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Dosage Regimen Design in Renal Impairment Clinical causes of renal impairment Assessment of renal function Influence of renal impairment on drug handling Dosage regimen design Influence of renal replacement on drug handling
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Acute Renal Failure

Prerenal Reduction in renal perfusion fluid loss, shock, infection, cardiac failure prostaglandin inhibition NSAIDs, angiotensin II, ACE inhibitors Intrarenal Renal tubular necrosis renal hypoperfusion, nephrotoxicity aminoglycosides, ciclosporin Interstitial nephritis nephrotoxicity penicillins, cephalosporins Glomerulonephritis immune complexes endocarditis, gold, phenytoin Postrenal Urinary tract obstruction Kidney stones, thrombosis, tumours, benign prostatic hypertrophy 2

Chronic Renal Failure

Progressive deterioration over months or years, symptoms <30 ml/min End stage renal failure
renal replacement required: haemodialysis, chronic ambulatory peritoneal dialysis or kidney transplantation

Definitions of renal impairment - eGFR

Normal Mild Moderate Severe urinary obstruction polycystic kidney disease diabetes mellitus
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Stage 1 Stage 2 Stage 3 Stage 4 Stage 5

> 90 ml/min/1.73m2
+ evidence of kidney damage

60 - 89 ml/min/1.73m2
+ evidence of kidney damage

30 - 59 ml/min/1.73m2 15 - 29 ml/min/1.73m2 <15 ml/min/1.73m2

Disease processes
chronic glomerulonephritis chronic pyelonephritis interstitial nephritis hypertension

Renal failure

Assessment of Renal Function

Glomerular filtration rate - exogenous markers: inulin, 51Cr EDTA - endogenous markers: Urea hydration state, variable input/output Creatinine filtered and secreted Cystatin C
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Creatinine Clearance
Measured creatinine CL: 24 h urine collection
Excretion rate concU x urineV CrCl = ------------------ = ------------------Midpoint Cp Plasma conc

- tedious to perform - often inaccurate

Estimated creatinine CL: clinical characteristics Dosing rate Production rate Cssav = --------------- = ------------------Clearance Clearance
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Cockcroft-Gault equation
Nephron 16: 31-41, 1976

Cockcroft-Gault Equation
Nephron, 1976 16: 31-41

249 males, 2 x 24 hour urine collections 24 hour excretion plotted against age & weight = input rate 1.23 x (140 age) x weight Steady state serum creatinine Creatinine production rate Creatinine Css = -------------------------------Creatinine CL a 15% reduction appears appropriate for women

Males CRCL (mlmin-1) Females CRCL (mlmin-1)

(140 age (y)) x wt (kg) = 1.23 x ------------------------------Creatinine (molL-1) (140 age (y)) x wt (kg) = 1.04 x ------------------------------Creatinine (molL-1)

Creatinine CL vs Creatinine conc

160 140 Creatinine clearance (ml/min) 120 100 80 60 40 20 0 0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 Creatinine concentration (mol/L)

Assumptions of Cockcroft-Gault Equation

Patient not obese (> 20% above IBW) Ideal body weight (IBW) Devine et al, 1974 Male = 50.0 kg + 2.3 kg for every 1" > 5 ft Female = 45.5 kg + 2.3 kg for every 1" > 5 ft Creatinine concentration at steady state not true if renal function rapidly changing Normal creatinine production
creatine (liver) creatine phosphate (muscle) creatinine

CrCl 1/creatinine

25 years 75 years

frail elderly patient malnutrition muscular dystrophy

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eGFR estimated GFR

Based on MDRD (modified diet in renal disease) equation Better estimate of GFR when renal function is poor F x 175 x 0.742 (female) x 1.21 (black) eGFR = -----------------------------------------------2 ml/min/1.73 m (Cr/88.4)1.154 x age0.203)
F = assay correction factor

Influence of Renal Impairment on Drug Handling

Absorption - bioavailability unchanged rate decreased? influence of nausea, vomiting, diarrhoea, drugs? Distribution - fluid retention / dehydration (water soluble drugs) most drugs: unchanged (except digoxin) Elimination - Renal metabolism impaired Hepatic metabolism may be affected Metabolites may accumulate active / toxic? - Renal clearance reduced clinical relevance?

standardised to 1.73 m2 therefore MUST correct for Body Surface Area to estimate individual GFR GFR ml/min = eGFR ml/min/1.73 m2 x (BSA/1.73) In practice, Cockcroft Gault equation normally used for drug dose adjustment

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Dose adjustment in renal impairment

Is the drug renally cleared?
Renal CL = filtration + secretion - reabsorption Total CL = renal CL + non-renal CL
Fe Fe 1 Fe = fraction excreted unchanged = renal clearance/total clearance = non-renal clearance

Dose adjustment in renal impairment

Loading dose Volume of distribution is not usually affected by renal impairment loading dose only depends on size, not renal function digoxin is the exception Maintenance dose? What is the target profile? Flat: adjust dose or dose interval High peak, low trough: adjust dose interval (possibly both)
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What is the target profile?

change dose amount or dose interval or both?

