drug dosing in renal insufficiency - philippine college of ... · drug dosing in renal...

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

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.

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

Oral absorption

Elimination

Parenteral drug administration

Tissue receptor action

Systemic Circulation

Protein-bound

Free

Liver First-pass effect

Bioavailability

Kidneys

Parent drug

Active / Inactive metabolites

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

Bioavailability in Renal Insufficiency

Decreased drug absorption Nausea and vomiting Alkalinizing effect of salivary urea Use of PPIs and H2-receptor blockers Use of phosphate binders Gut edema Bacterial colonization Altered intestinal motility

Altered hepatic first-pass metabolism

Bioavailability in CKD

Drug absorption Absolute bioavailability rarely altered

Reduced: furosemide, pindolol

Increased: Beta blockers, dihydrocodeine, dextropropoxyphene

Alterations in peak concentration (Cmax) and time at which peak concentration is attained (Tmax)

There is no quantitative strategy to predict changes for one drug based on data from

another in the same class


Bioavailability Drug Distribution

Volume of distribution (Vd) ratio of administered dose to the resulting plasma

concentration in equilibrium Dose Blood concentration Useful for predicting loading doses

Plasma protein binding

Vd =

Volume of distribution (Vd) in CKD

Increased Vd

Edema and ascites Hypoalbuminemia Potentially decrease

plasma drug levels of water-soluble and protein-bound drugs

Decreased Vd

Muscle wasting Volume depletion Potentially increase

plasma drug levels of water-soluble drugs

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 T1/2


Bioavailability Drug distribution Drug metabolism

Drug metabolism in CKD Slowing down of reduction and hydrolysis

reactions Normal rates of glucuronidation, sulfation,

conjugation and microsomal oxidation reactions Consider adverse effects of pharmacologically

active metabolites Seizures from meperidine Peripheral neuropathy from nitrofurantoin Respiratory depression from morphine

Since there is significant patient variation, no prior assumptions will substitute for careful

clinical evaluation.


Bioavailability Drug distribution Drug metabolism Renal handling of drugs

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 (ClCr) decreases, drugs dependent on tubular secretion are also excreted more slowly.

The ClCr is a reasonable estimate of GFR and the tubular capacity for drug excretion.

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

Drug metabolism and drug handling in AKI Changes in metabolism

Delayed drug metabolism

Variable effect on hepatic metabolic activity

Reduced drug clearance Hypoxia

Decreased protein synthesis

Competitive inhibition from medications

Decreased hepatic perfusion

There are large gaps in knowledge of drug metabolism and disposition in

patients with multiorgan dysfunction syndrome, multisystem organ failure and AKI; thus, patients are at risk of

underdosing and overdosing.

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

T1/2 = Vd x 0.693 Drug clearance

Application of Pharmacokinetic Parameters

Parameter Clinical Application Bioavailability (F) Determines amount of drug

reaching systemic circulation and

amount at site of action

Volume of distribution (Vd) Determines size of a loading dose

Clearance (C) Determines maintenance dose

Half-life (T1/2) Determines amount of time

needed to reach steady-state

serum concentrations

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

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

Estimation of GFR and Creatinine Clearance Cockcroft and Gault

(140 – age) x Wt (kg) S Cr (mg/dl) x 72

MDRD Study Equation GFR = 175.6 x SCr -1.154 x Age-0.203 x 1.212 [black] x 0.742 [female]

ClCr = x 0.85 (F)

Estimation of GFR and Creatinine Clearance CKD-EPI formula GFR = 141 x min(SCr/κ,1)α x max(SCr/

κ,1)-1.209 x 0.993Age x 1.159 [black] x 1.018 [female]

κ = 0.7 [females], 0.9 [males] α = -0.329 [females], -0.411 [males] Min = minimum of SCr/κ or 1 Max = maximum of SCr/ κ or 1 Age = measured in years

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

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

Prescribing for a patient with renal dysfunction

Ascertain level of renal function (% normal ClCr)

Establish integrity of liver metabolism

Establish loading dose

Maintenance dose: dose reduction vs interval extension

Check for drug interactions

Decide on blood level monitoring

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

LDPt = Usual LD x VdPt Normal Vd


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)


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 T1/2

Initiate at normal or near-normal dosage regiments considering the positive fluid balance in early AKI


Maintenance dose Changing dosing interval

Normal ClCr

Patient’s ClCr

Reducing dose given at standard intervals

Patient’s ClCr

Normal ClCr

Dosing interval = x Normal interval

Dose = x Normal dose


Maintenance dose Changing dosing interval

100

20

Reducing dose given at standard intervals

20

100

Dosing interval = x 8 hours = 40 hrs.

Dose = x 1000 mg = 200 mg

Dtsch Arztebl Int 2010; 107(37): 647–56

ke = 0.693 / T1/2


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 Dnorm T1/2 norm

Tau Taunorm T1/2 = .


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


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.

Dtsch Arztebl Int 2010; 107(37): 647–56

“Go fast, start high”


“Start low, go slow”

vs.

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

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

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

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

Drug dosing considerations for PD

Perform antibiotic loading by an extended cycle in CAPD and APD

Transperitoneal drug movement may be less effective in the acute phase of peritoneal infection when inflammation-related capillary hyperperfusion subsides

Short dwell times in APD may prevent accumulation of antibiotic in the peritoneal cavity.

Monitoring of drug blood levels is advocated.

KDIGO 2011

For most drugs in clinical use, there is little evidence of significant drug removal during

chronic PD.

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.

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.

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.

References

Am Fam Physician 2007; 75:1487-96

drug dosing in renal insufficiency - philippine college of ... · drug dosing in renal...

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