TDM1

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Concentration-Controlled Trials and Therapeutic
Drug Monitoring
RAPAMUNE

• James Zimmerman, PhD
• Senior Director, Clinical PharmacokineticsClinica
  l Research and DevelopmentWyeth-Ayerst Research

TM
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Key Messages in This Presentation

• There is sufficient understanding of sirolimus PK
  to apply therapeutic drug monitoring (TDM) in
  patients
• A robust and reliable sirolimus assay is
  available
• The concentration range for sirolimus TDM has
  been defined and is effective
• Data are available to show that physicians can
  use TDM in renal allograft patients

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Currently ApprovedRAPAMUNE Regimen

• The currently approved RAPAMUNE regimen is a
  fixed-dose regimen (RAPA administered 4 hours
  after cyclosporine)
• Fixed-dose administration is recommended for most
  patients during co-administration with
  cyclosporine

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Concentration-ControlledRAPAMUNE Administration

• Recommended when administered with cyclosporine
  (RAPA administered 4 hours after cyclosporine)
• in pediatric patients
• in hepatic impairment
• during administration with strong
  inducers/inhibitors of CYP3A and P-gp
• after marked changes in cyclosporine doses
• Required when administered without cyclosporine
• Method of dose administration for the proposed
  indication (RAPA administered 4 hours after
  cyclosporine)

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Two Sirolimus Assay Methods Were Used to Measure
Trough Levels

• Sirolimus concentrations in this presentation
• are expressed in terms of the immunoassay

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Sirolimus Dose-Proportionality and aLinear Cmin
vs AUC Relationship Simplify Concentration-
Controlled Dosing
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The Sirolimus Cmin vs AUC Relationship is Linear
(Study 301, RAPA Cyclosporine)
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Sirolimus Pharmacokinetics Influences the
Implementation of Concentration-Controlled Dosing
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Four Studies Contributed Data for RAPAMUNE
Concentration-Controlled Regimens
Time
RAPAMUNE
Post-transplant
Studies
Study Type
Formulation

310
Pivotal
Tablet
1 year
212
Supportive
Solution
207, 210
Early Studies
Solution
(RAPA
vs CsA)
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Sirolimus Target Concentration Ranges after
Cyclosporine Withdrawal in Studies 212 and 310

• Set prospectively based on results from Phase II
  Studies 207 and 210
• For sample analysis by Immunoassay, the ranges
  were
• 10 - 20 ng/mL (Study 212)
• 20 - 30 ng/mL (Study 310)
• The adequacy of the prospective target ranges
  were supported by
• Efficacy results
• Mean sirolimus trough levels (18 vs 23 ng/mL)

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Outcomes of Sirolimus Concentration Control Among
Studies (RAPA Group)
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Sirolimus and Cyclosporine Trough Levels for
Study 310 (RAPA Group)
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Comments Regarding the Rate of Cyclosporine
Withdrawal in Study 310

• Overall, the investigators were successful in
  this first RAPAMUNE trial that required the
  simultaneous adjustment of 2 drugs
• Cyclosporine was eliminated in 50 of patients by
  Week 6 after randomization
• The ability to achieve the sirolimus target range
  will improve as physicians gain more experience
  with cyclosporine withdrawal

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A Mean RAPAMUNE Dose of 8 mg/day Maintained
Sirolimus in the Target Range for Study 310
23.3
8.4
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Implementation of Sirolimus TDM

• Frequency of blood sampling for sirolimus assays
  after randomization in Study 310
• Number of days required to reach the target range
  in Study 310
• Number of dose changes required to reach the
  target range in Study 310
• Sirolimus TDM range
• Availability of sirolimus assays

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Frequency of Blood Sampling For SirolimusAssays
After the Start of Cyclosporine Withdrawal(Study
310)
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Number of Days and Dose Changes Required to
Achieve the Target Range in Study 310
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Sirolimus TDM Range

• The sirolimus TDM range was determinedbased on
• Distribution analyses of sirolimus trough levels
  among non-rejectors and rejectors
• Clinical outcomes for Studies 212 and 310

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Distributions of Average Sirolimus Trough Levels
Among Non-Rejectors in Studies 310 and 212
(RAPAMUNE Groups)
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Distributions of Sirolimus Trough Levels Among
Rejectors in Studies 310 and 212(RAPAMUNE Groups)
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Sirolimus TDM Considerably ReducedIntersubject
Variability in Study 310 Compared to a Predicted
8-mg Fixed-dose Regimen
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RecommendedSirolimus TDM Range

• A sirolimus TDM range of 15 to 25 ng/mL
  (Immunoassay) is recommended based on
• The distributions of sirolimus trough levels
  among non-rejectors and rejectors in Studies 310
  and 212
• The very similar clinical outcomes in Studies
  310 and 212 with respect to graft survival,
  patient survival, and improved renal function
  within the RAPAMUNE treatment groups

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23 Bioanalytical Laboratories Measure Sirolimus
Concentrations
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Guidance In Using Sirolimus TDM

• Guidance will be provided to physicians with
  respect to
• Algorithms for estimating both a new maintenance
  dose and a new loading dose
• Maximum recommended dose per day
• Timing of blood draws for dose adjustments
• Action guidelines based on assay results
• Limitations of TDM

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Conclusions (I)

• Experience with sirolimus TDM (without concurrent
  cyclosporine administration) has been obtained in
  4 clinical trials during 1 year post-transplant
  among 347 patients
• Efficacy outcomes in the TDM groups were
  equivalent to their respective fixed dose groups
• Pharmacokinetic data and clinical outcomes for
  Studies 310 and 212 defined the range of
  sirolimus trough concentrations for TDM
• The results show that TDM can guide the safe and
  effective use of sirolimus

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Conclusions (II)

• TDM without cyclosporine co-administration
  (proposed indication)
• Recommended sirolimus TDM range
• Immunoassay 15 to 25 ng/mL
• Chromatographic assay 12 to 20 ng/mL