Drug Dosing in

Hemodialysis
Katie Cardone, PharmD, BCACP, FNKF, FASN
Associate Professor of Pharmacy Practice

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Objectives
• Describe key considerations for designing drug dosing regimens in
patients on HD

• Develop an approach for finding information to inform drug dosing

decisions in patients on HD.

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Key Points
• Dialysis, Medication & Patient factors should be considered
when developing drug dosing regimens for patients on HD

• One Size Does Not Fit All

• Timing is important!

• Data are often limited.

• More studies are needed
• Primary literature often required
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“Is drug X removed by HD?”

“Can drug X be used in a patient on HD?”

“How is drug X dosed in HD?”

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Factors to consider…
• Medication

• Dialysis Procedure

• Patient

• Where to find this information?

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Clearance in Patients on Dialysis

𝐶𝐿=𝐶𝐿 𝑅 +𝐶𝐿 𝑁𝑅 +𝐶𝐿 𝐷𝑖𝑎𝑙𝑦𝑠𝑖𝑠

•   

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Example #1
A patient on HD requires vancomycin.

Loading dose: 1 gram at HD

Maintenance dose: 500 mg on subsequent doses at HD

What factors should be considered when selecting a dosage?

• Patient factors
• Severity of illness, infection type, patient size, scheduling
• Dialysis factors
• Filter, HD modality (frequency, duration)

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Drug-dosing considerations
Dialysis-Related Factors

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Dialysis-Related Factors in Drug Dosing
• Filter

• Schedule
• When dialysis occurs
• Frequency
• Duration

• Adequacy

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 HD Filters
• Conventional
• Small pores

• High Efficiency
• Large surface area
• Large or small pores

• High Flux
• Large pores
• Increased ‘middle molecule’ clearance (500 – 15K Daltons)

Boure´, Vanholder. Nephrol Dial Transplant 2004;19:293–6.

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Example #1
A patient on HD requires vancomycin.
Intermittent HD TIW
• Conventional Filter: 1000 mg Q7days

vs

• High flux filter: Much higher doses required

Zelenitsky et al. Clin Infect Dis 2012;55:527-33.

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Micromedex. Database on the internet. Truven Health Analytics; 2016.
Example #1
A patient on HD requires vancomycin.
Intermittent High-flux HD TIW
Patient Weight Loading Dose Maintenance Duration of
(kg) (mg) Dose Infusion
(mg) (min)

< 70 1000 500 60, 30

70 – 100 1250 750 90, 60
> 100 1500 1000 90, 60

Achievement of target trough concentrations

• 10 – 20 mg/L: 86%
• 15 – 20 mg/L: 35.2%
Zelenitsky et al. Clin Infect Dis 2012;55:527-33. 12
HD Prescription
• Intermittent / Conventional
• 3-4 sessions per week
• Daytime

• Frequent
• 5-7 sessions per week
• Daytime or nighttime, depending on duration

• Long
• Duration at least 5 hours
• Daytime or nighttime, depending on frequency and preference
National Kidney Foundation. Am J Kidney Dis. 2015;66(5):884-930. 13
HD Prescription
• Location
• In-center
• Home

• Assistance
• Fully assisted
• Partially assisted
• Self-care

National Kidney Foundation. Am J Kidney Dis. 2015;66(5):884-930. 14

HD Prescription
• BFR
• Standard
• Low flow <300 mL/min

• DFR
• Standard
• Low flow <500 mL/min

National Kidney Foundation. Am J Kidney Dis. 2015;66(5):884-930. 15

Dialysis Adequacy
• Kt/V
• Dimensionless number
• K= Dialyzer clearance of urea (L/h)
• t = dialysis duration (h)
• V= volume of distribution of urea (L); approx. total body water

Kt/V target = 1.4 (KDOQI 2015)

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National Kidney Foundation. Am J Kidney Dis. 2015;66(5):884-930.
Additional HD-related Factors
• HD filter reprocessing

• Access recirculation

• Drug Adsorption

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Example #1
A patient on HD requires vancomycin.

Scenario A: Patient receives conventional thrice weekly in-center HD

using a conventional filter x 3.5h per session

Scenario B: Patient receives short daily home HD Mon-Sat x 2.5h per

session using a high-flux filter

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Example #1
A patient on HD requires vancomycin.
• Short Daily HD (2.5-hour sessions, 6 days per week)
• LD 20 mg/kg with MD 10 mg/kg after every other SDHD

• Exact HD regimen may not be studied.

• TDM available (thankfully)

• Pre-HD “troughs”
• Do not check immediately post-HD due to rebound

Decker et al. Clin J Am Soc Nephrol 2010;5:1981-7. 19

Drug-dosing considerations
Medication-Related Factors

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Medication-Related Factors affecting HD Drug
Removal
• Molecular Weight / Size
• Larger = Less likely to be removed

• Protein Binding
• High degree of protein-binding = Less likely to be removed

• Volume of Distribution
• Large Vd = Less likely to be removed

• Water Solubility
• Not water soluble = Less likely to be removed

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Drug Exposure Changes in
ESRD
• Accumulation of parent drug and/or one or more
metabolites may occur.
• Absolute concentration changes (esp metabolites)
• AUC changes

• Patient exposed to new combination of substances ESRD

• PK? Normal Metabolite 2

20%
• PD? Metabolite 2
5%
Metabolite 1
15%
Drug X
45%

• Dialyzability
• Drug and metabolites?
Metabolite 1
Drug X 35%
80%
Example #2
Patient starting chronic HD using duloxetine.
• Duloxetine
• Highly protein bound (>90%)
• Hepatic metabolism to inactive metabolites
• Package insert:
• Mild to moderate renal impairment – no effect on drug
clearance

“Is duloxetine removed by HD?”

