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

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

CRRT Principles

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

CRRT Principles n Usual circuit priming volume ~ mL 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

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

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

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

Pharmacokinetic Parameters

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

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 = * ke hours -1 ke hours -1 = Vd L * Cl mL/min

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

CRRT Impact on Kinetic Parameters n Usual circuit priming volume ~ mL 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

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

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 =

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: DelDot, Br J Clin Pharmacol 2004;58:3, Malone, Antimicrobial Agents and Chemotherapy 2001; Mariat, Crit Care 2006;10:1,R26 Fuhrmann, Journal of Antimicrobial Chemotherapy 2004;54, Guenter, Pharmacotherapy 2002;2: Tegeder, Antimicrobial Agents and Chemotherapy 1997;41(12): Valtonen, Journal of Antimicrobial Chemotherapy 2001;48, Valtonen, Journal of Antimicrobial Chemotherapy 2000;45, Kraft, Pharmacotherapy 2003;23(8): Churchwell, Blood Purif 2006;24(5-6):

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 =

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

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)

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

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

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.

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

References n Gambro Renal Products, Intensive Care Division, Denver West Parkway Lakewood, Co n Golper, Dialysis Transpl 1993;22: n DelDot, Br J Clin Pharmacol 2004;58:3, n Malone, Antimicrobial Agents and Chemotherapy 2001; n Mariat, Crit Care 2006;10:1,R26 n Fuhrmann, Journal of Antimicrobial Chemotherapy 2004;54, n Guenter, Pharmacotherapy 2002;2: n Tegeder, Antimicrobial Agents and Chemotherapy 1997;41(12): n Valtonen, Journal of Antimicrobial Chemotherapy 2001;48, n Valtonen, Journal of Antimicrobial Chemotherapy 2000;45, n Kraft, Pharmacotherapy 2003;23(8): n Churchwell, Blood Purif 2006;24(5-6):