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Download Aspen, Colorado - Pediatric Continuous Renal Replacement Therapy
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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 [email protected] [email protected] www.pcrrt.com What impacts on Drug clearance Modality of renal replacement therapy Characteristics of drug RRT Modalities Modality CRRT SLED HD (standard PD or HF) Continuous Flow PD BFR 3-5 mls/kg/min access dependent 3-5 mls/kg/min access dependent 3-5 mls/kg/min access dependent 10-20 mls/kg/pass 10-20 mls/kg/hr Dialysis Flow Rate 0-4 liters/hr 6 liters /hr 30-50 liters/hr 0.5-2 liters/hr 0.5-2 liters/hr Convective Flow Rate 0-4 liters/hr 0 0 0 0 Systemic Anticoagulation Heparin or citrate Heparin or citrate Heparin or none none none Thermic control Yes yes yes partial partial Ultrafiltration control Yes yes yes partial partial Solutions Industry made On Line production On Line production Industry made Industry made Drug clearance Continuous Intermittent Intermittent Continuous Continuous Nutritional clearance Continuous Intermittent Intermittent Continuous Continuous Dialysis Dose 10 9 8 7 6 5 4 3 2 1 0 35ml/kg CRRT 20ml/kg EDD PD 0.3 0.5 0.7 0.9 1.1 1.3 1.5 eKt/V each dialysis Adapted from Gotch et al. Kidney Int 2000;58:S3-18 7 6 5 4 3 2 No. of Days/week Weekly stdKt/V 45ml/kg D Diffusive Clearance To increase clearance by diffusion, increase dialysate flow rate Convective Clearance To increase clearance by convection, increase ultrafiltration rate (will require more replacement fluids) Sieving Coefficients Solute (MW) Convective Coefficient Diffusion Coefficient Urea (60) 1.01 ± 0.05 1.01 ± 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 + 0.1 0.61 + 0.07 Cytokines (large) adsorbed minimal clearance *P<0.05 **P<0.01 D. “Known drug characteristics“ These recommendations made by panel of nephrologists and pharmacists Based on: Protein Binding Information Volume of Distribution Molecular Weight Characteristics of antifungals with Vancomycin as a known reference Drug VOD (l/kg) Protein Binding % Mol Wt (gm/mol) Elimination route Fluconazole 0.7 12 306 renal Itraconazole 10.7 99 705 hepatic Voriconazole 4.6 58 349 renal Micafungin 14 99 1270 stool Caspofungin 9.7 99 1093 Stool Amphotericin B 4 > 90 924 40% in urine AmBisome (Liposomal Ampho B) 0.4 > 90 924 40% in urine Abelcet Lipid Complex 131 > 90 924 40% in urine Vancomycin 0.7 75 1450 renal AmBisome Clearance of AmBisome in SPAD (single pass albumin dialysis) showed no excessive clearance Artif Organs 2006, 30: 118-21 Abelcet CVVHDF vs no CRRT clearance showed no difference in levels of drug Int J Antimicrob Agents 2103 42:335-42 Voriconazole Good penetration into the peritoneum but no clearance by PD CVVHDF shows no impact upon drug levels in the face of normal hepatic function Am J Kid Dis 2005 45:162-166 J Antimicrob Chemother 2007 60:1085-1090 Dose adjustment not needed in CVVH Ther Drug Monit 2011 33:393-397 Amphotericin B Not cleared on CVVHDF If overdose can be cleared with plasmapheresis and high flux HD Ann Pharmacother 2013 47 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 Drug Prescribing in Renal Failure edited by George Aronoff et al Commonly carried text by pharmacists http://www.kdpbaptist.louisville.edu/renalbook/ New edition to come out soon Recommendations for new drugs IHD and CRRT recommendations Pediatric recommendations Summary Drug Supplement dosing in CRRT Fluconazole 100% Itraconazole 100% Voriconazole 100% Micafungin 100% Caspofungin 100% Amphotericin B 100% AmBisome (Liposomal Ampho B) 100% Abelcet Lipid Complex 100% 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)
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