DRUG DOSING IN DIALYSIS

Calvin J. Meaney, PharmD, BCPS Clinical Assistant Professor University at Buffalo School of Pharmacy and Pharmaceutical Sciencescjmeaney@buffalo.edu

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Disclosures2

¨ I have no relevant financial relationships to disclose

1. Differentiate peritoneal and hemodialysis modalities in terms of patient perspective and drug removal

2. Describe pharmacologic properties that affect drug removal via dialysis

3. Identify what types of drugs should be given before, during, and after dialysis

4. Characterize the indication and appropriate clinical use of drugs used to treat complications of end-stage renal disease:

1. Mineral bone disease: Phosphate binders, active vitamin D, calcimimetics

2. Anemia: Iron supplements, erythropoiesis-stimulating agents

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Objectives

4 Dialysis Modalities

Terminology5

¨ Dialysis: the removal of waste products and fluid from the body on the basis of particle differences in their ability to pass through a membrane.

¨ CKD 5: GFR<15ml/min¤ Dialysis (CKD5D) or non-dialysis (CKD5ND)

¨ End-stage renal disease (ESRD)¤ Requirement of dialysis modality for >3 months to sustain life¤ Typically occurs once GFR<15ml/min¤ Related to diagnosis coding and payment structures

Methods of Drug Removal During DialysisDiffusion

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¨ Diffusion – random movement of particles in all directions¤ Particles tend to move across

concentration gradients¤ Temperature, surface area,

flux, diffusion coefficient, and membrane thickness

http://www.fmc-ag.com/36.htm

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¨ Convection – fluid movement due to pressure gradient¤ Ultrafiltration=fluid removal¤ “Solvent drag”¤ Independent of

concentration gradient or molecular size

http://www.toltec.biz/how_hemodialysis_works.htm

Methods of Drug Removal During DialysisConvection

Dialysis Modalities8

Hemodialysis (HD)

Peritoneal Dialysis (PD)

Continuous Renal Replacement

Therapy (CRRT)

Hemodialysis9

Hemodialysis10

Hemodialysis Access11

1. Arteriovenous fistula2. Arteriovenous graft3. Central venous catheter

Higher risk of: infection, thrombosis, inadequate dialysis (slower blood flow)

Hemodialysis Access – Fistula 12

¨ Preferred long-term access type¨ Requires 6-12 weeks to mature after surgical

creation¨ Lowest infection/thrombosis risk

Hemodialysis Access – Graft 13

Hemodialysis Access – Catheter 14

¨ Last-line option for hemodialysis access¨ Highest risk of infection, thrombosis¨ Used for short-term, i.e. bridge to AV fistula

Peritoneal Dialysis15

¨ CAPD: Continuous ambulatory peritoneal dialysis¨ Automated PD: machine assisted night-time PD with cycler

Peritoneal Dialysis Access - Catheter16

Continuous Renal Replacement Therapy17 Heintz B et al. Pharmacotherapy 2009;29:562-77.

Drug Dosing Considerations with Dialysis18

Factors Influencing Drug Removal by Dialysis

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Drug Factors* Patient Factors* Dialysis Factors

Molecular weight (size) Albumin Conventional vs. High Flux

Protein binding Fluid status Membrane type (cellulose,polyamide, polysulfone, polyacrylonitrile, polymethylmethacrylate)

Volume of distribution(Lipophilicity)

Blood pressure Blood and dialysate flow rates, length of dialysis

*Drug & Patient Factors are the same for all methods of dialysis: HD, PD, CRRT, etc.

• Drug removal is increased by:• Small molecular weight• Low protein binding• Small volume of distribution (low lipophilicity)• High-flux hemodialysis• Semi-synthetic and synthetic dialysis membranes

TDM Considerations20

¨ Timing of drug concentration monitoring:¤ Hemodialysis: Prior to HD session¤ Peritoneal dialysis: Random (refer to specific medications)¤ CRRT: Random (refer to specific medications)

¨ Hemodialysis procedure:1. Obtain drug concentrations prior to HD2. Estimate intra-HD drug removal3. Base additional doses on estimated post-HD concentration

and target concentration¨ E.g. Pre-HD vancomycin 22mg/L

¤ Intra-HD removal ~40% à post-HD 13mg/L¤ Re-dose 500-1000mg post-HD to achieve therapeutic

concentration (15-20mg/L)

Post-Dialysis Equilibrium21

¨ Re-distribution of drug from tissue stores and/or protein binding sites; fluid shifts

