Martial LC(1,2) Brüggemann RJ(1,2) Schouten JA(3) van Leeuwen HJ(4) van Zanten AR(5) de Lange DW(6) Verweij PE(7,2) Pickkers P(8) Muilwijk EW(1,2) Dorlo TPC(9,10).
(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)Department of Intensive Care, Rijnstate Hospital, Arnhem, The Netherlands (5)Department of Intensive Care, Gelderse Vallei Hospital, Ede, The Netherlands (6)Department of Intensive Care and National Poison Information Center, University Medical Center Utrecht, Utrecht, The Netherlands (7) Department of Medical Microbiology, Radboud university medical center, Nijmegen, The Netherlands (8)Department of Intensive Care, Radboud university medical center, Nijmegen, The Netherlands (9)Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden (10) Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Faculty of Science, Utrecht University, Utrecht, the Netherlands.
Objectives: Caspofungin (CAS) is an echinocandin antifungal agent and is used as first-line therapy for the treatment of invasive candidiasis. CAS is administered intravenous at a loading dose of 70mg on day 1, followed by 50mg QD. Maintenance dose should be increased to 70mg for bodyweight (BW) ≥80kg and decreased to 35mg for patients with Child-Pugh score B (CPB).[1] AUC/MIC is used as PK-PD target parameter.[2] CPB is only valid for patients with cirrhotic livers. Using CPB in non-cirrhotic patients may result in suboptimal exposure. We aimed to confirm this using a population PK approach, evaluating the target attainment.
Methods: CAS PK data from a study in ICU patients (21 patients; median(range) age and BW were 71(45-80) years and 75(50-99)kg; N=419 observations) were available.[3] A POP-PK model was built (NONMEM 7.2, Pirana, PsN, R). The following dosing regimens were simulated in a cohort of 1706 hematological patients, (assumed to be representative for ICU patients) median(range) BW 76(39-145)kg: licensed regimens (I) 70/50 for BW<80kg; 70/70 (for BW>80kg); (II)70/35 for CPB; adapted regimens (III) 100/50 (for CPB); (IV) 100/70; (V) 100/100. Target attainment based on a preclinical PK target (AUC/MIC≥865) for C.albicans was assessed on day 14 for three relevant MICs (0.03, 0.06, 0.125), as PK targets for CAS are lacking.[2]
Results: A 2-compartment PK model best fitted the CAS data. BW was scaled linear on V1 and allometric on CL. IIV on all parameters was estimated and a full omega-block was used. CPB could not be confirmed as a covariate on any parameter. Median AUC(95%CI) were for (a) BW≤80kg 106(37-316), BW>80kg 116(39-348); (b) BW≤Median AUC(range) were for (I) BW≤80kg 102(39-386), BW>80kg 113(44-459); (II) BW≤80kg 71(26-270), BW>80kg 56(22-230); (III) BW≤80kg 102(39-387), BW>80kg 80(32-328); (IV) BW≤80kg 142(55-541), BW>80kg 113(44-459) and (V) BW≤80kg 203(78-772), BW>80kg 160(64-656). PK target attainment was the for whole cohort for MIC0.03 (I) 100% (ii) >99% (III-V) 100%; for MIC0.06 (I) 99% (II) 73% (III) 95% (IV) >99% and (V) 100% and for MIC0.125 (I) 47% (II) 14% (III) 36% (IV) 69% (V) 97%.
Conclusions: CAS maintenance dose should not be reduced in non-cirrhotic (i.e. ICU) patients based on CPB as it results in 17-39% lower target attainment (MIC0.06 µg/mL), increasing the risk of therapeutic failure. Given the favorable safety of CAS, maintenance dose of 70 mg should be considered.
References:
[1] Summary of Product Characteristics Cancidas, http://www.ema.europa.eu
[2] Andes D, Diekema DJ, Pfaller MA, Bohrmuller J, Marchillo K, Lepak A. In vivo comparison of the pharmacodynamic targets for echinocandin drugs against Candida species. Antimicrob Agents Chemother. 2010 Jun;54(6):2497-506
[3] Muilwijk EW, Schouten JA, van Leeuwen HJ, van Zanten AR, de Lange DW, Colbers A, Verweij PE, Burger DM, Pickkers P, Brüggemann RJ. Pharmacokinetics of caspofungin in ICU patients. J Antimicrob Chemother. 2014 Dec;69(12):3294-9.
Reference: PAGE 24 (2015) Abstr 3372 [www.page-meeting.org/?abstract=3372]
Poster: Drug/Disease modeling - Infection