1. Drug Kinetics and CRRT: Parameters and Principles Morgan R. Cole, Pharm.D., BCPS Manager, HDVCH Pharmacy Services Clinical Pharmacy Specialist, Pediatric Critical Care

2. Objectives n Describe CRRT principles n Understand basic pharmacokinetic (Pk) parameters n Describe CRRT principles and effects on Pk n Describe variances in Pk parameters n Critically ill n Pediatrics & Neonates n Understand assumptions to estimate dosing regimens in pediatric CRRT

3. CRRT Principles

4. n Heparin Anticoagulation n Citrate Anticoagulation n Acid Citrate Dextrose – Anticoagulation (ACD-A) n Calcium Chloride Replacement n Convective Clearance n Hemofiltration ~ Ultrafiltration n Filter Replacement Fluid (FRF) n Diffusive Clearance n Hemodialysis n Dialysate

6. CRRT Principles n Usual circuit priming volume ~ 100-150mL n Blood, Saline, & Albumin n Usual Blood Flow Rate ~ 3-5mL/kg/min n Tubing and Membrane Filter impact n Adsorption Adapted with permission from: Gambro Training Manual 1 and 2 Slides from Gambro Training package Last Update: February, 2008

8. Ultrafiltration Adapted with permission from: Gambro Training Manual 1 and 2 Slides from Gambro Training package Last Update: February, 2008 n Movement of fluid through a semi- permeable membrane caused by a pressure gradient n Positive, negative and osmotic pressure from non-permeable solutes

9. Convective Clearance n Movement of solutes with water flow, “solvent drag”. n The more fluid moved through a semi- permeable membrane, the more solutes that are removed. n Replacement Fluid is used to create convection Adapted with permission from: Gambro Training Manual 1 and 2 Slides from Gambro Training package Last Update: February, 2008

11. Diffusive Clearance n Movement of solutes from an area of higher concentration to an area of lower concentration. n Dialysate is used to create a concentration gradient across a semi-permeable membrane. Adapted with permission from: Gambro Training Manual 1 and 2 Slides from Gambro Training package Last Update: February, 2008

13. Pharmacokinetic Parameters

14. n Volume of Distribution (Vd) = Volume a drug would occupy if one compartment model exists (conceptual) L / Total Body Weight (TBW) kg Vd L/kg = Volume L / TBW kg Loading Dose (LD) mcg/kg = Vd L/kg * serum concentration mcg/mL n Protein Binding (Pb) describes the bound fraction of drug but infers the free fraction of drug available for pharmacological action n Albumin is the largest contributor to protein binding, though other proteins contribute

15. Pharmacokinetic Parameters n Clearance describes the elimination of drug (volume) mL from the body per unit time min Cl mL/min = Volume mL / Time min Maintenance Dose (MD) mcg = Cl mL/min * serum concentration mcg/mL * dosing interval min n Terminal elimination half life (t 1/2 ) is the time hours that it takes for the serum concentration of a drug to be reduced by 50% t 1/2 hours = 0.693 * ke hours -1 ke hours -1 = Vd L * Cl mL/min

16. Pharmacokinetic Parameters Pk Parameter Healthy individual Critically ill patient variation Increases Decreases Vd One compartment model Two compartment model Volume resuscitation Ascites Capillary leak Edema Dehydration Volume loss Diarrhea/Vomitting Pb Total protein = 5-7 Albumin = 3-5 IVIG administration Albumin administration Adequate nutrition Hypoproteinemia Hypoalbuminemia Acidosis / Fever / Uremia Medication competition Cl First order kinetics Zero order kinetics Hemodialysis Peritoneal dialysis CRRT Oliguric renal failure Anuric renal failure Shock states t 1/2 First order kinetics Zero order kinetics Oliguric renal failure Anuric renal failure Shock states Hemodialysis Peritoneal dialysis CRRT

17. CRRT Impact on Kinetic Parameters n Usual circuit priming volume ~ 100-150mL n Increases Volume of Distribution (Vd) n Usual adult blood volume ~5000mL (0.07L/kg or 70mL/kg) n Usual pediatric blood volume ~80mL/kg n Tubing binds drug n Increases Vd n Adsorption n Membrane Filter binds drug by “Gibbs-Donnan Effect” n Increases Vd n Adsorption

18. CRRT Impact on Kinetic Parameters n Usual Blood Flow Rate ~ 3-5mL/kg/min n Higher the rate leads to increased Clearance (Cl) n Ultrafiltrate Rate ~ Filter Replacement Fluid (FRF) Rate if the patient is kept in even fluid balance ~ 35-40mL/kg/hr (2.5L/m 2 /hr) n Higher the rate leads to increased Cl n Dialysate Rate ~ 35-40mL/kg/hr (2.5L/m 2 /hr) n Higher the rate leads to increased Cl

19. CRRT Impact on Kinetic Parameters n Convective Clearance (Filter Replacement Fluid (FRF)) n Hemofiltration = Ultrafiltration n Clearance (Cl f ) depends on the sieving coefficient (S), small molecules (S = 1) and low protein bound drugs pass freely through the membrane filter based on pressure Drug concentration in filtrate (Cf) Drug concentration in plasma (Cp) *Clearance depends on Protein binding (Pb), independent from Molecular weight n Cl f mL/min = Q f mL/min * S **Q f is the ultrafiltrate rate mL/min = FRF rate mL/min and depends on membrane surface area and transmembrane pressure S =

