Therapeutic Drug Monitoring of Immunosuppressant Drug

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Therapeutic Drug Monitoring of Immunosuppressant
Drug

• Todd K Fox
• Medical Advisor
• Novartis Pharmaceuticals Canada
• email address toddk.fox_at_novartis.com

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Outline

• Introduction
• Pharmacology
• Cyclosporine, Tacrolimus, Sirolimus, Mycophenolic
  Acid
• Pharmacokinetics
• High Variable Drug
• Metabolized via Liver - Cyp 3A4
• P-Glycoprotein Substrate/Inhibitor
• Therapeutic Drug Monitoring

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Introduction

• Clinical Pharmacokinetics
• Is the discipline that describes the absorption,
  distribution, metabolism and elimination of the
  drug in patients requiring drug therapy.
• What the body does to the drug.

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Introduction

• Pharmacodymics
• The relationship between the concentration of a
  drug and the response obtained in a patient.
• What the drug does to the body.

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Introduction

• Therapeutic Drug Monitoring
• Measured drug levels to ensure appropriate effect
  or prevent toxic effect
• Assumes a concentration-effect correlation exists
  and is known

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Narrow Therapeutic Window
Drug A has a narrow therapeutic window
A
Probability ()
B
Therapeutic Response
Adverse Events
Drug Concentration (ng/mL)
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Introduction

• Immunosuppresants
• Narrow therapeutic index
• Pharmcodynamic Endpoints are crude

Rejection
Toxicity
Biopsy
Nephrotoxicity Neurotoxicity
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Pharmacology(Pharmacodynamics)
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PMN cells,
APC
NK cells,
IL-1
basophils, etc.
IL-2
Tc cell
Th cell
B cell
Cytotoxic Activity
Phagocytosis
Graft Rejection/Destruction
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Steroids
Cyclosporine, Tacrolimus
APC
IL-1
Aza, MMF, Brequinar, ERL 080
IL-2
CD3,CD25 Abs
Tc cell
Th cell
B cell
Aza, MMF, Brequinar, ERL 080
Sirolimus, RAD
Cytotoxic Activity
Phagocytosis
Graft Rejection/Destruction
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Calcineurin Inhibitors Cyclosporine Tacrolimus
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Antiproliferative Agents Sirolimus
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Cell cycle (Lymphocytes)
Mitosis
G2
G0

• DNA Synthesis

G1
S-phase
Hypoxanthine-guanine Phosphoribosyltransferase
Synthesis of Purines
Guanosine Monophosphate
Inosine Monophosphate
Guanine
5-Phosphoribosyl-1-Phosphate
Salvage Pathway

• Inosine
• Monophosphate
• Dehydrogenase
• (IMPDH)

Mycophenolate inhibits IMPDH
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Cell cycle (Lymphocytes)
Mitosis
G2
G0
Cyclosporine Tacrolimus
G1
S-phase
Sirolimus
Mycophenolic Acid
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Summary of Immunosuppresant Pharmacology
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Pharmacokinetics Cyclosporine, Tacrolimus,
Sirolimus, Mycophenolic Acid

• High Variable Drug
• Metabolized via Liver - Cyp 3A4
• P-Glycoprotein Substrate/Inhibitor

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Highly Variable Drugs
1. AUC 2. Cmax 3. Tmax
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Highly Variable Drugs
AUC0-4
1400
1200
AUC0-12
1000
800
Cyclosporine Concentration (ng/mL)
600
400
200
0
0
2
4
6
8
10
12
Hours Post-Dose
C-0
C-2
Extent and rate of absorption are highly
variable.Patient differences are highlighted in
the absorption phase.
Adapted from Johnston A et al. Transplant Proc.
20003253S-56S.
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Cyclosporine Pharmacokinetics Differs by Organ
Recipient Type
Dose-Normalised AUC(ngh/mL/mg)
De Novo Renal1
De Novo Liver3
De Novo Heart2
1. Kovarik JM et al. Transplantation.
199458658-663. 2. Cooney GF et al.
Transplantation. 1998301892-1894. 3. Freeman D
et al. Ther Drug Monit. 199517213-216.
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Mycophenolic Acidinter-subject variability of
MPA AUC
MMF 1 g bid
Shaw et al AJT 20033534
Shaw L. et al. Ther Drug Monit 200426347
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Metabolism of Immunosuppresents

• Tacrolimus, Cyclosporine, and Sirolimus are all
  low extraction Drugs
• Clearance of the drug is dependent on enzyme
  efficiency of the liver
• Protein binding is important - Unbound or Free
  Fraction is what can be metabolized.
• Enzyme substrate Cyp - 3A4

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Cyp 3A4 isoform
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Protein Binding Sites

• Red Blood Cells Whole Blood levels done for all
  3 drugs
• White Cells T-Lymphocytes
• Lipids HDL, LDL, Apolipoproteins
• Others Albumin, a-Acid Glycoprotein

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P-Glycoprotein

• Transmembrane protein first associated with MDR
  in certain tumor cells
• Acts as transporter pump which prevents drug
  accumulation in cells ( ? activity)
• Physiologic role not fully understood
• In transplant patients, P-gp is critically
  involved with T-cell apoptosis and the
  pharmacokinetics of corticosteroids,
  cyclosporine, tacrolimus (Tac), and sirolimus.

