Drug Dosing in Renal Insufficiency. Coralie Therese D. Dimacali, MD College of Medicine University of the Philippines Manila

Transcription

1 Drug Dosing in Renal Insufficiency Coralie Therese D. Dimacali, MD College of Medicine University of the Philippines Manila

2 Declaration of Conflict of Interest For today s lecture on Drug Dosing in Renal Insufficiency, I declare that I have no potential conflict of interest.

3 Objectives Discuss the effects of impaired kidney function on drug pharmacokinetics Describe the principles of pharmacotherapy in patients with renal disease Calculate drug dosages for patients with renal insufficiency

4 Oral absorption Parenteral drug administration Bioavailability Liver First-pass effect Systemic Circulation Protein-bound Free Elimination Kidneys Parent drug Active / Inactive metabolites Tissue receptor action

5 Drug Pharmacokinetics Bioavailability % of a drug dose that appears in the central circulation after oral administration compared to the IV route Drug distribution Drug metabolism Renal handling

6 Bioavailability in Renal Insufficiency Decreased drug absorption Nausea and vomiting Alkalinizing effect of salivary urea Use of PPIs and H 2 -receptor blockers Use of phosphate binders Gut edema Bacterial colonization Altered intestinal motility Altered hepatic first-pass metabolism

7 Bioavailability in CKD Drug absorption Absolute bioavailability rarely altered There Reduced: is no quantitative furosemide, pindolol strategy to predict changes Increased: for one Beta drug blockers, based dihydrocodeine, on data from dextropropoxyphene another in the same class Alterations in peak concentration (C max ) and time at which peak concentration is attained (T max )

8 Drug Pharmacokinetics Bioavailability Drug Distribution Volume of distribution (V d ) ratio of administered dose to the resulting plasma concentration in equilibrium V d = Dose Blood concentration Useful for predicting loading doses Plasma protein binding

9 Volume of distribution (V d ) in CKD Increased V d Edema and ascites Hypoalbuminemia Potentially decrease plasma drug levels of water-soluble and protein-bound drugs Decreased V d Muscle wasting Volume depletion Potentially increase plasma drug levels of water-soluble drugs

10 Plasma protein binding in CKD Acidic drugs have reduced plasma protein binding due to decreased albumin concentration and albumin affinity Unbound fractions may increase Increased drug toxicity Increased drug metabolism Lower drug plasma concentrations Altered protein binding may decrease T 1/2

11 Drug Pharmacokinetics Bioavailability Drug distribution Drug metabolism

12 Drug metabolism in CKD Slowing down of reduction and hydrolysis reactions Normal rates of glucuronidation, sulfation, Since there is significant patient variation, no conjugation and microsomal oxidation reactions prior assumptions will substitute for careful Consider adverse effects of pharmacologically clinical evaluation. active metabolites Seizures from meperidine Peripheral neuropathy from nitrofurantoin Respiratory depression from morphine

13 Drug Pharmacokinetics Bioavailability Drug distribution Drug metabolism Renal handling of drugs

14 Renal handling of drugs Renal excretion dependent on: Glomerular filtration rate (GFR) Molecular size Protein binding Tubular secretion May compensate for decreased protein binding Tubular reabsoprtion As rate of creatinine clearance (Cl Cr ) decreases, drugs dependent on tubular secretion are also excreted more slowly. The Cl Cr is a reasonable estimate of GFR and the tubular capacity for drug excretion.

15 Renal handling of drugs in CKD Decreased drug clearance Prolonged plasma half-life of drugs Accumulation of active drug metabolites Decreases in renal drug metabolism Changes in drug distribution: protein binding

16 Drug metabolism and drug handling in AKI Changes in metabolism There are large gaps in knowledge of Delayed drug metabolism drug Variable metabolism effect on hepatic and metabolic disposition activity in patients with multiorgan dysfunction Reduced drug clearance syndrome, multisystem organ failure Hypoxia and Decreased AKI; thus, protein synthesis patients are at risk of underdosing and overdosing. Competitive inhibition from medications Decreased hepatic perfusion

17 Mathematics of drug elimination Total body drug clearance = Drug dose AUC Renal clearance = Total amount of drug in urine Plasma drug concentration Renal clearance rate = Clearance Sample collection time T 1/2 = V d x Drug clearance

18 Application of Pharmacokinetic Parameters Parameter Bioavailability (F) Volume of distribution (V d ) Clearance (C) Half-life (T 1/2 ) Clinical Application Determines amount of drug reaching systemic circulation and amount at site of action Determines size of a loading dose Determines maintenance dose Determines amount of time needed to reach steady-state serum concentrations

19 Approach to adjust drug dosage 1. Obtain history and relevant clinical information. 2. Estimate GFR. 3. Review current medications. 4. Calculate individualized treatment regimen. 5. Monitor. 6. Revise regimen. KDIGO 2011

20 Assessment of kidney function GFR should be standard measure to evaluate kidney function for drug dosing purposes Clinicians should use the most accurate method/tool to assess kidney function for the individual patient KDIGO 2011

21 Estimation of GFR and Creatinine Clearance Cockcroft and Gault Cl Cr = (140 age) x Wt (kg) S Cr (mg/dl) x 72 x 0.85 (F) MDRD Study Equation GFR = x SCr x Age x [black] x [female]

22 Estimation of GFR and Creatinine Clearance CKD-EPI formula GFR = 141 x min(scr/κ,1) α x max(scr/ κ,1) x Age x [black] x [female] κ = 0.7 [females], 0.9 [males] α = [females], [males] Min = minimum of SCr/κ or 1 Max = maximum of SCr/ κ or 1 Age = measured in years

