AAPS Workshop on Exposure Response Relationships of Immunemodulators Sept' 22, 2003

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AAPS Workshop onExposure Response Relationships
ofImmunemodulatorsSept. 22, 2003

• THERAPEUTIC DRUG MONITORING
• IN IMMUNOSUPPRESSIVE THERAPY

Presented by E. Dennis Bashaw, Pharm.D. Office
of Clinical Pharmacology and Biopharmaceutics Divi
sion of Pharmaceutical Evaluation-III U.S. Food
and Drug Administration, Rockville, MD
2
Disclaimer The presentation today should not be
considered, in whole or in part as being
statements of policy or recommendation by the US
Food and Drug Administration.
3
TDM can be useful for some drugs in any patient
and for most drugs in some special
populations. P.D. Walson, M.D Clinical Chemistry
442 (p.415).
4
Abstract
Therapeutic Drug Monitoring, or TDM, has been
successfully used in the management of the
transplant patient. By suppressing the bodys
recognition of foreign bodies, immunosuppresants
such as cyclosporine (and others), combined with
improved methods of tissue typing, have greatly
improved life expectancy. In this presentation
we will review the elements of a successful TDM
strategy including known or expected sources of
variability. The management of these elements
will be discussed in relation to the use of some
of the immunosuppresants used in organ
transplantation. We will also discuss the role
of the package insert in disseminating this
information.
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Outline
I. Overview II. Therapeutic Drug Monitoring A.
Why and When B. Narrow Therapeutic Range
Drugs III. Organ Transplantation IV.
Immunomodulators/Immunosuppressants A.
Cyclosporine B. Tacrolimus (FK-506) C.
Sirolimus D. Mycophenolate Mofetil V.
Translation to the Clinician
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Therapeutic Drug Monitoring

• Underlying TDM is the observation that plasma
  levels are a reliable measure of clinical
  outcome.
• Organ Transplantation
• Too little, loss of organ function and ultimate
  rejection.
• Too much, risk of opportunistic infections, some
  type of tumors, viral complications, etc. along
  with Adverse Events independent of
  immunsuppression.

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TDM Balancing Risk
Patient Outcome
Risk of Opportunistic Infection
Risk of Organ Rejection
TDM
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Therapeutic Drug Monitoring

• Classic TDM (Marshall, 1938, JAMA)
• Aminoglycosides
• Digoxin
• Phenytoin
• Theophylline
• Pharmacokinetic Variability
• Low intra-subject
• High inter-subject

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Therapeutic Drug Monitoring-Variability

• Regardless of the source of variability, in order
  for TDM be clinically useful within an
  individual, these drugs must have low
  intra-subject variability.
• That is they must be PREDICTABLE.

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Therapeutic Drug Monitoring-Variability

• In contrast, the inter-subject variability of PK
  and/or PD measures is relatively high for NTI
  drugs and hence, therapeutic monitoring is needed
  for individualization of dose.

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Therapeutic Drug Monitoring-Variability

• When the inter-subject variability of a PD
  measure is high, PD monitoring is required for
  dose selection and titration.
• If the inter-subject variability of a PK measure
  is high and a PK-PD relationship exists, PK
  monitoring is often used for optimization of dose.

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Sources of TDM Variability

• Patient Factors
• Compliance
• Concomitant drugs (drug-drug interactions)
• Body weight/height ratio (volume factors)
• GI absorption factors (including nutritional
  status)
• Genomics (increasing importance)

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Sources of TDM Variability

• Non-Patient Factors
• Formulation (prescribability)
• Cyclosporine (Sandimmune vs. Neoral)
• Analytical Technique (RIA vs. HPLC)
• -interference/non-specificity
• Biological Matrix (whole blood vs. plasma)
• Sampling Time
• ideal vs. actual
• influence of meals
• chronopharmacokinetics
• Drug-Drug Interactions

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Why do Therapeutic Drug Monitoring?

