Upload
giles-johns
View
223
Download
0
Tags:
Embed Size (px)
Citation preview
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