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

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

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 distribution 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 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

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.

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

CRRT EFFECT ON Pk

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

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

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

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 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)

Critical illness and Pk

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)

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

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 dose CLnr = non renal clearance Qf x S = extracorporeal clearance Dn x [CLnr + (Qf x S)] CVVH Dose = 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