Dose adjustment in renal impairment

Loading dose (mg) = C target (mgL-1) x V (L) / s
Conc Ctarget

Dose calculation flat profile Continuous intravenous infusion Infusion rate = Target Css x CL /s (mgL-1) (Lh-1) (mgh-1) Oral maintenance dose Dose = Target Cssav x CL x / F.s (Lh-1) (h) (mg) (mgL-1)
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generally UNCHANGED in renal disease increased importance (longer time to steady state)
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Dose adjustment in renal impairment

Does the drug have a narrow therapeutic range? No follow BNF or SPC or Renal Drug Handbook Yes use local dose guidelines initially (Population pk) measure drug concentration(s) adjust dose according to concentration(s) renal function may change if the patient is clinically unstable
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Renal replacement therapies

Haemodialysis
Chronic renal failure Arteriovenous fistula in place Usually performed for 4 hours x 3 per week

Chronic Ambulatory Peritoneal Dialysis (CAPD)

Chronic renal failure Abdominal catheter for entry and exit of exchange fluids changed every 4-6 hours

Continuous venovenous haemodiafiltration (CVVHDF)

Acute renal failure Continuous haemofiltration +/- dialysis

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Haemodialysis

Principles of Haemodialysis (CRCL <10 ml/min)

Drug removal by diffusion Dialysate flow

Pump Blood flow

Drug

Concentration gradient - drug moves from high conc (blood) to low conc (dialysate)
Oxford Textbook of Medicine, Warrell, David A., Cox, Timothy M., Firth, John D., Benz, Edward J. 4th Edition 2003 Oxford University Press

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Drug clearance by haemodialysis

Relevance of HD to overall clearance depends on endogenous clearance (e.g. hepatic metabolism) Dialysis 4 h three times weekly - CL during dialysis up to 100 ml/min Small, water soluble molecules (<500 Da) with low protein binding and low V cleared efficiently, varies according to membrane Sometimes top-up drug doses are given after dialysis
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Continuous Veno-venous Haemofiltration (acute renal failure)

Pump pressure Drug in plasma Drug removal by convection

Ultrafiltrate

Semipermeable membrane
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Continuous Veno-Venous Haemodiafiltration (CVVHDF) acute renal failure

Drug removal by diffusion and convection Dialysate flow

Drug Removal in CVVHDF

Continuous equivalent to GFR 15 30 ml/min Efficiency of drug removal depends on Physicochemical factors (drug) Filtration conditions (system) Pharmacokinetic factors (drug and patient) Dose adjustment can be difficult due to lack of pharmacokinetic data (Renal Drug Handbook)
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Pump Blood flow

Drug

Concentration gradient - drug moves from high conc (blood) to low conc (dialysate)
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Influence of physicochemical and membrane factors on CVVHDF Diffusion clearance (dialysis) membrane type and surface area molecular weight blood and dialysate flow rates Convection clearance (ultrafiltration) membrane type and surface area up to MW 20 - 30,000 Da removed, most drugs <1500 Da (vancomycin 1448 Da) ultrafiltration rate (1 L/h, 2 L/h)

PK factors that influence drug removal in renal replacement

Endogenous clearance residual renal function (variable!) if < 20 - 30% cleared renally, haemofiltration is unlikely to have a significant effect but non-renal clearance may also alter
hepatic impairment effect of uraemia on metabolism

PK factors and drug removal by renal replacement Volume of distribution

large volume limits drug removal (> 2 L/kg) slow transfer rate from tissues => rebound (haemodialysis) less important for CVVH

PK factors and drug removal by renal replacement Protein binding

Albumin and alpha-1-acid glycoprotein (AAG) not filtered (>50,000 Da) Only unbound drug passes through filter
membrane

Blood

Tissues

Blood

Tissues

Blood

Determination of filtration clearance

Measure ultrafiltrate and plasma concs

Summary: dosing in renal impairment

Consider Degree of renal impairment? Proportion cleared renally? Concentration-effect relationship? Target profile? Narrow therapeutic range? Renal replacement therapy?
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CVVH
sieving coefficient (s) = ConcUF/ Cplasma
filter CL = s x Flow rate (QF)

CVVHDF
saturation coefficient (sa) = CUF+D/Cplasma
filter CL = sa x Flow rate (QF+QD)