2014. Intern Med J 44:1364–1388. doi:10.1111/imj.12600.
    1. Sabatelli F, Patel R, Mann PA, Mendrick CA, Norris CC, Hare R, Loebenberg D, Black TA, McNicholas PM. 2006. In vitro activities of posaconazole, fluconazole, itraconazole, voriconazole, and amphotericin B against a large collection of clinically important molds and yeasts. Antimicrob Agents Chemother 50:2009–2015. doi:10.1128/AAC.00163-06.
    1. Cornely OA, Maertens J, Winston DJ, Perfect J, Ullmann AJ, Walsh TJ, Helfgott D, Holowiecki J, Stockelberg D, Goh YT, Petrini M, Hardalo C, Suresh R, Angulo-Gonzalez D. 2007. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 356:348–359. doi:10.1056/NEJMoa061094.
    1. Walsh TJ, Raad I, Patterson TF, Chandrasekar P, Donowitz GR, Graybill R, Greene RE, Hachem R, Hadley S, Herbrecht R, Langston A, Louie A, Ribaud P, Segal BH, Stevens DA, van Burik JA, White CS, Corcoran G, Gogate J, Krishna G, Pedicone L, Hardalo C, Perfect JR. 2007. Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: an externally controlled trial. Clin Infect Dis 44:2–12. doi:10.1086/508774.
    1. Storzinger D, Borghorst S, Hofer S, Busch CJ, Lichtenstern C, Hempel G, Weigand MA, Hoppe-Tichy T. 2012. Plasma concentrations of posaconazole administered via nasogastric tube in patients in a surgical intensive care unit. Antimicrob Agents Chemother 56:4468–4470. doi:10.1128/AAC.06167-11.
    1. Ray J, Campbell L, Rudham S, Nguyen Q, Marriott D. 2011. Posaconazole plasma concentrations in critically ill patients. Ther Drug Monit 33:387–392. doi:10.1097/FTD.0b013e31821fb197.
    1. Maertens J, Cornely OA, Ullmann AJ, Heinz WJ, Krishna G, Patino H, Caceres M, Kartsonis N, Waskin H, Robertson MN. 2014. Phase 1B study of the pharmacokinetics and safety of posaconazole intravenous solution in patients at risk for invasive fungal disease. Antimicrob Agents Chemother 58:3610–3617. doi:10.1128/AAC.02686-13.
    1. Dolton MJ, Ray JE, Chen SC, Ng K, Pont L, McLachlan AJ. 2012. Multicenter study of posaconazole therapeutic drug monitoring: exposure-response relationship and factors affecting concentration. Antimicrob Agents Chemother 56:5503–5510. doi:10.1128/AAC.00802-12.
    1. Ressaire Q, Padoin C, Chaouat M, Maurel V, Alanio A, Ferry A, Soussi S, Benyamina M, Denis B, Mimoun M, Mebazaa A, Legrand M. 2015. Muscle diffusion of liposomal amphotericin B and posaconazole in critically ill burn patients receiving continuous hemodialysis. Intensive Care Med 41:948–949. doi:10.1007/s00134-015-3754-9.
    1. Roberts JA, Abdul-Aziz MH, Lipman J, Mouton JW, Vinks AA, Felton TW, Hope WW, Farkas A, Neely MN, Schentag JJ, Drusano G, Frey OR, Theuretzbacher U, Kuti JL, International Society of Anti-Infective Pharmacology, the Pharmacokinetics and Pharmacodynamics Study Group of the European Society of Clinical Microbiology and Infectious Diseases. 2014. Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions. Lancet Infect Dis 14:498–509. doi:10.1016/S1473-3099(14)70036-2.
    1. Schiller DS, Fung HB. 2007. Posaconazole: an extended-spectrum triazole antifungal agent. Clin Ther 29:1862–1886. doi:10.1016/j.clinthera.2007.09.015.
    1. Ulldemolins M, Roberts JA, Rello J, Paterson DL, Lipman J. 2011. The effects of hypoalbuminaemia on optimising antibiotic dosing in critically ill patients. Clin Pharmacokinet 50:99–110. doi:10.2165/11539220-000000000-00000.
    1. Lipp HP. 2010. Clinical pharmacodynamics and pharmacokinetics of the antifungal extended-spectrum triazole posaconazole: an overview. Br J Clin Pharmacol 70:471–480. doi:10.1111/j.1365-2125.2010.03680.x.
