Martial LC(1,2), ter Heine R(1,2), Schouten JA(3), Hunfeld NG(4), van Leeuwen HJ(5) Verweij PE(6,2) Pickkers P(7), Lempers VJ (1,2), Brüggemann RJ(1,2,8)
(1)Department of Pharmacy, Radboud university medical center, Nijmegen, The Netherlands; (2)The Netherlands Radboud Institute for Health Sciences, Nijmegen, The Netherlands; (3)Department of Intensive Care, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands; (4) Erasmus Medical Center, Department of Intensive Care, Rotterdam, The Netherlands; (5)Department of Intensive Care, Rijnstate Hospital, Arnhem, The Netherlands (6) Department of Medical Microbiology, Radboud university medical center, Nijmegen, The Netherlands (7)Department of Intensive Care, Radboud university medical center, Nijmegen, The Netherlands; (8) On behalf of the FANTASTIC consortium.
Objectives: Micafungin (MFG) is used as first line treatment of invasive candidiasis/ candidemia in critically ill (ICU) patients. The pharmacokinetics (PK) of many drugs are altered in this population.[1-3] The PK of MFG have been well studied in a wide population of non-ICU patients but there is only limited knowledge on the causes of PK variability and therapy failure in ICU patients.[3] PK of MFG is correlated with treatment outcome: the ratio of the area under the concentration time curve over the minimal inhibitory concentration (AUC/MIC) of ≥3000 is associated with favorable response (85.1%).[4] The aim of our study was to develop a population PK model to identify sources of PK variability of MFG in ICU patients and guide future dose individualization studies.
Methods:MFG PK data from 20 ICU patients with possible or proven candidemia treated with 100 mg MFG daily were used.[3] Two PK curves with daily trough concentrations were drawn. NONMEM 7.3, PsN, R and Pirana were used for model building. V1 and CL were allometrically scaled to body weight (BW). IIV was tested on all parameters and IOV on clearance (CL) and volume of distribution (V). The model was used to calculate the area under the concentration time curve of the dosing interval (AUC0-24h) and AUC/MIC on day 3 of therapy, using an ECOFF for C.albicans (MIC 0.016 mg/L).[5] Precision of the parameter estimates were obtained from the covariance step in NONMEM.
Results: Median(range) age and BW were 68(20-84) years and 77(50-134) kg. 356 observations were available for model building. A 2-compartment first order kinetic model described the data well. CL was 1.1 L/h, Q 0.72 L/h, V1 16.7 L and V2 5.43 L, relative standard errors (RSE) 10, 22 16, and 12% respectively. IIV on CL and V1 were 40% and 69% (coefficient of variation [CV]) with RSE 22 and 48%. The correlation between IIV of CL and IIV of V1 was 48%CV (RSE 33%). IOV on V1 resulted in a significant improvement (δOFV -52.5) and was estimated to be 42%CV.
The median AUC0-24h on day 3 of therapy was 75 mg*h/L (range 75-160). Median AUC/MIC was 4662 (range 2974-10020).
Conclusions: Higher IIV of CL and V1 was observed compared to non-ICU patients.[5] 95% attained the PTA (based on an ECOFF MIC of 0.016 mg/L).[6] We are currently exploring covariates to further improve the model and explain variability in this population. Next we aim to simulate alternative dose strategies to aid further dose individualization of MFG in critically ill patients.
References:
[1]Martial LC, Brüggemann RJ, Schouten JA, van Leeuwen HJ, van Zanten AR, de Lange DW, Muilwijk EW, Verweij PE, Burger DM, Aarnoutse RE, Pickkers P, Dorlo TPC. Dose Reduction of Caspofungin in Intensive Care Unit Patients with Child Pugh B Will Result in Suboptimal Exposure.
[2] Lempers VJ, Schouten JA, Hunfeld NG, Colbers A, Leeuwen HJ, Burger DM, Verweij PE, Pickkers P, Brüggemann RJ. Altered Micafungin Pharmacokinetics in Intensive Care Unit Patients. Antimicrob Agents Chemother 59:4403–4409. Clin Pharmacokinet. 2015 Dec 9. [Epub ahead of print]
[3] Roberts JA, Abdul-Aziz MH, Lipman J, Mouton JW, Vinks AA5 Felton TW, Hope WW, Farkas A, Neely MN, Schentag JJ, Drusano G, Frey OR, Theuretzbacher U, Kuti JL; International Society of Anti-Infective Pharmacology and the Pharmacokinetics and Pharmacodynamics Study Group of the European Society of Clinical Microbiology and Infectious Diseases. Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions. Lancet Infect Dis. 2014 Jun;14(6):498-509.
[4]Andes D, Ambrose PG, Hammel JP, van Wart SA, Iyer V, Reynolds DK, Buell DN, Kovanda LL, Bhavnani SM. Use of Pharmacokinetic-Pharmacodynamic Analyses To Optimize Therapy with the Systemic Antifungal Micafungin for Invasive Candidiasis or Candidemia. AAC, May 2011, p. 2113–2121.
[5] EUCAST Antifungal Clinical Breakpoint Table v. 8.0 valid from 2015-11-16. http://www.eucast.org/clinical_breakpoints/ Accessed 29-02-2016.
[6]Hebert MF, Smith HE, Marbury TC, Swan SK, Smith WB, Townsend RW, Buell D, Keirns J, Bekersky I. Pharmacokinetics of micafungin in healthy volunteers, volunteers with moderate liver disease, and volunteers with renal dysfunction. J Clin Pharmacol. 2005 Oct;45(10):1145-52.
Reference: PAGE 25 () Abstr 5941 [www.page-meeting.org/?abstract=5941]
Poster: Drug/Disease modeling - Infection