Drug Kinetics and CRRT: Parameters and Principles

Morgan R. Cole, Pharm.D., BCPS

Manager, HDVCH Pharmacy Services

Clinical Pharmacy Specialist,

Pediatric Critical Care

Objectives

Describe CRRT principles Understand basic pharmacokinetic (Pk)

parameters Describe CRRT principles and effects on Pk Describe variances in Pk parameters

Critically ill Pediatrics & Neonates

Understand assumptions to estimate dosing regimens in pediatric CRRT

CRRT Principles

CRRT Principles

Heparin Anticoagulation Citrate Anticoagulation

Acid Citrate Dextrose – Anticoagulation (ACD-A)

Calcium Chloride Replacement Convective Clearance

Hemofiltration ~ Ultrafiltration Filter Replacement Fluid (FRF)

Diffusive Clearance Hemodialysis Dialysate

CRRT Principles

Usual circuit priming volume ~ 100-150mL Blood, Saline, & Albumin

Usual Blood Flow Rate

~ 3-5mL/kg/min

Tubing and Membrane Filter impact 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

Movement of fluid through a semi-permeable membrane caused by a pressure gradient

Positive, negative and osmotic pressure from non-permeable solutes

Convective Clearance

Movement of solutes with water flow, “solvent drag”.

The more fluid moved through a semi-permeable membrane, the more solutes that are removed.

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

Movement of solutes from an area of higher concentration to an area of lower concentration.

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

CRRT Impact on Kinetic Parameters

Usual circuit priming volume ~ 100-150mL Increases Volume of Distribution (Vd) Usual adult blood volume ~5000mL (0.07L/kg or 70mL/kg) Usual pediatric blood volume ~80mL/kg

Tubing binds drug Increases Vd Adsorption

Membrane Filter binds drug by “Gibbs-Donnan Effect” Increases Vd Adsorption

CRRT Impact on Kinetic Parameters

Usual Blood Flow Rate ~ 3-5mL/kg/min Higher the rate leads to increased Clearance (Cl)

Ultrafiltrate Rate ~ Filter Replacement Fluid (FRF) Rate if the patient is kept in even fluid balance ~ 35-40mL/kg/hr (2.5L/m2/hr) Higher the rate leads to increased Cl

Dialysate Rate ~ 35-40mL/kg/hr (2.5L/m2/hr) Higher the rate leads to increased Cl

Sample sieving coefficients (S)

Medication S

Gentamicin ~0.8

Tobramycin ~0.8

Amikacin ~0.9

Ceftazidime ~0.85

Cefepime ~0.85

Imipenem ~0.8

Meropenem ~0.8

Medication S

Levofloxacin ~0.8

Moxifloxacin ~0.85

Ciprofloxacin ~0.75

Pip / Tazo ~>1

Linezolid ~0.8

Daptomycin ~0.15

Vancomycin ~0.7Adapted from Golper, Dialysis Transpl 1993;22:185-188DelDot, Br J Clin Pharmacol 2004;58:3,259-268Malone, Antimicrobial Agents and Chemotherapy 2001;3148-3155Mariat, Crit Care 2006;10:1,R26Fuhrmann, Journal of Antimicrobial Chemotherapy 2004;54,780-784Guenter, Pharmacotherapy 2002;2:175-83Tegeder, Antimicrobial Agents and Chemotherapy 1997;41(12):2640-2645

Valtonen, Journal of Antimicrobial Chemotherapy 2001;48,881-885Valtonen, Journal of Antimicrobial Chemotherapy 2000;45,701-704Kraft, Pharmacotherapy 2003;23(8):1071-1075Churchwell, Blood Purif 2006;24(5-6):548-554

CRRT Impact on Kinetic Parameters

Combined hemofiltration plus dialysis (Cldf) Convective Clearance (Filter Replacement Fluid (FRF))

Diffusive Clearance (Dialysate)

Cldf = Qf * S + Qd * Sd

Native clearance must be taken into account if the patient maintains renal function despite CRRT support

Convective + Diffusive Clearance

Ultrafiltrate Rate ~

Filter Replacement Fluid (FRF) Rate

~ 35-40mL/kg/hr

(2.5L/m2/hr)

Dialysate Rate

~ 35-40mL/kg/hr

(2.5L/m2/hr)

Clinical Pearls

Medications unaffected by CRRT Ceftriaxone Metronidazole Clindamycin Lansoprazole Pantoprazole Cyclosporin Phenytoin

Clinical Pearls

Due to extracorporeal clearance provided by CRRT remember to hold the following if CRRT circuit goes down and consult the primary service /nephrology service Total Parenteral Nutrition / Enteral Nutrition Antibiotics except ceftriaxone, clindamycin,

metronidazole Potassium, and Phosphorus supplementation H2 receptor antagonists

Clinical Pearls

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 Sedation (Midazolam, Lorazepam, Fentanyl, & Morphine) Pressors (Norepinephrine, Epinephrine, & Dopamine) Inotropes (Milrinone, Dobutamine, & Epinephrine)

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

Understand CRRT principles Ultrafiltration / Convective vs Diffusive Clearance

Understand basic pharmacokinetic (Pk) parameters Vd / Pb / Cl / t1/2

Describe variances in Pk parameters Critically ill Pediatrics & Neonates

Understand CRRT principles and effects on Pk Adsorption / Vd / Cl

Understand assumptions to estimate dosing regimens in pediatric CRRT Pb / MW / S / Sd / Clf / Cld / Cldf

References

Gambro Renal Products, Intensive Care Division, 14143 Denver West Parkway Lakewood, Co.  80401

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