Everolimus and Cyclosporine Exposure-Effectiveness and Nephrotoxicity Relationships

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Everolimus and Cyclosporine Exposure-Effectiveness
and Nephrotoxicity Relationships

• Joga Gobburu, Ph.D.
• Office of Clinical Pharmacology and
  Biopharmaceutics

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Summary

• Effectiveness is higher in patients with higher
  cyclosporine/everolimus troughs
• Nephrotoxicity (?CrCL) occurs more often in
  patients with higher cyclosporine troughs
  (cyclosporine-everolimus combination)
• Alternate dosage regimen for cyclosporine and
  everolimus may improve the benefit-risk profile

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Potential Dosing to be Tested in Future Trial
(A2310)

• Cyclosporine
• First month
• Achieve concentrations as observed in Study B253
• Subsequent months
• Faster tapering of cyclosporine concentrations
• Everolimus (use TDM)
• Low Dose 3-8 ng/mL
• High Dose 6-12 ng/mL

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Methods

• Data
• B253, Heart Transplant Trial
• Exposure-Response Analysis
• Effectiveness (N201, 387)
• Pre-specified composite endpoint relationship
• Nephrotoxicity (N208, 404)
• Change in creatinine clearance (CrCL) from
  baseline through 6 months

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Why Understand Exposure-Response Relationships?

• Large variability in drug concentrations
• Drug concentrations are believed to drive the
  effects (desired / undesired)
• Everolimus-cyclosporine PD interaction
  (effectiveness toxicity)
• Time course of CrCL cannot be ignored
• To derive time course of target exposures
• Derive alternative dosing regimen(s) for future
  trials

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Everolimus Troughs Exhibit Considerable
Variability
Number of Patients
Everolimus trough, ng/mL
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About 50 of Patients had Cyclosporine Troughs
within the Target Range
Cyclosporine trough, ng/mL
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Higher Cyclosporine, Everolimus Troughs Lead to
Better Effectiveness
Probability of Failure ()
Greater effectiveness unlikely at everolimus gt 12
ng/mL
Cyclosporine trough, ng/mL
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Higher Cyclosporine- Everolimus Troughs Lead to
Greater Nephrotoxicity
Cyclosporine trough, ng/mL
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Alternate Dosing CsA Tapering, Targeted
Everolimus
Month Post-Transplant Cyclosporine Target Concentrations (ng/mL) Cyclosporine Target Concentrations (ng/mL)
Month Post-Transplant Low Dose Everolimus (3-8 ng/mL) High Dose Everolimus (6-12 ng/mL)
1 200-350 200-350
2 150-250 120-210
3-4 100-200 65-130
5-6 75-150 50-100
7-24 50-100 50-100
Based on observed CsA concentrations in B253 Use
TDM to achieve target everolimus concentrations
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Simulated Benefit-Risk for CsA Tapering, Targeted
Everolimus
Treatment Benefit Risk
Primary efficacy events in 6 mo. Mean change in CrCL (mL/min) from baseline at 6 mo.
Observed results with standard CsA trough concentrations from Study B253 Observed results with standard CsA trough concentrations from Study B253 Observed results with standard CsA trough concentrations from Study B253
0.75 mg bid Everolimus 36 -13
1.5 mg bid Everolimus 27 -19
Simulated results with lower target cyclosporine concentrations during 2-6 months post transplantation Simulated results with lower target cyclosporine concentrations during 2-6 months post transplantation Simulated results with lower target cyclosporine concentrations during 2-6 months post transplantation
Everolimus 3-8 ng/mL, with CsA tapering 36 -2
Everolimus 6-12 ng/mL, with CsA tapering 28 -2
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Summary

• Effectiveness is higher in patients with higher
  cyclosporine/everolimus troughs
• Nephrotoxicity (?CrCL) occurs more often in
  patients with higher cyclosporine troughs
  (cyclosporine-everolimus combination)
• Alternate dosage regimen for cyclosporine and
  everolimus may improve the benefit-risk profile

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Back Up Slides
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Exposure Metrics

• Effectiveness
• Time normalized mean cyclosporine and everolimus
  troughs between 0-6 months
• Nephrotoxicity
• Time course of cyclosporine and everolimus
  troughs between 0-6 months

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Variability in Everolimus Exposure
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Exposure-Effectiveness Relationship

• Patients with effectiveness failure were given a
  1 and others a zero.
• Probability of effectiveness failure was
  significantly correlated with cyclosporine and
  everolimus exposures.

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Exposure-Effectiveness Relationship
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Estimated Mean Creatinine Clearance (mL/min)
Change from Baseline (Safety Population - 24
Month Analysis)
Azathioprine
Everolimus 0.75 mg bid
Everolimus 1.5 mg bid
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Exposure-Nephrotoxicity Relationship
Cyclosporine Exposure
Surgery
Everolimus Exposure



Creatinine Clearance
Input
Output
Surgery effect
Creatinine Clearance
Net Effect
Cyclosporine Toxicity
Time
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Was baseline CrCL accounted for in the
exposure-nephrotoxicity analysis?

• Yes. First, this relationship considers the
  change in CrCL over time relative to the baseline
  (post-surgery) in each patient.
• Second, the CrCL adjusted for the baseline is
  correlated to the drug exposures over time.

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Emax model does not capture the
exposure-nephrotoxicity relationship well
Cyclosporine trough, ng/mL