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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
• 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
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
Drug removal in CRRT
• Drug parameters
– Volume of
distribution
– Solubility
– Protein binding
– Molecular weight
– Drug charge
• Filter parameters
– Filter type
– Flow rate
– Membrane
properties
Drug Parameters
Pharmacokinetics (Pk)
drug
absorption
efficacy
&
toxicity
drug
metabolism
drug + metabolites
excretion
drug + metabolites
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
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
Protein Binding
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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
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.
• Drugs are cleared by CRRT
– Small volume of distribution
– Not highly protein bound
– Water soluble
– High renal clearance
CRRT EFFECT ON Pk
CVVH
Post dilution
replacement fluid (B)
Filter
Patient
Ultra
filtrate
Pump
Anticoagulant
Pre-dilution
replacement fluid (A)
• Simplest form of CRRT
• Plasma water,
electrolytes and
molecules pass through
a pressure gradient
• Good removal of
molecules up to 30,000
daltons
Removal mainly by CONVECTION
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 )
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
0.95
Phenytoin
0.45
0.1
Theophylline
0.8
0.47
(Golper et al 2001)
CVVHDF
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)
• Diffusion, movement of
solutes from high to low
conc.
• Combines the benefits
of diffusion and
convection
• Cldf = Qf * Sc + Qd * Sd
Removal mainly by CONVECTION and DIFFUSION
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
Plasma clearance
• Normal Healthy
– 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)
Critical illness and Pk
Pharmacokinetics in Critically ill child
Liver disease, Renal
Failure, DDI
drug
absorption
efficacy
&
toxicity
drug
metabolism
Sepsis, ascites,
hypoalbuminaemia,
hyper / hypovolaemia,
CPB, ECMO
GI motility / function:
infection,sepsis,surgery,
drugs, diet
Liver failure, Renal
Failure, heart failure,
infection, sepsis, hypoxia,
hypothermia, co-meds
drug + metabolites
Renal Failure, Billiary
excretion
drug + metabolites
disease, comedication,
infection, sepsis
(H Mulla)
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
Effect of Critical illness on Pk
Increased
Decreased
Cl
Haemodialysis
Peritoneal dialysis
CRRT
Oliguric renal failure
Anuric renal failure
Shock states
T1/2
Oliguric renal failure
Anuric renal failure
Shock states
Haemodialysis
Peritoneal dialysis
CRRT
Dose Adjustments in CRRT
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
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
CVVH Dose =
Dn = normal dose
CLnr = non renal clearance
Qf x S = extracorporeal clearance
Dn x [CLnr + (Qf x S)]
Cl
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
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.
• 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?
References
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Churchwell J et al. Drug dosing during continuous renal replacement therapy. Seminars in Dialysis 2009;
22(2) 185-188
Awdishu et al .How to optimise drug delivery in renal replacement therapy Seminars in Dialysis 20011;
24(2) 176-182
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: 645-651.
Pea F et al. PK considerations for antimicrobial therapy in patients receiving CRRT; Clin Pharmacokinet
2007; 46 (12): 997-1038
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; 41:1159-66
Bugge J. Pharmacokinetics and drug dosing adjustments during continuous venovenous filtration or
hemodiafiltration in critically ill patients. Acta Anaesthesiol Scand 2001; 45: 929-934
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, 929-937
Ulldemolins et al. Beta-lactam dosing in critically ill patients with septic shock and continuous renal
replacement therapy. Critical care 2014, 18:227