    1. Hachem RY, Langston AA, Graybill JR, Perfect JR, Pedicone LD, Patino H, Raad II. 2008. Posaconazole as salvage treatment of invasive fungal infections in patients with underlying renal impairment. J Antimicrob Chemother 62:1386–1391. doi:10.1093/jac/dkn401.
    1. Courtney R, Sansone A, Smith W, Marbury T, Statkevich P, Martinho M, Laughlin M, Swan S. 2005. Posaconazole pharmacokinetics, safety, and tolerability in subjects with varying degrees of chronic renal disease. J Clin Pharmacol 45:185–192. doi:10.1177/0091270004271402.
    1. Moton A, Krishna G, Ma L, O'Mara E, Prasad P, McLeod J, Preston RA. 2010. Pharmacokinetics of a single dose of the antifungal posaconazole as oral suspension in subjects with hepatic impairment. Curr Med Res Opin 26:1–7. doi:10.1185/03007990903364657.
    1. Kersemaekers WM, van Iersel T, Nassander U, O'Mara E, Waskin H, Caceres M, van Iersel MLPS. 2015. Pharmacokinetics and safety study of posaconazole intravenous solution administered peripherally to healthy subjects. Antimicrob Agent Chemother 59:1246–1251. doi:10.1128/AAC.04223-14.
    1. Payne KD, Hall RG. 2016. Dosing of antifungal agents in obese people. Expert Rev Anti Infect Ther 14:257–267. doi:10.1586/14787210.2016.1128822.
    1. Blot SI, Pea F, Lipman J. 2014. The effect of pathophysiology on pharmacokinetics in the critically ill patient—concepts appraised by the example of antimicrobial agents. Adv Drug Deliv Rev 77:3–11. doi:10.1016/j.addr.2014.07.006.
    1. Rohatagi S, Kan S, Derendorf H. 1997. Non-compartmental analysis of pharmacokinetic data after multiple intravenous and oral administration. Pharmazie 52:529–532.
    1. Andes D, Marchillo K, Conklin R, Krishna G, Ezzet F, Cacciapuoti A, Loebenberg D. 2004. Pharmacodynamics of a new triazole, posaconazole, in a murine model of disseminated candidiasis. Antimicrob Agents Chemother 48:137–142. doi:10.1128/AAC.48.1.137-142.2004.
    1. Mavridou E, Bruggemann RJ, Melchers WJ, Mouton JW, Verweij PE. 2010. Efficacy of posaconazole against three clinical Aspergillus fumigatus isolates with mutations in the cyp51A gene. Antimicrob Agents Chemother 54:860–865. doi:10.1128/AAC.00931-09.
    1. Howard SJ, Lestner JM, Sharp A, Gregson L, Goodwin J, Slater J, Majithiya JB, Warn PA, Hope WW. 2011. Pharmacokinetics and pharmacodynamics of posaconazole for invasive pulmonary aspergillosis: clinical implications for antifungal therapy. J Infect Dis 203:1324–1332. doi:10.1093/infdis/jir023.
    1. Howard SJ, Felton TW, Gomez-Lopez A, Hope WW. 2012. Posaconazole: the case for therapeutic drug monitoring. Ther Drug Monit 34:72–76. doi:10.1097/FTD.0b013e31823cdeac.
    1. Jang SH, Colangelo PM, Gobburu JV. 2010. 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 88:115–119. doi:10.1038/clpt.2010.64.
    1. Jang SH, Colangelo PM, Gobburu JVS. 2010. 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 88:115–119. doi:10.1038/clpt.2010.64.
    1. Cornely OA, Duarte RF, Haider S, Chandrasekar P, Helfgott D, Jimenez JL, Candoni A, Raad I, Laverdiere M, Langston A, Kartsonis N, Van Iersel M, Connelly N, Waskin H. 2016. Phase 3 pharmacokinetics and safety study of a posaconazole tablet formulation in patients at risk for invasive fungal disease. J Antimicrob Chemother 71:718–726. doi:10.1093/jac/dkv380.
    1. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. 1985. APACHE II: a severity of disease classification system. Crit Care Med 13:818–829. doi:10.1097/00003246-198510000-00009.
    1. Vincent JL, de Mendonca A, Cantraine F, Moreno R, Takala J, Suter PM, Sprung CL, Colardyn F, Blecher S. 1998. Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. Working group on “sepsis-related problems” of the European Society of Intensive Care Medicine. Crit Care Med 26:1793–1800.
    1. Department of Health and Human Services, FDA, U.S. Center for Drug Evaluation and Research (CDER). 2001. Guidance for industry: bioanalytical method validation. Food and Drug Administration, Rockville, MD: .

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться