Chief Pediatric Nephrology Nemours/A.I. duPont Hospital for Children Drug Dosing in CRRT Joshua Zaritsky MD PhD Chief Pediatric Nephrology Nemours/A.I. duPont Hospital for Children

Disclosure Disclosure: Kaneka: Paid Speaker I am not a pharmacist

Why is this such a difficult topic? PICU patients on CRRT represent an overlap of: Disturbed pharmacokinetics induced by critical illness Extracorporeal drug removal Often a rapidly changing clinical situation Current drug dosing during CRRT: Are based on a wider variation of CRRT techniques Use a very heterogeneous (often ADULT) population Often lack data to back them up

Pharmacokinetics Absorption Volume of distribution (Vd) Decreased gastric or subcutaneous absorption due to shock and vasopressors Intravenous route preferred in severe sepsis / septic shock Volume of distribution (Vd) Hydrophilic medications generally stay in the plasma volume (Vd < 0.7 L/kg) Influenced by fluid administration and capillary leak Lipophilic medications distribute into intracellular and adipose tissue (Vd > 1 L/kg) Not generally affected by fluid administration and third spacing Crit Care Clin 2011;27:1-34 Crit Care Clin 2006;22:255-71 Chest 2012;141;1327-36

Pharmacokinetics Metabolism Excretion Hepatic metabolism consists of two phases Phase 1: oxidation, reduction and hydrolysis Cytochrome P450 Phase 2: glucuronidation, sulfation and acetylation Drugs can be classified by extraction ratio High (> 0.7): depends on hepatic drug flow Intermediate (0.3-0.7) Low (< 0.3): depends on hepatic (intrinsic) function Excretion Renal excretion is the primary excretory pathway for most parent drugs or their metabolites Crit Care Clin 2011;27:1-34 Crit Care Clin 2006;22:255-71 Chest 2012;141;1327-36

A Twist of Antibiotics into the mix! Good news: Most data available for CRRT dosing Bad news: Must consider pharmacodynamics as well Beta lactams and gylcopeptides: These are “time dependent” antibiotics Therefore the percentage that the plasma concentration remains above the MIC is the major determinant of efficacy In theory a continuous infusion would maximize pharmacodynamic exposure

Antibiotics Fluoroquinolones and Aminoglycosides: These are “concentration dependent” antibiotics with a post antibiotic effect Aminoglycoside efficacy: ratio of the peak concentration to the MIC Fluroquinolones efficacy: ratio of the AUC to MIC In both cases you want a high dosing with prolonged dosing interval

Pharmacodynamics Clin Inf Dis 1998;26:1-12 Crit Care Clin 2011;27:1-34 Crit Care Med 2009;37:840-51

What determines extracorporeal drug removal? Drug characteristics Physico-chemical properties Pharmacokinetic parameters Drugs with large volumes of distribution have less access to the dialyzer Access to the deeper compartments (tissues) is related to the rate of extracorporeal removal and rate of transfer between compartments (Vd plays less of a role during CRRT) Treatment characteristics Solute transport mechanism (diff vs. convection) Setting of the machine Membrane characteristics (early saturation)

Convection + Diffusion = Confusion!

Convection + Diffusion = Confusion! Clearance Diffusive Clearance Convective Clearance Molecular Weight 100 1,000 10,000 10

What determines extracorporeal drug removal? The capacity of the drug to pass a membrane is the sieving coefficient (S) S = Ceffluent/Cplasma or S = AUCeff/AUCp The major determinant of S is the drug’s protein binding (PB) S= (1-PB) =free fraction of drug PB can vary!

What determines extracorporeal drug removal? Post dilution Hemofiltration (pure convection) Cl= S x Qeffluent (S can be estimated at 1-PB) Predilution hemofiltration Cl= S x Qeff x (Qb/[Qb+Qpre]) Dialysis modalities We need to introduce dialysate saturation Sd = Cd/Cp Fortunately in CRRT Sd approaches 1-PB Cl = Sd x Qd x Kdrel

Fractional extracorporeal clearance FrEC = ClEC/(ClEC + ClNR + ClR FrEC will be low with: Low ClEC as in cases of high protein binding High ClNR as in cases of hepatic metabolism High ClR which is unlikely Some examples: Levofloxacin has a low Pb and low hepatic elimination vs. moxifloxacin with a high Pb and high hepatic elimination In general- drugs with renal elimination will require dosage adaptation during CRRT (FrEC>25%)

A Stepwise and Practical Approach Is the drug highly protein bound or hepatically cleared? Adaptation of the maintenance dose to the reduced renal function Augmentation of the maintenance dose when the FrEC is >25%

Some methods Method 1: Use general table or literature values for specific medications Trotman RL. CID 2005;41:1159-66 Pea F. Clin Pharmacokinet 2007;46:997-1038 Heintz BR. Pharmacotherapy 2009;29:562-77 Shortfalls include Lack of data Is the data valid due to heterogeneous patient populations and the use of different CRRT techniques and setting? Kidney International 2011;80:1122-37

Some methods Method 2a: Dose as if the CrCl ~ 20-50 ml/min This is based on the total creatinine clearance to help with dosing. Problems include: Overdosing of drugs with tubular secretion Underdosing of drugs with tubular re-absorption; an example is fluconazole in which CRRT clearance may be higher than in pts with normal renal function Method 2b: Divide hourly effluent rate by 60 to get estimated CrCl (i.e. 3000 ml/hour divided by 60 = est CrCl of 50 ml/min) Kidney International 2011;80:1122-37

Some Methods Method 3: Start with normal dosing and reduces it to take into effect the of CRRT clearance Dose= Dosenormal x [CLnonrenal + (Qeffluent x S)]/Clnormal Method 4: Start with anuric dosing and augment it with the drug fraction you expect to be removed Dose= Doseanuric x [1- FrEC] FrEC = ClEC/(ClEC + ClNR + ClR) Dosing interval= Dosing intervalanuric x [1- FrEC] If concentration dependent drug: Increase total dose, keep same interval If time dependent drug: Keep same dose, change interval Kidney International 2011;80:1122-37

Example: Acyclovir in a 70kg person undergoing CVVH with an Qeff = 2450ml/hr Dose= Doseanuric x [1- FrEC] FrEC = ClEC/(ClEC + ClNR + ClR) ClEC = S x Qeffluent = 0.85 x 2450ml/hr = 34.7ml/min S= 1-PB; Protein binding = 15% CLNR = Vd x KHD = 56L x 0.04hr-1 = 2.24L/hr = 37.3ml/min Vd = 0.8 L/kg; t1/2 = 19.5 hrs; KHD = 0.04 hr-1 ClR = 0 ml/min FrEC = 34.7/(34.7 + 37.3 + 0)=0.48 CRRT dose = anuric dose/ [1-0.48] = 5mg/kg/day/0.52 = 9.6 mg/kg/day Dosing interval= Dosing intervalanuric x [1- FrEC] Will change interval so would give: 5mg/kg IV Q12H

Summary Get to know your pharmacist Get to know your drug (Is the FrEC >25%?) FrEC = ClEC/(ClEC + ClNR + ClR) The more its protein bound, the less you need to worry The more its cleared hepatically, the less you need to worry Converse: More renal clearance means your need to account for the effects of CRRT Choose your poison as to how you are going to adjust the dose and recognize its limitations KDIGO: Kidney International 2011;80:1122-37