IPCP Core C ActivitiesAprepitant Dose-exposure Relationship in the Monkey

Jeffrey S. Barrett, Ph.D., FCP

The Children’s Hospital of PhiladelphiaDivision of Clinical Pharmacology and Therapeutics

The University of Pennsylvania Medical SchoolDepartment of Pediatrics

IPCP Core C ActivitiesOutline

• Background– Relevance of PK, PK/PD and M&S to IPCP– Overall grant strategy – M&S– M&S 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

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.

IPCP Core C ActivitiesBackground – What we promised . . .

Cross-validate aprepitantLC/MS/MS method

(Constanzer et. al., 2004)

PK (NCA) of aprepitant in HIV-infected patients

(2-stage approach)

Individual predicted pop-PK from final

model (MAP Bayesian)

PD: Exposure-responsePsychologic Disturbances

(Categorical Analysis)

PD: Exposure-ResponseViral Dynamics

(NLMEM)

PD: Exposure-ResponseNK response(NLMEM)

PD: Exposure-responseSafety Indices

(Logistic Regression)

Population PK Model(NLMEM)

• Structural Model• Covariate Model • Error Model• Validation (data

splitting or bootstrapping)

Clinical Trial Simulation Model for Proof-of-Concept Phase IIA Trial

IPCP Core C ActivitiesRelevance of PK, PK/PD and M&S to IPCP

IPCP Core C ActivitiesOverall Strategy -- M&S

Aprepitant Background

Aprepitant PK CharacteristicsAbsorption • 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-∞ 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

Aprepitant PK Characteristics125 mg80 mg 80 mg

Time Postdose (hr)N=12

Aprepitant Dose SelectionCINV Indication

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

Analytical Methods

• SFBC analysis / method – Monkey Plasma• Constanzer method (Merck); no IS• LOQ = 10 ng/mL

* CHOP / LAPKPD method for Monkey CSF

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

Pilot Study Results:Aprepitant in Rhesus Macaque Monkeys (n=3)

Time DG23 DF42 CB18

4/26/05 1.04 0.17 0.221

5/3/05 0.666 0.368 0.931

CSF Levels (ng/mL)

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

Recent FDA Discussion:

Recent FDA Discussion:

Recent FDA Discussion:

Recent FDA Discussion:

Recent FDA Discussion:

Recent FDA Discussion:

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