1. Honorary Clinical Lecturer Kings College London
Pharmacokinetic Parameters & Drug Handling in Continuous Renal Replacement Therapy (CRRT)
PCRRT London 18th July 2015
Marie O’Meara
Pharmacist
Honorary Clinical Lecturer Kings College London

2. Disclosures
I am currently an employee of Abbvie Ltd, the opinions expressed throughout this presentation are my own.

3. Patterns of Medication Exposures in Hospitalized Pediatric Patients With Acute Renal Failure Requiring Intermittent or Continuous Hemodialysis.
10% medications - dosing guidance without limitation for all age groups patients with renal replacement.
Rizkalla et al PaediatrCritCareMed.2013 Aug

5. Scope
Pharmacokinetic (Pk) parameters important for drug removal by CRRT
CRRT system effect on Pk parameters
Effect of critical illness on Pk
Dose adjustments in CRRT

6. Drug removal in CRRT Drug parameters Volume of distribution Solubility
Protein binding
Molecular weight
Drug charge
Filter parameters
Filter type
Flow rate
Membrane properties

7. Drug Parameters .

8. Pharmacokinetics (Pk)
drug
absorption
efficacy
&
toxicity
distribution
drug
metabolism
drug + metabolites
excretion
drug + metabolites

9. Volume of Distribution (Vd)
Fictitious volume in which drug would have been distributed
Vd L/kg = Volume L / TBW kg
Lipid soluble drugs (diazepam) or highly tissue-bound drugs (digoxin) → high Vd
Water soluble drugs (neuromuscular blockers) remain in the blood →low Vd
Large Vd >0.7L/kg → less likely drug will be filtered
Loading Dose (LD) mcg/kg = Vd L/kg * serum concentration mcg/ml

10. Molecular Weight & Charge
Molecules (>500Da) less likely to be removed using IHD
Most drugs MW ≤ 500 Da, few > 1500 Da (vancomycin 1448 Da)
CRRT removes 20,000-30,000 Da
Drug molecular charge affects clearance during CRRT: Gibbs-Donnan effect
Anionic proteins retain cationic drug molecules

11. Protein Binding Protein Binding (Pb), bound fraction of drug.
Plasma protein binding → Vd
Albumin(68,000Da) largest contributor
Only unbound drug available for pharmacological action
>80% bound not likely to be significantly removed

12. Cl mL/min = Volume mL / Time min
Clearance (Cl)
Clearance : elimination of drug from the body/unit time
Cl mL/min = Volume mL / Time min
Is the drug predominantly renally cleared?
Drugs with > 25% renal clearance influenced by CRRT
Residual renal function
Maintenance Dose rate = Cl * Target Concentration
T ½- time necessary to halve the plasma conc.

13. Drugs are cleared by CRRT
Small volume of distribution
Not highly protein bound
Water soluble
High renal clearance

14. CRRT EFFECT ON Pk

15. Removal mainly by CONVECTION
CVVH
Simplest form of CRRT
Plasma water, electrolytes and molecules pass through a pressure gradient
Good removal of molecules up to 30,000 daltons
Post dilution replacement fluid (B)
Filter
Patient
Ultra
filtrate
Pump
Anticoagulant
Pre-dilution replacement fluid (A)
Removal mainly by CONVECTION

16. Sieving Coefficient (Sc)
Ratio of Drug concentration in the ultrafiltrate to the pre-filter water plasma concentration.
Sc= Cf/Cp Values near 1 – good removal
Sc= 1-protein binding or free drug
Cl = Sc x Qf Filtration rate(Qf )
(Golper et al 2001)
Observed Sc
Expected Sc
Amikacin
0. 95
0.95
Ceftriaxone
0.2
0.15
Fluconazole 1
0.88
Ganciclovir
0.84
0.98
Gentamicin
0.81
Phenytoin
0.45
0.1
Theophylline
0.8
0.47

17. Removal mainly by CONVECTION and DIFFUSION
CVVHDF
Diffusion, movement of solutes from high to low conc.
Combines the benefits of diffusion and convection
Cldf = Qf * Sc + Qd * Sd
Post dilution replacement fluid (B)
Dialysis pump A
Dialysis fluid in
Filter
Patient
Dialysis fluid out
Pump
Dialysis pump B
Anticoagulant
Pre-dilution replacement fluid (A)
Removal mainly by CONVECTION and DIFFUSION

18. Filter properties Membrane Hydrophobic, adsorption Pore Size
SA effective for clearance is  with life of filter
Flow rates
Blood flow rates & dialysate flow rate
More rapid the rates → better clearance. Concentration differences between blood & dialysate are maximised - diffusion

