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Principles of Drug Dosing in CRRT

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Correct drug dosing during CRRT requires an understanding of basic kinetic ... protein binding (PB), volume of distribution (Vd), clearance (CL) & half-life (T ... – PowerPoint PPT presentation

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Title: Principles of Drug Dosing in CRRT


1
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

2
  • FrEC ClEC / ClEC ClR ClNR
  • ClHDF (Qf x S) (Qd x Sd)
  • S Cuf / Cp

3
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.

4
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.

5
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.

6
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

7
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.
8
CRRT Drug Removal Mechanisms
  • Drug-membrane interactions
  • Convection
  • Diffusion

9
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.

10
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.

11
2) ConvectionTransmembrane pressure gradient
Blood In
to waste
(from patient)
Repl. Solution
Blood Out
(to patient)
HIGH PRESS
LOW PRESS
12
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

13
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).

14
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

15
Relationship Between Free Fraction (fu) and
Sieving Coefficient (SC)
16
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)

17
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

18
3) Diffusion Transmembrane concentration
gradient
to waste
Blood In
(from patient)
Dialysate Solution
Blood Out
(to patient)
(Diffusion)
HIGH CONC
LOW CONC
19
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

20
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.

21
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.

22
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

23
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?)

24
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
25
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
26
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.

27
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).

28
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.

29
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).

30
Supplemental Dose Based on Measured Plasma Level
31
Adjusted Dose Based on Clearance Estimates

32
CRRT Drug Removal Mechanisms
  • Drug-membrane interactions
  • Convection
  • Diffusion

33
Future research needed
ECMO
Ped CRRT
PLEX
MARS
SLED
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