¨ Fluctuating drug concentrations post-HD

¨ Unreliable for TDM

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Post-Hemodialysis Equilibrium

4-6 hours of re-distribution phase

Dotted line reflects “true” post-HD concentrationExample Conc vs. Time curve for vancomycin

Practical Dosing Considerations:Dialysis Modalities

¨ 3 sessions per week¨ ~4 hours per session¨ Dialysis machine removes

solutes, toxins, and fluid

¨ Continuous ambulatory peritoneal dialysis (CAPD)

¨ Automatic cycler peritoneal dialysis (nighttime)

¨ Peritoneal membrane used for removal of solutes, toxins, and fluid

Hemodialysis Peritoneal Dialysis

Practical Dosing Considerations:Hemodialysis¨ Dosing is complex!

¤ Assume nothing¤ Always look-up

¨ In general should dose drug post-hemodialysis if possible¨ If significant amount of drug removed will need to give a

supplemental dose after hemodialysis¨ Therapeutic drug monitoring:

¤ Obtain drug concentrations prior to hemodialysis¤ Post-dialysis fluid shifts à unreliable drug concentrations for 4-6 hours

Hemodialysis Drug Removal24

Drug removal

Conventional• ≤1,000 Da

High-Flux• ≤20,000 Da

http://healthinformatics.wikispaces.com/Dialysis

Hemodialysis Dosing ConsiderationsTimeline

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Hemodialysis

Hold pre-HD anti-hypertensive drugs

Check drug concentrations

Administer medications with significant HD

removal (e.g. antibiotics)

Supplemental dosing

Intra-dialytic medications:

Erythropoiesis stimulating agents (ESAs), activated

vitamin Ds

¨ Common Schedule: Three times per week, 3-4 hours per session¨ Novel Schedules: home hemodialysis, night-time hemodialysis

Hemodialysis Dosing ConsiderationsCase Application

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¨ TM is a 62yo AAM with ESRD on HD MWF, HTN, seizure disorder, Afib, CAD, HF with EF 30-35%.

¨ Medications:¤ Nifedipine ER 60mg PO BID¤ Carvedilol 12.5mg PO BID¤ Lisinopril 20mg PO daily¤ Levetiracetam (Keppra®) 1000mg PO QAM¤ Phenytoin 100mg PO TID¤ Atorvastatin 40mg PO daily¤ Epoetin alfa 5,000 units IV MWF with dialysis

¨ How would you instruct TM to take his medications surrounding dialysis?

Hemodialysis Dosing ConsiderationsGeneral Rules

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¨ General Rule: Dose drugs with significant removal post-HD

¨ Obtain drug concentrations prior to HD¨ Hold pre-HD anti-hypertensive agents¨ Supplemental dose: replacement of the amount of drug

that was removed by HD procedure¤ Determine need for supplemental dose:

n >30-40% removal by HD? à yes n Supplemental dose=normal dose X fraction removed by HDn E.g. Keppra undergoes 50% hemodialysis removal

n Suppl dose=1000mg x 50% = 500mg post-HD

Hemodialysis Dosing ConsiderationsTimeline

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Hemodialysis

Hold pre-HD anti-hypertensive drugs

Check drug concentrations

Administer medications with significant HD

removal (e.g. antibiotics)

Supplemental dosing

Hold nifedipine and carvedilol

Check phenytoin concentration

Supplemental dosing of Keppra 500mg

Epoetin alfa to be given with dialysis

Practical Dosing Considerations:Peritoneal Dialysis

¨ Drug removal is not as efficient as with HD¨ Significant removal occurs if:

¤ Very low VD¤ Low protein binding¤ Few other routes of elimination¤ Above factors, and rapid exchanges

¨ If giving drug by peritoneal route (i.e. to treat peritonitis) be aware that can achieve potentially toxic serum levels (eg. aminoglycosides 40-50%)

Peritoneal DialysisSystemic Drug Removal

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¨ Substantially less drug removal than with hemodialysis¤ 10ml/min maximum clearance¤ Dosing guidelines based on CrCl<15ml/min range

¨ Majority of pores are small: 40-60 Å, account for 95% of surface area¤ Large pores (100-200Å) account for 3% of surface area

L Goldman and AE Schafer. Goldman’s Cecil Medicine Volume 2, 24th Edition, Elsevier. 2012. Figure 133-2.

http://www.webmd.com/a-to-z-guides/peritoneal-dialysis

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Peritoneal DialysisPeritoneal/Systemic Drug Administration

Drug

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Peritoneal DialysisPeritoneal/Systemic Drug Administration

Drug

¨ Treatment of peritonitis, systemic infections, hyperglycemia, anemia

¨ Stability and compatibility of drug in dialysate fluid is critical (see de Vin et al. Perit Dial Int 2009;29(1):5-15.)