Cymbalta (duloxetine). Package insert. Eli Lilly. Indianapolis, IN. 2015. 23
Drug Dosing Considerations
• Pharmacokinetic Considerations
• Absorption
• Distribution
• Metabolism
• Elimination

• Pharmacodynamic Considerations
• Efficacy
• Safety

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Pharmacodynamic Properties
• Concentration-dependent

• Time-dependent

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Example #3
Aminoglycoside dosing in HD
• Properties
• 450 – 600 Da
• Low protein binding
• Small Vd

• Pharmacodynamic Target (Gram-negative infections)

• Concentration-dependent

Eschenauer et al. Semin Dial 2016;29:204-13. 26

Example #3
Aminoglycoside dosing in HD

• Traditional Dose Adjustment: Half dose post-HD

• Does not achieve pharmacodynamics target (peak)
• (Unclear whether this is optimal target in HD patients)

Eschenauer et al. Semin Dial 2016;29:204-13. 27

Adapted from: Eschenauer et al. Semin Dial 2016;29:204-13. 28
Adapted from: Eschenauer et al. Semin Dial 2016;29:204-13. 29
Adapted from: Eschenauer et al. Semin Dial 2016;29:204-13. 30
Adapted from: Eschenauer et al. Semin Dial 2016;29:204-13. 31
Drug-dosing considerations
Patient-Related Factors

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Patient-Level Considerations in HD
• Medication Regimen • Payment Issues
• Complex instructions / timing • Multiple dosages of the same drug
• Multiple medications
• Frequent drug interactions
• Comorbid illness
• Adherence
• Treatment
• Diet
• Medications

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Example #4
Intradialytic Hypotension
• The patient is a 76 y.o. woman with ESRD secondary to T2DM.
PMH includes T2DM x 35 yrs, HF and intradialytic hypotension.

• Home medications include:

• Losartan 50 mg QAM
• Carvedilol 25 mg BID
• Furosemide 40 mg QAM
• Insulin glargine 12 units HS
• Sevelamer carbonate 800 mg 2 tablets TID
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Example #4
Intradialytic Hypotension
• Carefully consider timing of BP medications
• Avoid peak concentration during HD

• Select anti-hypertensives that will be removed by HD

• Losartan, Carvedilol, Furosemide – not removed by HD
• Most ACEi removed by HD (exception fosinopril)

Levin et al. Kidney Int 2010;77:273-84 35

Example #5
Patient is non-adherent to BP medication
• The patient is a 52 y.o. A. A. man who frequently arrives for TIW HD
with SBP 175-200 mmHg. He is adherent to dialysis treatments, but
admits he sometimes forgets to take his morning medications.
• PMH: ESRD x3 yr; HTN, LVH
• Medications:
• Amlodipine 10 mg QAM
• Carvedilol 12.5 mg BID
• Minoxidil 5 mg BID
• Ramipril 5 mg QDay
• Clonidine 0.1 mg PRN at HD

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Example #4
Patient is non-adherent to BP medication
• Use of long-acting agents TIW after HD?

• Atenolol Properties
• Renal elimination (40-50% excreted unchanged in the urine)
• Half-Life 6-7 hours (normal renal fxn); 100 hours (anuric patients)
• Significantly removed by HD

Micromedex. Database on the internet. Truven Health Analytics; 2016. 37

 HDPAL Study
• Open-label study
• HD patients with LVH
• Patients randomized to lisinopril
(n = 100) or atenolol (n = 100)
TIW post-HD
• Home BP target <140/90 mmHg
• Atenolol group:
• Better BP control
• Less CV events
• Less HF hospitalizations

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Adapted from: Agarwal et al. Nephrol Dial Transplant 2014;29:672-681
Finding & Evaluating Data

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Dosing Recommendations in HD: Limitations
• Many resources provide dosing recommendations based on little data

• Clinical trials generally exclude patients on HD

• Data may be from small cohort of patients on HD

• Adverse event reporting often limited in patients with CKD

• Dosing may not be optimal for both AKI and CKD-5D patients.

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FDA Guidance for Industry
• Initially no guidance; Must rely on post-marketing data

• 1998: First guidance issued

• How to conduct studies in patients with renal impairment

• 2010: Proposed Update to 1998 Guidance

• Conduct studies for medications likely to be used in patients with CKD
(renally or non-renally cleared)
• Conduct studies in patients on HD
• Study PK of therapeutic proteins
• Categorize kidney fxn based on MDRD or C-G
• Change how information is presented in package inserts
References
• Primary Literature

• Secondary Sources

• Tertiary Sources

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Key Points
• Dialysis, Medication & Patient factors should be considered
when developing drug dosing regimens for patients on HD

• One Size Does Not Fit All

• Timing is important!

• Data are often limited.

• More studies are needed
• Primary literature often required
43
Objectives
• Describe key considerations for designing drug dosing regimens in
patients on HD

• Develop an approach for finding information to inform drug dosing

decisions in patients on HD.

44