20. Sample sieving coefficients (S) MedicationS Gentamicin~0.8 Tobramycin~0.8 Amikacin~0.9 Ceftazidime~0.85 Cefepime~0.85 Imipenem~0.8 Meropenem~0.8 MedicationS Levofloxacin~0.8 Moxifloxacin~0.85 Ciprofloxacin~0.75 Pip / Tazo~>1 Linezolid~0.8 Daptomycin~0.15 Vancomycin~0.7 Adapted from Golper, Dialysis Transpl 1993;22:185-188 DelDot, Br J Clin Pharmacol 2004;58:3,259-268 Malone, Antimicrobial Agents and Chemotherapy 2001;3148-3155 Mariat, Crit Care 2006;10:1,R26 Fuhrmann, Journal of Antimicrobial Chemotherapy 2004;54,780-784 Guenter, Pharmacotherapy 2002;2:175-83 Tegeder, Antimicrobial Agents and Chemotherapy 1997;41(12):2640-2645 Valtonen, Journal of Antimicrobial Chemotherapy 2001;48,881-885 Valtonen, Journal of Antimicrobial Chemotherapy 2000;45,701-704 Kraft, Pharmacotherapy 2003;23(8):1071-1075 Churchwell, Blood Purif 2006;24(5-6):548-554

21. CRRT Impact on Kinetic Parameters n Diffusive Clearance (Dialysate) n Hemodialysis n Clearance (Cl d ) depends on the dialysate saturation (S d ), small molecules including small, low protein bound drugs pass through the membrane filter based on diffusion & pressure Drug concentration in dialysate (C d ) Drug concentration in plasma (C p ) *Clearance depends on Protein binding (Pb) & Molecular weight <40,000 daltons n Cl d mL/min = Q d mL/min * S d **Q d is the dialysate rate mL/min and depends on membrane surface area, pore size, and blood flow rate and dialysate rate S d =

22. CRRT Impact on Kinetic Parameters n Combined hemofiltration plus dialysis (Cl df ) n Convective Clearance (Filter Replacement Fluid (FRF)) n Diffusive Clearance (Dialysate) Cl df = Q f * S + Q d * S d n Native clearance must be taken into account if the patient maintains renal function despite CRRT support

23. Convective + Diffusive Clearance n Ultrafiltrate Rate ~ Filter Replacement Fluid (FRF) Rate ~ 35-40mL/kg/hr (2.5L/m 2 /hr) n Dialysate Rate ~ 35-40mL/kg/hr (2.5L/m 2 /hr)

25. Clinical Pearls n Medications unaffected by CRRT n Ceftriaxone n Metronidazole n Clindamycin n Lansoprazole n Pantoprazole n Cyclosporin n Phenytoin

26. Clinical Pearls n Due to extracorporeal clearance provided by CRRT remember to hold the following if CRRT circuit goes down and consult the primary service /nephrology service n Total Parenteral Nutrition / Enteral Nutrition n Antibiotics except ceftriaxone, clindamycin, metronidazole n Potassium, and Phosphorus supplementation n H2 receptor antagonists

27. Clinical Pearls n Due to extracorporeal clearance provided by CRRT remember to monitor closely for toxicity + reduce the dose for the following if CRRT circuit goes down and consult the primary service /nephrology service n Sedation (Midazolam, Lorazepam, Fentanyl, & Morphine) n Pressors (Norepinephrine, Epinephrine, & Dopamine) n Inotropes (Milrinone, Dobutamine, & Epinephrine) n If a new circuit is initiated, a reloading phase will occur until complete adsorption occurs and a new steady state with the circuit is reached.

28. Summary n Understand CRRT principles n Ultrafiltration / Convective vs Diffusive Clearance n Understand basic pharmacokinetic (Pk) parameters n Vd / Pb / Cl / t 1/2 n Describe variances in Pk parameters n Critically ill n Pediatrics & Neonates n Understand CRRT principles and effects on Pk n Adsorption /  Vd /  Cl n Understand assumptions to estimate dosing regimens in pediatric CRRT n Pb / MW / S / Sd / Clf / Cld / Cldf

29. References n Gambro Renal Products, Intensive Care Division, 14143 Denver West Parkway Lakewood, Co. 80401 n Golper, Dialysis Transpl 1993;22:185-188 n DelDot, Br J Clin Pharmacol 2004;58:3,259-268 n Malone, Antimicrobial Agents and Chemotherapy 2001;3148-3155 n Mariat, Crit Care 2006;10:1,R26 n Fuhrmann, Journal of Antimicrobial Chemotherapy 2004;54,780- 784 n Guenter, Pharmacotherapy 2002;2:175-83 n Tegeder, Antimicrobial Agents and Chemotherapy 1997;41(12):2640-2645 n Valtonen, Journal of Antimicrobial Chemotherapy 2001;48,881-885 n Valtonen, Journal of Antimicrobial Chemotherapy 2000;45,701-704 n Kraft, Pharmacotherapy 2003;23(8):1071-1075 n Churchwell, Blood Purif 2006;24(5-6):548-554