19. Plasma clearance Normal Healthy Peritoneal Dialysis CVVHF CVVHDF
GFR 60 – 120 mls/min
Peritoneal Dialysis
GFR 5 – 10 mls/min
CVVHF
GFR 15 – 25 mls/min
CVVHDF
GFR 30 – 40 mls/min
(Bugge et al 2001)

20. Critical illness and Pk

21. Pharmacokinetics in Critically ill child
drug
Liver disease, Renal Failure, DDI
absorption
GI motility / function: infection,sepsis,surgery, drugs, diet
efficacy
&
toxicity
distribution
drug
Liver failure, Renal Failure, heart failure, infection, sepsis, hypoxia, hypothermia, co-meds
metabolism
Sepsis, ascites, hypoalbuminaemia, hyper / hypovolaemia, CPB, ECMO
drug + metabolites
Renal Failure, Billiary disease, comedication, infection, sepsis
excretion
drug + metabolites (H Mulla)

22. Effect of Critical illness on Pk
Increased Decreased Vd
Volume resuscitation
Ascites
Capillary leak
Odema
Dehydration
Volume loss
Diarrhea/Vomiting Pb
IVIG administration
Albumin administration
Adequate nutrition
Hypoproteinemia
Hypoalbuminemia
Acidosis / Fever / Uremia
Medication competition

23. Effect of Critical illness on Pk
Increased Decreased Cl
Haemodialysis
Peritoneal dialysis
CRRT
Oliguric renal failure
Anuric renal failure
Shock states
T1/2

24. Dose Adjustments in CRRT

25. Drug dosing during CRRT in Critical illness
Loading Dose
No adjustment required (dependent on Vd)
? Fluid overload, capillary leak, ascities,
Maintenance Dose
Adapt the maintenance dose to the reduced renal function
? Augmentation of the maintenance dose where FrCRRT > 0.25 & residual renal function

26. Approaches to defining Maintenance Dose in CRRT
1. Based on total creatinine clearance (CrCL)
Sum of extracorporeal and endogenous CrCL
Modern CRRT techniques achieve CrCL of between 25 – 50 ml/min.
Unknown parameters
2. Based on renal and non renal clearance
Dn = normal dose
CLnr = non renal clearance
Qf x S = extracorporeal clearance
Dn x [CLnr + (Qf x S)]
CVVH Dose = Cl

27. Approaches to defining Maintenance Dose in CRRT
3. Consult available literature
Usually adult data
Tells us drug properties, can be extrapolated
Not always generlisable, heterogeneity of patient population, different CRRT techniques, settings etc
Patient specific factors

28. Approaches to defining Maintenance Dose in CRRT
4. Therapeutic Drug Monitoring
Possible for some drugs e.g. aminoglycosides, glycopeptides
Dose adaptations should with reference to pharmacodynamic effect e.g. concentration or time dependent killing.

29. Understand your drug
Review available literature
Establish route(s) of elimination of drug
Review pharmacokinetic data
Will accumulation cause adverse effects?
Will treatment failure be worse than toxicity?

31. References
Churchwell J et al. Drug dosing during continuous renal replacement therapy. Seminars in Dialysis 2009; 22(2)
Awdishu et al .How to optimise drug delivery in renal replacement therapy Seminars in Dialysis 20011; 24(2)
Bohler J et al. PK principles during CRRT: Drugs and Dosage; Kidney International, vol. 56, suppl. 72 (1999)
Schetz M. Drug dosing in CRRT: general rules; Curr Opin Crit Care 13:
Pea F et al. PK considerations for antimicrobial therapy in patients receiving CRRT; Clin Pharmacokinet 2007; 46 (12):
Zuppa AF Understanding Renal ReplacementTherapy and Dosing of Drugs in Pediatric Patients With Kidney Disease . J Clin Pharmacol 2012;52:134S-140S
Veltri et al. Drug dosing during Intermittent Haemodialysis and continuous renal replacement therapy. Special considerations in paediatric patients. Pediatr drugs. 2004; 6(1)45-65
Patterns of Medication Exposures in Hospitalized Pediatric Patients With Acute Renal Failure Requiring Intermittent or Continuous Hemodialysis. Rizkalla N.A. 2013
Trotman et al. Antibiotic dosing in critically ill adult patients receiving continuous renal replacement therapy. Clinical infectious diseases 2005; 41:
Bugge J. Pharmacokinetics and drug dosing adjustments during continuous venovenous filtration or hemodiafiltration in critically ill patients. Acta Anaesthesiol Scand 2001; 45:
Li A et al. A systematic review of antibiotic dosing regimens for septic patients receiving continuous renal replacement therapy: do current studies provide sufficient data? Journal of antimicrobial chemotherapy. (2009) 64,
Ulldemolins et al. Beta-lactam dosing in critically ill patients with septic shock and continuous renal replacement therapy. Critical care 2014, 18:227