Jeffrey S. Barrett, Ph.D., FCP The Children

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Jeffrey S. Barrett, Ph.D., FCPThe Childrens
Hospital of PhiladelphiaDivision of Clinical
Pharmacology and TherapeuticsThe University of
Pennsylvania Medical SchoolDepartment of
Pediatrics
IPCP Core C ActivitiesAprepitant Dose-exposure
Relationship in the Monkey
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IPCP Core C ActivitiesOutline

• Background
• Relevance of PK, PK/PD and MS to IPCP
• Overall grant strategy MS
• MS Integration with Decision Making
• Aprepitant Review
• PK Signature
• Dose-selection rationale for CINV
• PK Assessment Suggestions for CDP
• Current Core C Efforts
• Analytical Methods
• CFAR Pilot PK Results
• Collaborative Efforts
• SIV Dose Prediction
• SIV Dose Prediction ? SIV PK/PD ? Projection to
  HIV
• Analytical Effort
• Druggability / Screening Criteria

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IPCP Core C ActivitiesBackground What we
promised . . .

1. An evaluation of the correlation between single
   agent activity experiments and druggability
   properties theorized to benefit HAART.
2. An evaluation of the ability to generalize
   activity based on structural similarities of
   investigated agents.
3. Correlation of non-human primate to human
   pharmacokinetics via allometric modeling in order
   to guide clinical dosing based on pharmacokinetic
   considerations. Correlation of drug exposure to
   specific agent toxicities in non-human primates.
4. Construction of human PK/PD models built from in
   vitro, animal PK/PD and assumptions about human
   activity (efficacy and toxicity).
5. Correlation of non-human primate to patient
   exposure-response relationships.
6. Clinical trial simulation models to evaluate
   trial design sensitivities, drug combination and
   dosing scenarios and population characteristic
   dependencies.

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IPCP Core C ActivitiesBackground What we
promised . . .
PK (NCA) of aprepitant in HIV-infected
patients (2-stage approach)
Cross-validate aprepitant LC/MS/MS method
(Constanzer et. al., 2004)

• Population PK Model
• (NLMEM)
• Structural Model
• Covariate Model
• Error Model
• Validation (data splitting or bootstrapping)

Individual predicted pop-PK from final model (MAP
Bayesian)
PD Exposure-response Safety Indices (Logistic
Regression)
PD Exposure-response Psychologic
Disturbances (Categorical Analysis)
PD Exposure-Response Viral Dynamics (NLMEM)
PD Exposure-Response NK response (NLMEM)
Clinical Trial Simulation Model for
Proof-of-Concept Phase IIA Trial
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IPCP Core C ActivitiesRelevance of PK, PK/PD and
MS to IPCP
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IPCP Core C ActivitiesOverall Strategy -- MS
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Aprepitant Background
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Aprepitant PK Characteristics

• Absorption
• Mean absolute oral bioavailability of aprepitant
  is approximately 60 to 65
• Mean peak plasma concentration (Cmax) at
  approximately 4 hours (Tmax).
• The pharmacokinetics of aprepitant are non-linear
  across the clinical dose range.
• Increase in AUC0-8 was 26 greater than dose
  proportional between 80-mg and 125-mg single
  doses administered in the fed state.
• Distribution
• Aprepitant is greater than 95 bound to plasma
  proteins. The mean apparent volume of
  distribution at steady state (Vdss) is
  approximately 70 L in humans.
• Metabolism  
• Aprepitant undergoes extensive metabolism.
• Metabolized primarily by CYP3A4 with minor
  metabolism by CYP1A2 and CYP2C19. Metabolism is
  largely via oxidation at the morpholine ring and
  its side chains.
• No metabolism by CYP2D6, CYP2C9, or CYP2E1
  detected.
• Seven metabolites of aprepitant (weakly active)
  identified in human plasma.
• Excretion
• Aprepitant is eliminated primarily by metabolism
  not renally excreted.
• The apparent plasma clearance of aprepitant
  ranged from approximately 62 to 90 mL/min. The
  apparent terminal half-life ranged from
  approximately 9 to 13 hours

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Aprepitant PK Characteristics
Time Postdose (hr)
N12
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Aprepitant Dose SelectionCINV Indication

• Correlation of aprepitant plasma trough
  concentration with binding of aprepitant to
  striatal NK1 receptors (each point represents an
  individual subject)

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Analytical Methods

• SFBC analysis / method Monkey Plasma
• Constanzer method (Merck) no IS
• LOQ 10 ng/mL
• CHOP / LAPKPD method for Monkey CSF

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LC-MS/MS CSF Method
API 4000 mass spectrometry coupled w/ Alliance
Waters HPLC Electrospray ionization source
Positive ion mode C18 Hypersil Column
Mobile phase (MP) a gradient MP of
methanol and H2O with 0.1 formic acid
Multiple reaction monitoring at m/z 535.3 and
277.3 for aprepitant Lowest of detection
limit - 20 pg/mL
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Pilot Study ResultsAprepitant in Rhesus Macaque
Monkeys (n3)
CSF Levels (ng/mL)
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Future Efforts
Integrated model for aprepitant plasma CSF
exposure Simulation PK/PD model to study
regimens in SIV (cellular PD used as input to
define target) PK/PD in SIV Scaling of SIV
/ HIV based on PK/PD Implement FDA HIV
disease model Validate human analytical method
at CHOP / LAPKPD
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Recent FDA Discussion
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Recent FDA Discussion
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Recent FDA Discussion
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Recent FDA Discussion
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Recent FDA Discussion
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Recent FDA Discussion
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Recent FDA DiscussionTake Home Message
Tipranavir has more warts than aprepitant
Viral load reduction modest at best FDA
assisted with trial design, analysis and
interpretation Indication is focused on
special population treatment-resistant
Exposure-response indicates narrow therapeutic
window Many DDIs Viability established on
after numerous clinical evaluations