• To optimize drug effect, thus improving the
  therapeutic outcome
• To minimize untoward adverse events

These outcomes must be DOCUMENTABLE for TDM to be
successful
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Organ Transplantation
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Cost of Transplantation
Mid-America Transplant Services
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Waiting List by Type of Transplant
Kidney 53,851 Pancreas 1,407
Kidney/Pancreas 2,409 Liver 16,949
Intestine 185 Heart 3,774 Lung
3,825 Heart/Lung 198 Total (as of
3/14) 80,667
United Network for Organ Sharing
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The Immune System
All blood cells are derived from pluripotent
hematopoietic stem cells. These cells can divide
without differentiation to renew themselves, and
they can differentiate into, more mature cells.
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Immunomodulators/Immunosuppressants
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Guidance for Industry Immunotoxicology Evaluation
of Investigational New Drugs Oct. 2002
IMMUNOSUPPRESSION The term immunosuppression
refers to impairment of any component of the
immune system resulting in decreased immune
function (Descotes et al., 2000). Indicators of
immunosuppression can be observed in standard
nonclinical toxicology studies and include
Evidence of myelosuppression, such as
pancytopenia, leukopenia, lymphopenia, or other
blood dyscrasias Alterations in immune system
organ weights and histology (e.g.,
hypocellularity of immune system tissues such as
the thymus, spleen, lymph nodes, or bone marrow)
Decreased serum globulin levels Increased
incidence of infections Increased incidence of
tumors
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Immunomodulator

A drug that modifies the immune response or the
functioning of the immune system
Rheumatoid Arthritis, Psoriasis, Cancer, Viral
Infections,..

• Arava Tablets (Aventis) Leflunomide
• Avonex (Biogen) Interferon Beta-1a
• Betaseron for SC Injection (Berlex) Interferon
  Beta-1b
• Ergamisol Tablets (Janssen) Levamisole
  Hydrochloride
• Rebetol Capsules (Schering) Ribavirin
• Thalomid Capsules (Celgene) Thalidomide

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Immunosuppressant

• CellCept Capsules Mycophenolate Mofetil
• GenGraf Capsules(Abbott) Cyclosporine
• Neoral Soft Gelatin Capsules (Novartis)
  Cyclosporine
• Prograf Tablets and Capsules (Fujisawa)
  Tacrolimus
• Rapamune Oral Tablets and Solution (Wyeth)
  Sirolimus
• Simulect for Injection (Novartis) Basiliximab

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Other Immunosuppressants

• Corticosteroids work by many mechanisms including
  inhibition of monocyte IL-1 production causing a
  decrease in IL-2 and Interferon g production. In
  addition they cause an inhibition of neutrophils/
  monocytes chemotaxis and a leukopenia/neutropenia.
  
• Azathioprine interferes with nucleic acid
  metabolism thus, reducing lymphoid cell
  proliferation following stimulation. It also
  destroys stimulated lymphoid cells by the
  disruption of purine metabolism.

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Comparison of Immunosuppressants
Tacrolimus Ointment (Protopic) is approved for
treatment of atopic dermatitis. Negative
outcome in hepatic studies cited in
label Approved for use in combination with
cyclosporine
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TDM and Immunosuppressants

• Discussion will be limited to
• Cyclosporine -Mycophenolate Mofetil
• Sirolimus -Tacrolimus
• Mechanisms of action related to the inhibition of
  gene transcription factors. Cyclosporine and
  tacrolimus work through inhibition of
  calcineurin, while sirolimus binds to a member of
  the immunophilin family of cytosolic binding
  proteins. Both mechanisms result in suppression
  of IL-2 and the complimentary mechanisms allow
  for combined use of cyclosporine with sirolimus.