¨ Systemic absorption mediated via bi-directional transport of peritoneal membrane¤ Reduced absorption:

n Post-acute phase of peritoneal infection when inflammation related capillary hyperperfusion subsides

http://www.webmd.com/a-to-z-guides/peritoneal-dialysis

¨ Monitor systemic drug concentrations if possible

Vancomycin Dosing with Dialysis33

VancomycinPrinciples

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Bactericidal antibacterial

agent

Gram positive coverage• MRSA

Growing resistance concerns

Optimize AUC/MIC http://www.medscape.com/viewarticle/479024_2

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¨ Initial dose¤ 15-20mg/kg

¤ 25-30mg/kg loading dose if severe infection

¨ Maintenance dose¤ 5-15mg/kg¤ Heavily depends on

pre-HD concentration, severity of illness, and site of infection

Pharmacokinetic Parameters for Vancomycin

Volume of distribution 0.7L/kg of actual body weight

Clearance ~ CrCl

Elimination 90% unchanged in urine10% non renal routes

Half-lifeNormal renal functionAnephric

6-10hr200-250hr

Protein bindingESRD

30-55%10-25%

Target peak concentrations 30-40mg/L

Target trough concentrations 10-20mg/L

VancomycinPharmacokinetics

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¨ ESRD à ↑Vd ~30%, Markedly ↓CL and ↑T½

¨ Modern hemodialysis removes 33-65% of vancomycin¨ Post-HD redistribution¨ Draw pre-HD concentration

¤ Predict 33-50% removal¤ Re-dose post-HD if predicted concentration <15-20mg/L¤ 10-15mg/kg Actual BW post-HD dose

VancomycinDialysis Considerations

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¨ Case: TM, 62yo AAM, ESRD on HD.Presents with SIRS + presumed AV fistula infection.

¨ 68” (173cm) 185lbs (84kg)¨ Design an initial vancomycin regimen

¨ 15-20mg/kg x 84kg = 1260-1680mg1500mg IV x1 loading dosing

¨ Follow-up vancomycin concentration prior to next HD session¤ Target concentration 15-20mg/L

VancomycinInitial Dosing, Method 1

Use ACTUAL BODY WEIGHT for Vancomycin

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¨ Target pre-HD concentration: 15-20mg/L¨ Target peak concentration (immediate post-dose)=

target pre-HD concentration X 1.2 = 18-24

¨ Vd = 0.7L/kg x 84kg = 58.8L¨ Dose = Desired Concentration X Vd

= 18mg/L X 58.8L = 1058mg= 24mg/L x 58.8L = 1411mg

¨ Dose: 1500mg IV x1

VancomycinInitial Dosing, Method 2

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Vancomycin Dosing in Hemodiaylsis

HD removes ≈ 40%

Target Range

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¨ 5-15mg/kg following hemodialysis

¨ Guided by therapeutic drug monitoring¤ Trough goal 10-20mg/L (15-20mg/L)¤ True “Trough” concentrations do NOT reflect pre-HD concentration

¨ Ultimate goal: AUC/MIC > 400¤ Over 24hr period¤ Continuous concentration of 17mg/L with MIC of 1mg/L à

AUC/MIC=408 (17 x 24)

VancomycinMaintenance Dosing

Vancomycin pre-HD concentration (mcg/ml)

Post-dialysis vancomycin dose (mg)

Post-dialysis vancomycin dose (mg/kg )*

< 5 2000 15-20mg/kg5-15 1500 15mg/kg15-20 1000 10-15mg/kg20-25 500 5-10mg/kg> 25 Hold Hold

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¨ TM received a 1500mg IV x1 loading dose¨ Pre-HD concentration was 19mg/L¨ Peripheral blood cultures positive for MRSA¨ What dose would you order post-HD?

