Principles of Drug Dosing in CRRT

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Principles of Drug Dosing in CRRT

• Lisa Burry, BSc.Pharm, Pharm.D., FCCP
• Clinical Pharmacy Specialist /Associate Scientist
• Mount Sinai Hospital
• lburry_at_mtsinai.on.ca

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• FrEC ClEC / ClEC ClR ClNR
• ClHDF (Qf x S) (Qd x Sd)
• S Cuf / Cp

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Background

• ICU patients represent a very heterogeneous
  population with high illness severity failure
  of multiple organs.
• ICU patients frequently need complex drug
  therapies, many of which are vital require
  adequate dosing.
• Tolerance towards the toxic effects of drug
  overdosing is decreased in this population.
• Pharmacokinetics and pharmacodynamics are
  typically altered in this population in view of
  organ dysfunction.

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Background

• Available literature on the removal of individual
  drugs with CRRT is often limited to case
  reports/series
• the results are not generalizable in view of the
  wide variation in CRRT techniques, settings
  heterogeneity of the patients.
• Artificial models and predictions have limited
  clinical value.
• Therefore, determining the correct dose in ICU
  patients receiving CRRT is extremely difficult
  because extracorporeal drug removal is
  superimposed on the disturbed kinetics induced by
  critical illness.

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Starting with the basics

• Correct drug dosing during CRRT requires an
  understanding of basic kinetic parameters
  including protein binding (PB), volume of
  distribution (Vd), clearance (CL) half-life
  (T½).
• Prevalent critical illness-related kinetic
  changes include
• ? Vd of water-soluble drugs due to extra-cellular
  volume expansion.
• Altered PB (e.g. ? albumin)
• ? CL due to kidney and/or liver dysfunction
• ? Supranormal CL during the hyperdynamic phase of
  early sepsis.

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Factors determining extracorporeal solute removal

• Depends on drug CRRT treatment characteristics
• the physical principle used for solute
  transport, the membrane the settings of the
  dialysis or hemofiltration machine.
• Only a fraction of the drug that is present is
  available for removal
• Drugs with large Vd have less access to removal.
• Many drugs exhibit 2 or 3 compartment
  characteristics, with the plasma being the
  central compartment.
• Whether CRRT treatment has access to the deeper
  compartments depends on the relationship between
  the rate of CRRT removal the rate of transfer
  between compartments

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During IHD, rate of removal exceeds the
inter-compartmental transfer rebound Impact of
Vd on CRRT is smaller because of continuous
re-equilibration.
Mueller BA, Pasko DA. Artif Organs 200327808-14.
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CRRT Drug Removal Mechanisms

• Drug-membrane interactions
• Convection
• Diffusion

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1) Drug-membrane interactions

• Although most drug removal occurs through the
  membrane, some drugs may be eliminated by a
  membrane interaction.
• Relates to the drugs charge the Gibbs-Donan
  effect with concentration of negatively charged
  proteins along the membrane resulting in the
  retention of anionic drugs.

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Drug-membrane interactions

• These adsorptive phenomena are membrane drug
  dependent.
• Hydrophobic synthetic membranes have a high
  adsorptive capacity (e.g. sulfonated
  polyacrylonitrile) vs. cellulosetriacetate
  membranes
• Clinical importance has not been widely
  investigated, but is probably limited due to
  early saturation.

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2) ConvectionTransmembrane pressure gradient
Blood In
to waste
(from patient)
Repl. Solution
Blood Out
(to patient)
HIGH PRESS
LOW PRESS
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Convective Therapies

• Solute carried along with plasma water that is
  driven through the membrane by a pressure
  gradient.
• Independent of molecular weight (lt 15000 Da)
• as long as they can fit through membrane
• Good for clearance of middle molecules
• PB will be an important determinant

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Convective Therapies

• Drug removal relatively easy to calculate.
• The capacity of a drug to pass the membrane by
  convection is mathematically expressed in the
  sieving coefficient (S) or the ratio between the
  drug concentration in the ultrafiltrate (Cuf) and
  the plasma (Cp).

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Sieving Coefficient (S)

• The capacity of a drug to pass through the
  hemofilter membrane
• S Cuf / Cp
• Cuf Drug concentration in the
  ultrafiltrate
• Cp Drug concentration in the
  plasma
• S 1 Solute freely passes through
  the filter
• S 0 Solute does not pass through
  the filter

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Relationship Between Free Fraction (fu) and
Sieving Coefficient (SC)
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Influence of Pre or Post-dilution

• Post dilution hemofiltration
• depends on the filtration rate (Qf) and S.
• CLHFpost Qf x S
• Pre-dilution hemofiltration
• Blood entering the filter is diluted.
• Drug clearance will be lower than in
  post-dilution.
• Will be influenced by blood flow (Qb) and the
  pre-dilution substitution rate (Qspre).
• CLHFpre Qf x S x Qb/ (Qb Qspre)

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Determinants of Hemofiltration CL