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P-Glycoprotein

• Location
• Adrenal Cortex - Cortisol secretion
• Kidney - Brush Border - Urinary Excretion
• Liver - Biliary Excretion
• Small Intestine - Absorption
• Brain - Blood Brain Barrier

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P-Glycoprotein

• P-glycoprotein (P-gp) can actively transport
  drug from cells, resulting in
• decreased drug absorption (gastrointestinal
  tract) enhanced elimination into bile (liver)
  and urine (kidney) prevention of drug entry
  into the central nervous system
  (blood-brain-barrier).

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P-Glycoprotein
Drug
Drug
Drug
Extracellular space
Drug
On
Drug
Plasma Membrane
/-

• Allosteric Binding Site

off
Drug
ATP
ATP
Cytoplasm
Drug
P-glycoprotein
Drug
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P-Glycoprotein
P-Glycoprotein Interactions Increasing
recognition as an important factor in influencing
drug pharmacokinetics and efficacy Can
significantly affect disposition of medications
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P-Glycoprotein

• Substrates
• ImmunosuppressantCyclosporine, Tacrolimus,
  Sirolimus,
• Calcium Channel Blockers Verapamil, Diltiazem,
  Nifediine
• Antineoplastics Etoposide, Doxorubicin, Taxol
• Opioids Morphine, Methadone
• Misc Digoxin, Corticosteroids

• Inhibitors
• Cyclosporine, Tacrolimus
• Nifedipine, Diltiazem, Verapamil

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Summary P-Glycoprotein
Tacro/siro/cyclo
P-GP
Cyclosporine
Metabolites
Cyp 3A4
Hepatic Portal Vein To Liver
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General TDM Monitoring Strategy

• Starting Dose Loading Dose may be required
• Obtain Trough (C0) Level Determine Desired
  Trough level
• Assess Patients Risk
• Introduction or discontinuation of Cyp-3A4
  inducers or inhibitors
• Introduction or discontinuation of P-GP
  substrates or inhibitors
• Assess blood work - Serum Creatinine, Lipid
  profile, WBC,RBC
• Repeat serum levels based on risk assessment

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General Strategies of TDMLoading Dose
Van Hest et al. Ther Drug Monit 2005
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General Strategies of TDMLoading Dose
Van Hest et al. Ther Drug Monit 2005
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Drug exposure and systemic effect

• MPA AUC Acute Efficacy
  mghr/L Rejection
• 0 60 0
• 15 30 50
• 25 15 75
• 40 6 90
• MPA AUC 0-12 median over first 6 months
• Hale et al Clin Pharm Ther 1998
• Shaw et al TDM 2000
• Weber et al JASN 2002

Therapeutic threshold
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Therapeutic threshold
60
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General TDM Monitoring Strategy

• Starting Dose Loading Dose may be required
• Obtain Trough (C0) Level Determine Desired
  Trough level
• Assess Patients Risk
• Introduction or discontinuation of Cyp-3A4
  inducers or inhibitors
• Introduction or discontinuation of P-GP
  substrates or inhibitors
• Assess blood work - Serum Creatinine, Lipid
  profile, WBC,RBC
• Repeat serum levels based on risk assessment

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Desired Levels
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Pharmacokinetics Equations

• Current Status Algebra
• Assumes Linearity
• Provides no phsiologically meaningful
  information I.E. Clearance

Cpss Desired
New Dose
Current Dose

Cpss Current
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Pharmacokinetics Equations
Pharmacokinetics Equations

• Example
• 45 yr old Renal Tx patient
• Current Dose 200mg Twice a day
• Current Level - 105
• Desired Level - 200

200
Cpss Desired
200 380.9
Current Dose

New Dose
105
Cpss Current
Dose 375-400mg
Is this a steady State? Renal Function of
Patient? Cyp 3A4 or P-GP drugs
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Pharmacokinetics Equations

• Traditional Methods
• Clearance Total Body
• Cltb Ke Vd

Cltb
Ke
or
Vd
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Pharmacokinetics Equations

• Traditional Methods
• Patient Elimination Rate (Kd)

(S)(F)(Dose)
Cpss min
Vd
ln
Cpss min
Kd
t
Patient Specifics Measurements Dose Cpssmin
Vd,S, F are reference Values
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Pharmacokinetics Equations

• Traditional Methods
• Calculate New Dose

-kdt
(Cpss min)(Vd)(1-e )
Dose
-kdt
(S)(F)(e )
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New Approaches

• C2 - Monitoring
• Abbreviated AUC
• Absorption Profile AUC absorption Phase

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Case

• BG 51 yr old female
• Admitted for Liver tx - Amyloidosis
• Hx of Seizures 6 months earlier
• Meds - Dilantin and Phenobarb
• Started on Sirolimus and Mycophenolate
• What dose of Sirolimus do you recommend?

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Case

• What do we need to worry about for the dilantin
  or phenobarb?