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Immunosuppression Mechanism
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What is Exposure-Response?
Guidance for Industry Exposure-Response
Relationships Study Design, Data Analysis, and
Regulatory Applications April, 2003
Exposure refers to the dose (or drug input to the
body) and various measures of acute and/or
integrated drug concentrations in plasma and
other biological fluid (e.g., Cmax, Cmin, Css,
AUC). Similarly, response refers to a direct
measure of the pharmacologic effect of the drug.
Response includes a broad range of endpoints or
biomarkers such as organ rejection.
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Cyclosporine
Cyclosporine is a cyclic polypeptide
immunosuppressant agent consisting of 11 amino
acids. It is produced by the fungus species
Beauveria nivea. It is available in two forms,
as a solution (Sandimmune) and as a microemulsion
(Neoral).
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Cyclosporine Bioavailability and TDM
Sandimmune Soft Gelatin Capsules (cyclosporine
capsules, USP) and Sandimmune Oral Solution
(cyclosporine oral solution, USP) have decreased
bioavailability in comparison to Neoral Soft
Gelatin Capsules (cyclosporine capsules, USP)
MODIFIED and Neoral Oral Solution (cyclosporine
oral solution, USP) MODIFIED. Sandimmune and
Neoral are not bioequivalent and cannot be used
interchangeably without physician supervision.
The absorption of cyclosporine during chronic
administration of Sandimmune Soft Gelatin
Capsules and Oral Solution was found to be
erratic... ...Numerous assays are being
developed to measure blood levels of
cyclosporine. Comparison of levels in published
literature to patient levels using current assays
must be done with detailed knowledge of the assay
methods employed. (See Blood Level Monitoring
under DOSAGE AND ADMINISTRATION)
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Cyclosporine Bioavailability Prediction
From Kundt, p. 45 46
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Analysis of the data from this trial showed that
although the bioavailability of oral cyclosporine
was variable between individuals as few as two
samples (C1 and C3) would be sufficient for
estimating AUC0-12. This type of analysis may be
necessary in dealing with the poorly compliant
patient in determining their compliance status.
Clinical practice has shown that effective TDM
management can be accomplished by a Single Point.
From Kundt, p. 46
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Two Hour Concentrations for Cyclosporine
(microemulsion)
Kahan, B.D., Therapeutic Drug Monitoring
17560-563
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Cyclosporine
Blood Level Monitoring Several study centers
have found blood level monitoring of cyclosporine
useful in patient management. While no fixed
relationships have yet been established, in one
series of 375 consecutive cadaveric renal
transplant recipients, dosage was adjusted to
achieve specific whole blood 24-hour trough
levels of 100-200 ng/mL as determined by
high-pressure liquid chromatography (HPLC). Of
major importance to blood level analysis is the
type of assay used. The above levels are specific
to the parent cyclosporine molecule and correlate
directly to the new monoclonal specific
radioimmunoassays (mRIA-sp). Nonspecific assays
are also available which detect the parent
compound molecule and various of its
metabolites. Older studies often cited levels
using a nonspecific assay which were roughly
twice those of specific assays. Assay results
are not interchangeable and their use should be
guided by their approved labeling. If plasma
specimens are employed, levels will vary with the
temperature at the time of separation from whole
blood. Plasma levels may range from 1/2-1/5 of
whole blood levels. Refer to individual assay
labeling for complete instructions. In addition,
Transplantation Proceedings (June 1990) contains
position papers and a broad consensus generated
at the Cyclosporine-Therapeutic Drug Monitoring
conference that year. Blood level monitoring is
not a replacement for renal function monitoring
or tissue biopsies.
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Trends in Immunosuppresion
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Tacrolimus
Tacrolimus has many biochemical and clinical
similarities to cyclosporin A. It is produced by
the soil fungus streptomyces tsukubaensis. Unlike
cyclosporin A, tacrolimus is a macrolide with
some structural similarities to the antibiotic
erythromycin.
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Tacrolimus TDM
Winkler, M.,Plasma vs. whole blood for
therapeutic drug monitoring of patients receiving
FK506 for immunosuppression. Clin Chem 40
2247-22521994.
39
Genomics and Tacrolimus Dosing
Hesselink, D.A., et al, Clin Pharmacol Ther
200374245-54
40
Tacrolimus
Blood Concentration Monitoring Monitoring of
tacrolimus blood concentrations in conjunction
with other laboratory and clinical parameters is
considered an essential aid to patient management
for the evaluation of rejection, toxicity, dose
adjustments and compliance. Factors influencing
frequency of monitoring include but are not
limited to hepatic or renal dysfunction, the
addition or discontinuation of potentially
interacting drugs and the post transplant time.
Blood concentration monitoring is not a
replacement for renal and liver function
monitoring and tissue biopsies. Two methods
have been used for the assay of tacrolimus, a
microparticle enzyme immunoassay (MEIA) and an
ELISA. Both methods have the same monoclonal
antibody for tacrolimus. Comparison of the
concentrations in published literature to patient
concentrations using the current assays must be
made with detailed knowledge of the assay methods
and biological matrices employed. Whole blood is
the matrix of choice and specimens should be
collected into tubes containing ethylene diamine
tetraacetic acid (EDTA) anti-coagulant. Heparin
anti-coagulation is not recommended because of
the tendency to form clots on storage. Samples
which are not analyzed immediately should be
stored at room temperature or in a refrigerator
and assayed within 7 days if samples are to be
kept longer they should be deep frozen at -20C
for
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Sirolimus
Sirolimus is a macrocyclic lactose produced by
the actinomycete Streptomyces Hygroscopicus and
was first isolated in soil samples collected on
Rapa Nui (Easter Island).
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Effect of Drug-Drug Interactions
Sirolimus is highly metabolized by CYP 3A4. It
is thus susceptible to drug-drug interactions
with a variety of agents. Some of which, such as
the anti-fungals are commonly used in the
treatment of the transplant patient.
From MacDonald, p. 106
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Plasma Levels and Rejection
From MacDonald, p. 112
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Sirolimus
Blood Concentration Monitoring Routine
therapeutic drug level monitoring is not required
in most patients.Blood sirolimus levels should be
monitored in pediatric patients, in patients with
hepatic impairment, during concurrent
administration of strong CYP3A4 inducers and
inhibitors, and/or if cyclosporine dosing is
markedly reduced or discontinued. In controlled
clinical trials with concomitant cyclosporine,
mean sirolimus whole blood trough levels, as
measured by immunoassay, were 9 ng/mL (range 4.5
- 14 ng/mL 10 th to 90 th percentile) for the 2
mg/day treatment group, and 17 ng/mL (range 10 -
28 ng/mL 10 th to 90 th percentile) for the 5
mg/day dose. Results from other assays may
differ from those with an immunoassay. On
average, chromatographic methods (HPLC UV or
LC/MS/MS) yield results that are approximately
20 lower than the immunoassay for whole blood
concentration determinations. Adjustments to the
targeted range should be made according to the
assay utilized to determine sirolimus trough
concentrations. Therefore, comparison between
concentrations in the published literature and an
individual patient concentration using current
assays must be made with detailed knowledge of
the assay methods employed. A discussion of the
different assay methods is contained in Clinical
Therapeutics, Volume 22, Supplement B, April
2000..
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Mycophenolate Mofetil
Mycophenolate Mofetil is an ester pro-drug of
mycophenolic acid (MPA). It is a selective,
reversible non-competitive inhibitor of inosine
monophosphate dehydrogenase (IMP-DH), which is a
critical enzyme for the de-novo synthesis of
guanosine nucleotides. The drug appears to have
some degree of specifity for the IMP-DH isoform
found in the lymphocytes (both T and B).
MPA
It has no effect on the production or release of
the cytokines (IL-1 and IL-2) associated with
early T-cell signal transduct-ion. Hence, it is
not effective in the treatment of ongoing acute
rejection as a single agent.
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Mycophenolate and TDM
Although TDM is currently not recommended in the
label the results of a randomized concentration
controlled clinical trial demonstrated that
AUC0-12 and other early measures of absorption
were related to acute rejection.
Van Gelder, T, et al, Transplantation,
199968261-266
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Mycophenolate and TDM
Another study compared trough levels (C0), 30min
post dose levels (C30), and AUC0-12 (AUC12). The
results showed that there is a sub-group of
subjects with a rapid clearance, as assessed by
the C30 concentrations, that was associated with
both efficacy and reduced adverse events.
Mourad, M, et al, Clin. Chem. 200147(1)88-94
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Mycophenolate and TDM

• Currently the package insert makes no
  recommendation on the use of TDM
• Accumulating experience in the clinical setting
  suggests that, like other agents before, TDM in
  the form of exposure/response surrogates may
  eventually be proposed for inclusion in the
  package insert by the NDA holder.

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Translation to the Clinician
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Determinants of a Successful Transplant
Proper Tissue Typing
Patient Compliance
Surgical Technique
Drug Therapy and TDM
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Dissemination of Information on TDM and
Immunosuppressants
The primary source of information on the utility
of TDM with any drug will initially be the
package insert. While limited in size the
package insert should provide the prescriber with
sufficient information to dose the drug properly
and should identify the known sources of
variability to be taken into consideration. In
general it should identify

• The target concentration, if known
• Known risk factors, such as drug-drug
  interactions
• Known formulation issues
• Information on the assay or assays available

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Sources of TDM Variability

• Non-Patient Factors
• Formulation (prescribability)
• Cyclosporine (Sandimmune vs. Neoral)
• Analytical Technique (RIA vs. HPLC)
• -interference/non-specificity
• Biological Matrix (whole blood vs. plasma)
• Sampling Time
• ideal vs. actual
• influence of meals
• chronopharmacokinetics
• Drug-Drug Interactions

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Conclusions-Points to Consider

• TDM can be a powerful tool for the optimization
  of therapy.
• It is not a replacement for close monitoring of
  the patient including functional monitoring of
  the transplanted tissue/organ and tissue biopsies
  when indicated.
• As part of any TDM program, sources of
  variability must be identified and controlled
  a priori.
• The best TDM program cannot make up for poor long
  term patient compliance.

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Conclusions-Points to Consider

• TDM can be a early warning marker of poor
  compliance.
• Although limited, the package insert attempts to
  provide the prescriber with those elements
  identified during the clinical development that
  were predictors of drug effect/safety.
• A successful TDM program can be measured by the
  improved quality of life of the patient.

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TDM can be useful for some drugs in any patient
and for most drugs in some special
populations. P.D. Walson, M.D Clinical Chemistry
442 (p.415).
56
Selected Reading
Aspeslet, L.J., Yatscoff, R.W., Requirements for
Therapeutic Drug Monitoring of Sirolimus, an
Immunosuppressive Agent Used in Renal
Transplantation, Clinical Therapeutics 22(suppl.
B) 2000 Hesselink, D.A., et al, Genetic
Polymorphisms of the CYP3A4, CYP3A5, and MDR-1
genes and the pharmacokinetics of the calcineurin
inhibitors, cyclosporine and tacrolimus, Clin
Pharmacol Ther 200374245-54 Kahan, B.D., The
Evolution of Therapeutic Immunosuppression and
the Potential Impact of Drug Concentration
Monitoring, Therapeutic Drug Monitoring
17560-563 Kahan, B.D. et al, Therapeutic Drug
Monitoring of Immunosuppressant Drugs in Clinical
Practice, Clinical Therapeutics
24(3)330-350 MacDonald, M.D., et al, Clinical
Pharmacokinetics and Therapeutic Drug Monitoring
of Sirolimus, Clinical Therapeutics 22(suppl. B)
2000 Safarcik, K., et al, Evaluation and
Comparison of Therapeutic Monitoring of
Whole-blood Levels of Cyclosporin A and its
Metabolites in Renal Transplantation by HPLC and
RIA Methods. Clinica Chimica Acta, 310(2001)
165-171 Schumacher, G.E. Barr, J.T., Economic
and Outcome Issues for Therapeutic Drug
Monitoring in Medicine, Therapeutic Drug
Monitoring 20(5) 539-542