drug dosing in dialysis · 2019. 6. 4. · ¤hemodialysis: prior to hd session ¤peritoneal...
TRANSCRIPT
DRUG DOSING IN DIALYSIS
Calvin J. Meaney, PharmD, BCPS Clinical Assistant Professor University at Buffalo School of Pharmacy and Pharmaceutical [email protected]
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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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Con
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n (m
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Time (hours)
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 [email protected]
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