1. 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

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

3. 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

4. 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;

5. 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 ( )
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;

6. 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

7. 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

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

9. 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)

10. Convection + Diffusion = Confusion!

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

12. 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!

13. 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

14. 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%)

15. 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%

16. Some methods
Method 1: Use general table or literature values for specific medications
Trotman RL. CID 2005;41:
Pea F. Clin Pharmacokinet 2007;46:
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:

17. 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 ml/hour divided by 60 = est CrCl of 50 ml/min)
Kidney International 2011;80:

18. 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:

19. 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/( )=0.48
CRRT dose = anuric dose/ [1-0.48] =
5mg/kg/day/ = 9.6 mg/kg/day
Dosing interval= Dosing intervalanuric x [1- FrEC]
Will change interval so would give: 5mg/kg IV Q12H

20. 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: