Pharmacokinetic Parameters & Drug Handling in Continuous Renal Replacement

Therapy (CRRT)

PCRRT London 18th July 2015Marie O’Meara

PharmacistHonorary 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

drug + metabolites

drug + metabolites

absorption

drug

metabolism

excretion

efficacy

&

toxicitydis

tributio

n

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

• 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

• Simplest form of CRRT• Plasma water,

electrolytes and molecules pass through a pressure gradient

• Good removal of molecules up to 30,000 daltons

Patient

Post dilution replacement fluid (B)

Filter

Anticoagulant Pre-dilution replacement fluid (A)

UltrafiltratePump

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 )

(Golper et al 2001)

Observed Sc Expected ScAmikacin 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

Patient

Post dilution replacement fluid (B)

Filter

Anticoagulant Pre-dilution replacement fluid (A)

PumpDialysis pump B

Dialysis pump A

Dialysis fluid out

Dialysis fluid in

CVVHDF• 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

drug

drug + metabolites (H Mulla)

drug + metabolites

absorption

drug

metabolism

excretion

efficacy

&

toxicity distri

bution

GI motility / function: infection,sepsis,surgery, drugs, diet

Liver failure, Renal Failure, heart failure, infection, sepsis, hypoxia, hypothermia, co-meds

Renal Failure, Billiary disease, comedication, infection, sepsis

Liver disease, Renal Failure, DDI

Sepsis, ascites, hypoalbuminaemia, hyper / hypovolaemia, CPB, ECMO

Pharmacokinetics in Critically ill child

Effect of Critical illness on Pk

Increased Decreased

Vd Volume resuscitationAscitesCapillary leakOdema

DehydrationVolume lossDiarrhea/Vomiting

Pb IVIG administrationAlbumin administrationAdequate nutrition

HypoproteinemiaHypoalbuminemiaAcidosis / Fever / UremiaMedication competition

Effect of Critical illness on Pk

Increased Decreased

Cl HaemodialysisPeritoneal dialysisCRRT

Oliguric renal failureAnuric renal failureShock states

T1/2 Oliguric renal failureAnuric renal failureShock states

HaemodialysisPeritoneal dialysisCRRT

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

Dn = normal doseCLnr = non renal clearanceQf x S = extracorporeal clearance

CVVH Dose =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• 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