1. Dosing of Anti-Fungal agents on CRRT Timothy E. Bunchman Professor and Director Pediatric Nephrology & Transplantation Children’s Hospital of Richmond Virginia Commonwealth Univ. School of Medicine tbunchman@mcvh-vcu.edu pedscrrt@gmail.com www.pcrrt.com

2. What impacts on Drug clearance Modality of renal replacement therapy Characteristics of drug

3. RRT Modalities ModalityCRRTSLED HD (standard or HF) PDContinuous Flow PD BFR3-5 mls/kg/min access dependent 10-20 mls/kg/pass 10-20 mls/kg/hr Dialysis Flow Rate0-4 liters/hr6 liters /hr 30-50 liters/hr0.5-2 liters/hr Convective Flow Rate0-4 liters/hr0 000 Systemic Anticoagulation Heparin or citrate Heparin or nonenone Thermic controlYesyes partial Ultrafiltration controlYesyes partial SolutionsIndustry madeOn Line production Industry made Drug clearanceContinuousIntermittent Continuous Nutritional clearanceContinuousIntermittent Continuous

4. Dialysis Dose 0 1 2 3 4 5 6 7 8 9 10 Weekly stdKt/V 0.30.50.70.91.11.31.5 eKt/V each dialysis 2 3 4 5 6 7 No. of Days/weekEDD 35ml/kg45ml/kg20ml/kg Adapted from Gotch et al. Kidney Int 2000;58:S3-18 CRRT PD

5. D Diffusive Clearance To increase clearance by diffusion, increase dialysate flow rate

6. Convective Clearance To increase clearance by convection, increase ultrafiltration rate (will require more replacement fluids)

7. Sieving Coefficients Solute (MW)Convective Coefficient Diffusion Coefficient Urea (60)1.01 ± 0.051.01 ± 0.07 Creatinine (113)1.00 ± 0.09 1.01 ± 0.06 Uric Acid (168)1.01 ± 0.04 0.97 ± 0.04* Vancomycin (1448)0.84 ± 0.10 0.74 ± 0.04** Calcium (protein bound)0.67 + 0.10.61 + 0.07 Cytokines (large)adsorbedminimal clearance *P<0.05 **P<0.01

8. D. “Known drug characteristics“ These recommendations made by panel of nephrologists and pharmacists Based on: Protein Binding Information Volume of Distribution Molecular Weight

9. Characteristics of antifungals with Vancomycin as a known reference DrugVOD (l/kg)Protein Binding % Mol Wt (gm/mol) Elimination route Fluconazole0.712306renal Itraconazole10.799705hepatic Voriconazole4.658349renal Micafungin14991270stool Caspofungin9.7991093Stool Amphotericin B4> 9092440% in urine AmBisome (Liposomal Ampho B) 0.4> 9092440% in urine Abelcet Lipid Complex 131> 9092440% in urine Vancomycin0.7751450renal

10. AmBisome Clearance of AmBisome in SPAD (single pass albumin dialysis) showed no excessive clearance Artif Organs 2006, 30: 118-21

11. Abelcet CVVHDF vs no CRRT clearance showed no difference in levels of drug Int J Antimicrob Agents 2103 42:335-42

12. Voriconazole Good penetration into the peritoneum but no clearance by PD Am J Kid Dis 2005 45:162-166 CVVHDF shows no impact upon drug levels in the face of normal hepatic function J Antimicrob Chemother 2007 60:1085-1090 Dose adjustment not needed in CVVH Ther Drug Monit 2011 33:393-397

13. Amphotericin B Not cleared on CVVHDF If overdose can be cleared with plasmapheresis and high flux HD Ann Pharmacother 2013 47

14. Fluconazole Once steady state obtained no adjustment needed for CVVHF NDT 2006 21:1019-1023 In SLED 72% clearance obtained after 6 hours as compared to 34% on Hemodialysis Int J Antimicrob Agents 2015 45:192-195

15. Drug Prescribing in Renal Failure edited by George Aronoff et al Commonly carried text by pharmacists http://www.kdp- baptist.louisville.edu/renalbook/ http://www.kdp- baptist.louisville.edu/renalbook/ New edition to come out soon Recommendations for new drugs IHD and CRRT recommendations Pediatric recommendations

16. Summary DrugSupplement dosing in CRRT Fluconazole100% Itraconazole100% Voriconazole100% Micafungin100% Caspofungin100% Amphotericin B100% AmBisome (Liposomal Ampho B) 100% Abelcet Lipid Complex 100%

17. Conclusion Dose antifungal agents normally due to fact that many are hepatically metabolized and not effected by clearance Many of these meds interact with other meds (e.g. conazoles and P450 enzyme meds such as tacrolimus or cyclosporine)