VancomycinMaintenance Dosing

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Vancomycin Dosing in Hemodiaylsis

HD removes ≈ 40%

Target Range 15-20mg/L

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¨ 19mg/L x 0.6 = 11.4mg/L Sub-therapeutic¨ Desired post-HD concentration: 25mg/L¨ Dose = ∆Conc X Vd = (25-11.4) x 58.8L = 800mg

750mg or 1000mg IV following dialysis

¨ Alternatively: 10-15mg/kg x 84kg=840-1260mg

VancomycinMaintenance Dosing

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Vancomycin Dosing in Hemodiaylsis

HD removes ≈ 40%

Target Range 15-20mg/L

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VancomycinHemodialysis Dosing Scheme

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HD removes ≈ 40%

Target Range 15-20mg/L

MIC=1mg/L

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CRRT Modality Loading Dose Maintenance Dose

CVVH 15-25mg/kg 10-15mg/kg Q24-48hr

CVVHD 15-25mg/kg 10-15mg/kg Q24hr

CVVHDF 15-25mg/kg 7.5-10mg/kg Q12hr

VancomycinCRRT and Peritoneal Dialysis Dosing

Peritoneal Dialysis

¨ ~38-50% Systemic absorption¨ 15-30mg/L via peritoneal dialysate solution¨ 25-30mg/kg IV or IP load, followed by 7.5-10mg/kg IV

or IP Q48-72hrs¤ Monitoring of systemic levels Q2-3 days

Case 144

¨ PB is a 58-year old male (69”, 80kg) with end-stage renal disease on hemodialysis MWF who presents to the ED with 2 days of fever and chills.

¨ PMH: ESRD, DM, CAD s/p PCI x2 in 2013, seizure disorder, and insomnia

¨ Vital Signs: BP 110/70mmHg, HR 115bpm, RR 18bpm, T 102F

¨ Home Medications: sevelamer carbonate 2,400mg PO TID with meals, atorvastatin 20mg PO QHS, aspirin 81mg PO daily, metoprolol XL 50mg PO daily, levetiracetam 1000mg PO QAM, zolpidem 10mg PO QHS

¨ Diagnosis and Initial Management: PB is diagnosed with suspected bacteremia and admitted to the medical floor for IV antibiotics and close monitoring.

Case 1 Question 145

¨ PB is given a loading dose of vancomycin 1.5g IV x1 today (Wednesday) after his routine dialysis.

¨ A vancomycin concentration of 15mg/L is observed on Friday before dialysis. At this point, a diagnosis of MRSA bacteremia is confirmed and PB is showing initial improvement to antibiotics.

¨ What do you recommend for additional vancomycin therapy?

Case 1 Question 146

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Vancomycin Dosing in Hemodiaylsis

HD removes ≈ 40%

Target Range 15-20mg/L

Case 1 Question 147

¨ 15mg/L x 40% dialysis removal = 6mg/L removed¨ Post-HD concentration ~ 9mg/L

¤ SUB-THERAPEUTIC¤ Need to re-dose to attain target peak of 20-25mg/L¤ This target peak is likely to achieve a pre-dialysis target of

15-20mg/L prior to the next dialysis sessionn Residual renal and Non-renal clearance

¨ Dose = ∆Concentration x VD¤ ∆Concentration = Target – Current = 25mg/L-9mg/L =

16mg/L¤ VD=0.7L/kg x 80kg = 56L¤ =16mg/L x 56L = 896mg

Case 1 Question 148

¨ Answer: provide vancomycin 750-1000mg IV x1 dose following dialysis on Friday¤ Follow-up with random pre-dialysis concentration on Monday¤ Monitor for toxicities: ototoxicity, red man’s syndrome¤ Monitor for efficacy: WBC, fever curve, repeat blood cultures, BP etc.

Case 1 Question 449

¨ Levetiracetam is an anti-epileptic drug that is normally dosed at 1000mg once daily in end-stage renal disease. It undergoes removal via hemodialysis by approximately 50%. What is the best option to ensure effective pharmacotherapy of levetiracetam in PB?A. Monitor for seizure activityB. Provide levetiracetam 1000mg PO BIDC. Provide levetiracetam 500mg PO post-dialysisD. Provide levetiracetam 500mg PO BIDE. A and C

Medication Management

Complications of ESRD50

CKD-Mineral Bone Disease

¨ Phosphate binder comparison: Calcium based, non-calcium based, iron-based

¨ When to use active vitamin D vs calcimimetic

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Anemia52

¨ Oral vs. intravenous iron¨ ESAs-target hgb and risks¨ New agents: HIF-PH inhibitors

DRUG DOSING IN DIALYSIS

Calvin J. Meaney, PharmD, BCPS Clinical Assistant Professor cjmeaney@buffalo.edu

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