• Protein binding - Only unbound drug passes
  through the filter
• PB changes in critical illness
• Adsorption of proteins and blood products onto
  filter
• Related to filter age
• Decreased efficiency of filter ?
• Whether S decreases over the lifetime of a
  hemofilter has not been thoroughly investigated.
  (Bouman et al CCM 2006)
• ? Vancomycin
• What about other clearances?
• Clearance total CLCRRT CL residual renal
  CL non-renal
• S equations only account for ClCRRT

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3) Diffusion Transmembrane concentration
gradient
to waste
Blood In
(from patient)
Dialysate Solution
Blood Out
(to patient)
(Diffusion)
HIGH CONC
LOW CONC
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Diffusive Therapies

• Hemodialysis uses diffusive solute transport that
  is based on a concentration gradient between
  blood and dialysate.
• Dependent on molecular weight (MW)
• Good clearance for small solute removal (lt500
  Daltons)
• diffusion rate inversely proportional to MW

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Diffusive Therapies

• Diffusive transmembrane transport is
  mathematically expressed in the dialysate
  saturation (Sd).
• Sd is derived by dividing the drug concentration
  in the dialysate outflow by plasma concentration.

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Dialysate Saturation (Sd)

• Countercurrent dialysate flow (10 - 30 ml/min) is
  always less than blood flow (100 - 200 ml/min).
• Allows complete equilibrium between blood serum
  and dialysate.
• Dialysate leaving filter will be 100 saturated
  with easily diffusible solutes.
• Diffusive clearance will equal dialysate flow.

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Dialysate Saturation (Sd)

• Sd Cd / Cp
• Cd drug concentration in the dialysate
• Cp drug concentration in the plasma
• Increasing molecular weight decreases speed of
  diffusion
• Increasing dialysate flow rate decreases time
  available for diffusion

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Dialysate Saturation (Sd)

• Efficiency of solute removal dependent on
• Blood flow (Qb)
• Dialysate flow (Qd)
• Filter type
• Membrane pore size
• Thickness (flux properties)
• Surface area
• Solute molecular weight
• Less good for larger solutes (MM, Vancomycin?)

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Dialysate Saturation (Sd)

• If Qf Qd, vancomycin clearance will be greater
  with hemofiltration than with hemodialysis.
• In continuous dialysis with a low Qd/Qb, small
  solutes have enough time to saturate the
  dialysate PB becomes the main determinant of
  Sd.
• Extracorporeal drug clearance with CVVHD (CLHD)
  depends on Sd and dialysate flow rate (Qd)

ClHD Qd x Sd
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Combing convection diffusionContinuous
Veno-Venous Hemodiafiltration
to waste
Blood In
(from patient)
Dialysate Solution
Repl. Solution
Blood Out
(to patient)
(Convection)
HIGH PRESS
LOW PRESS
(Diffusion)
HIGH CONC
LOW CONC
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Continuous Hemodiafiltration (CVVHDF)

• Hemofiltration clearance (ClHF Qf x S)
• Qf Ultrafiltration rate
• S Seiving coefficient
• Hemodialysis clearance (ClHD Qd x Sd)
• Qd Dialysate flow rate
• Sd Dialysate saturation
• Hemodialfiltration clearance
• ClHDF (Qf x S) (Qd x Sd)
• Simply adding the 2 together will overestimate
  clearance.

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Basic Principles

• Extracorporeal clearance (ClEC) is usually
  considered clinically significant only if its
  contribution to total body clearance exceeds 25 -
  30
• FrEC ClEC / ClEC ClR ClNR
• Not relevant for drugs with high non-renal
  clearance
• Only drug not bound to plasma proteins can be
  removed by extracorporeal procedures
• Recent use of higher doses of hemofiltration or
  dialysis increases the FrEC.
• A particular problem for semi-continuous
  high-efficiency treatments (SLED, pulse
  high-volume hemofiltration).

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Basic Principles

• Importance of ClNR can be illustrated with the
  example of 2 fluoroquinolones.
• Levofloxacin 35 PB low hepatic elimination
  (15-20)
• Moxifloxacin 50 PB mainly hepatic metabolism
  (80)
• Despite almost similar CLEC CVVH with Qf of 40
  mL/min in an anuric patient will require dosage
  adjustment for levofloxacin but not for
  moxifloxacin.

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Practical Approach

• Administration of a loading dose that only
  depends on the target plasma Vd does not
  typically require adaptation for CRRT.
• Adaptation of the maintenance dose (MD) to the
  reduced renal function.
• Augmentation of the maintenance dose in case of
  clinically important CLEC (FrEC gt 0.25).

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Supplemental Dose Based on Measured Plasma Level
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Adjusted Dose Based on Clearance Estimates

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CRRT Drug Removal Mechanisms

• Drug-membrane interactions
• Convection
• Diffusion

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Future research needed
ECMO
Ped CRRT
PLEX
MARS
SLED