23 Estimation of GFR in AKI No estimating equations can provide an accurate estimate of GFR in AKI Timed clearances of creatinine and urea may be particularly of value for AKI Measure creatinine clearance with incorporation of mean of the beginning and ending serum creatinine value as an estimate of GFR KDIGO 2011

24 Goals of therapy Maintain efficacy while avoiding drug accumulation and associated adverse reactions. Maintain peak, trough or average steady-state drug concentration Optimize time above the MIC or ratio of AUC to MIC

25 Prescribing for a patient with renal dysfunction Ascertain level of renal function (% normal Cl Cr ) Establish integrity of liver metabolism Establish loading dose Maintenance dose: dose reduction vs interval extension Check for drug interactions Decide on blood level monitoring

26 Calculating individualized regimen Loading dose (LD) required if: drug has a long half-life there is need to rapidly achieve desired steady-state concentration volume of distribution (VD) is significantly increased LD P t = Usual LD x Vd Pt Normal Vd

27 Calculating individualized regimen Generally no change in LD EXCEPT for digoxin (50-75% of usual LD due to reduced Vd in renal failure) With volume contraction, lower standard LD of aminoglycosides by 20-25% to avoid toxicity In AKI, increased Vd of many drugs, especially hydrophilic antibiotics (Beta lactams, cephalosporins, penems) necessitates administration of aggressive loading doses (25-50% greater)

28 Calculating individualized regimen Maintenance dose Prolonging dose interval and maintaining same dose results in achievement of similar peak and trough concentrations and AUC Adjust to patient s renal function, as reflected by the drug s T 1/2 Initiate at normal or near-normal dosage regiments considering the positive fluid balance in early AKI

29 Calculating individualized regimen Maintenance dose Changing dosing interval Normal Cl Cr Dosing interval = x Normal interval Patient s Cl Cr Reducing dose given at standard intervals Dose = Patient s Cl Cr Normal Cl Cr x Normal dose

30 Calculating individualized regimen Maintenance dose Changing dosing interval 100 Dosing interval = x 8 hours = 40 hrs. 20 Reducing dose given at standard intervals 20 Dose = x 1000 mg = 200 mg 100

31 ke = / T 1/2 Dtsch Arztebl Int 2010; 107(37):

32 Calculating individualized regimen Dettli s proportionality rules: Rule 1: Dose of a drug must be reduced in inverse proportion to the T1/2 Rule 2: The interval (Tau) between doses must be prolonged proportionally to the T1/2 D D norm. T1/2 norm = Tau Tau norm T1/2

33 Calculating individualized regimen Dettli s proportionality rules: If dosing interval unchanged, AUC same but with higher trough values may prompt physician to wrongly lower the dose Implies absurdly low doses or wide intervals between doses

34 Calculating individualized regimen Halving rule of Kunin: Starting dose should be the same as the normal dose, and thereafter half the starting dose should be given at intervals equal to one half-life. If the half-life is shorter than the dosing interval, dose adjustment is usually unnecessary. Achieves effective peak levels but markedly higher trough levels more adverse effects.

35 Dtsch Arztebl Int 2010; 107(37):

36 Calculating individualized regimen Start low, go slow vs. Go fast, start high

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38 Drug dosing considerations for CKD Drug dosing recommendations may be different from original pharmacokinetic study due to variability in serum creatinine determinations Use the most appropriate tool to assess kidney function Drug dosages should be adjusted according to FDA or EMA approved product labeling KDIGO 2011

39 Drug dosing considerations for CKD Peer-reviewed literature recommendations should be used to guide drug-dosage adjustments Obese CKD patients with large variations in protein levels should have drug dosage individualized based on best available evidence. KDIGO 2011

40 Drug level monitoring Ensures therapeutic levels while avoiding toxicity Measurement of serum drug concentrations should be done especially for drugs with a narrow therapeutic range Drug assays only measure total blood concentrations and may underestimate plasma levels or the active or free form of the drug If not possible, dosage adjustments should be done in the presence of excessive pharmacologic effects or toxicity

41 Drug dosing considerations for HD Dose should be given post-hd. Consider supplementary dose in addition to the dose adjusted to kidney failure after HD. Supplementary dose derived from studies of low-flux membranes should be empirically increased by 50% when using hi-flux dialyzers. Extended dialysis regimens with high diffusive membranes increase drug clearance and supplementary dose may need to be increased. KDIGO 2011

42 Drug dosing considerations for PD Perform antibiotic loading by an extended cycle in CAPD and APD Transperitoneal For most drugs drug in clinical movement use, may there be is less little effective in the acute phase of peritoneal evidence infection when of significant inflammation-related drug removal capillary during hyperperfusion subsides chronic PD. Short dwell times in APD may prevent accumulation of antibiotic in the peritoneal cavity. Monitoring of drug blood levels is advocated. KDIGO 2011

43 Key points Renal dysfunction may result in altered pharmacokinetics and pharmacodynamics of individual drugs. The goal of therapy is to maintain efficacy while avoiding drug accumulation and associated adverse effects. An individualized approach is recommended, taking into consideration the integrity of other organ systems and potential drug interactions.

44 Key points Monitoring drug levels may be necessary to ensure therapeutic levels while avoiding toxicity. Physicians should be vigilant in recognizing adverse events. In the intensive care unit, a Go fast, start high policy avoids subtherapeutic blood levels.

45 Key points Consider giving scheduled doses after HD sessions OR give supplemental doses immediately post HD For most drugs in clinical use, there is little evidence of significant drug removal during chronic PD.

46 References Am Fam Physician 2007; 75:

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