1. Human studies of neurokinin-1 receptor antagonists in HIV-1
Project 4
Human studies of neurokinin-1 receptor antagonists in HIV-1
PI: Pablo Tebas, M.D.
Co-PI: Jeffrey Barrett, Ph.D.
Dwight Evans, M.D.
David Dinges, Ph.D.
Jordan Orange, M.D., Ph.D.
Ruben Gur, Ph.D.

2. Project 4
Aim 1: Examine the safety and tolerability of the SP antagonist aprepitant in HIV-infected patients over 4-weeks of therapy. Assess the exposure-response relationship to evaluate aprepitant’s ability to suppress HIV-1 RNA.

3. Rationale for the selection of Aprepitant

4. Substance P antagonists have antiviral activity in vitro
Effect of CP-96,345 on HIV infection of MDM
Lai, Jian-Ping et al. (2001) Proc. Natl. Acad. Sci. USA 98,

5. Aprepitant Blocks Brain NK1 Receptors in Humans
Mean (± SD) Plasma Trough Concentrations of the Aprepitant 3-Day Regimen
Binding of PET tracer to NK1 receptors prior to aprepitant dosing 10 20 30 40 50 60 70 80 90
100
Brain NK1 Receptor Occupancy (%)
Blockade of
NK1 receptors after aprepitant dosing 1 10
100
1000
10000
Aprepitant Plasma Trough Concentration (ng/mL)
Low High
Tracer Binding

6. Aprepitant Plasma Concentration (ng/mL)
Aprepitant has well-characterized PK that permits once daily dosing in CINV
125 mg
80 mg
80 mg
Aprepitant Plasma Concentration (ng/mL)
N=12
Time Postdose (hr)

7. Aprepitant works and it has been tried in large populations.
Complete Response: Acute and Delayed Phases
Protocol 052
Protocol 054
p<0.001
p<0.001
p<0.001
p<0.001
89%
83%
78%
75%
68%
68%
56%
47% N=
259
260
260
260
261
263
260
263

8. Clinical Development Program
Number of Patients Receiving Aprepitant
Phase I clinical pharmacology studies
Studies in non-cancer patients
Studies in patients receiving cancer chemotherapy
Phase II Phase III 544
711
1172
1459
Total

9. 5. Aprepitant is safe, approved & available.
Clinical Adverse Experience Summary
APR 125/80
(N=544) %
69.1
17.1
13.4
7.7
3.7
Control (N=550) %
67.6
12.7
13.6
5.8
3.8
Adverse experiences (AEs)
Drug-related AEs
Serious AEs
Discontinuations due to AEs
Deaths
Percent of Patients with:
Phase III: Cycle 1
Aprepitant is approved by the FDA for emesis
Readily available

10. How do we want to test it? Phase 1b randomized blinded study

11. Main inclusion criteria
HIV-1 infection
CD4+ cell count ≥ 350/mm3
Plasma HIV-1 RNA of ≥2000 copies/mL
Stable hepatic, renal, and hematological indices
Not pregnant
No current serious psychiatric disorder (by SCID)

12. Endpoints Primary endpoints Safety and PK
HIV-1 RNA compared with baseline.
Secondary endpoints
CD4+ and CD8+ T-cell counts, T-cell activation, and proliferation
If we demonstrate antiviral activity: check for amino acid substitutions
CCR5 expression in peripheral PBMCs
Fasting plasma glucose, insulin, HDL, FFA, and TG at 28 days.
Fatigue and poor sleep, anxiety and depressed mood; neuropsychiatric measures

13. Schedule of events

14. Sample size justification
True Toxicity Level
Prob to observe > 1 event w n=13
Prob to observe > 1 event w n=26
.02
.23
.41
.04
.65
.06
.55
.80
.08
.66
.89 .1
.75
.94 .2
.95
.997
With a total of 13 subjects in a group, the width of a 95% confidence interval around the
D log 10 viral load, with 90% coverage, will be 1.5 s.d.’s of the D log viral load distribution.
(approximately 0.5 logs)
The Table shows the probability of observing a toxicity at least once, based on true underlying levels of the toxicities
Study large enough for viral dynamics analysis

15. Project 4
Aim 2: Determine aprepitant plasma concentrations over the 4 weeks of clinical evaluation in order to develop a population-based pharmacokinetic-pharmacodynamic (PK/PD) model for aprepitant in HIV-infected patients.

16. Why PK is so important with this drug? The problem of PK interactions
Aprepitant is extensively metabolized primarily by CYP3A4 isozyme
Inhibits CYP3A4 with aprepitant regimen (as early as 1 hr after Day 1 dosing)
Induces CYP2C9 with aprepitant regimen
Induces its own metabolism upon dosing for 2 weeks (autoinduction)

17. Effect of Aprepitant on CYP3A4 Drugs
Gastrointestinal Drugs Advisory Committee Meeting
March 6, 2003

18. Effect of Other Drugs on Aprepitant
Gastrointestinal Drugs Advisory Committee Meeting
March 6, 2003

19. Aprepitant Is a Moderate CYP3A4 Inhibitor
Inhibition of CYP3A4 Ranked According to Fold Increase in Oral Midazolam AUC
Clarithromycin
Itraconazole
Ketoconazole
Erythromycin
Diltiazem
Verapamil
Grapefruit juice
Weak
Moderate
Strong
Day: 1 5
Aprepitant (125 mg Day 1; 80 mg/d Days 2 to 5)
Aprepitant regimen for CINV produces CYP3A4 inhibition comparable to grapefruit juice and widely used drugs (e.g., diltiazem, verapamil).

20. Potential for interactions with other antiretrovirals that are metabolized or inhibited by CYP3A4
Moderate CYPA4 inhibitor
May increase the systemic exposure of antiretroviral drugs metabolized by CYP3A4 which can have a double effect:
Positive: increase antiretroviral exposure
Negative: increased risk for toxicity
Potential impact of antiretrovirals on aprepitant exposure (especially ritonavir)

21. Aprepitant Pharmacology: Summary
Novel potential mechanism of action
Blockade of (substance P) NK1 receptors
Effective against both acute and delayed emesis in humans through the same mechanism/s that we are proposing it will work as an antiviral
Favorable pharmacokinetics/pharmacodynamics
Once daily oral dosing
No dose adjustment in special populations
Well characterized drug interaction potential
Further characterization needed to evaluate interactions with other antiretrovirals (if antiviral activity is confirmed)

22. How are we going to do this?
Cross-validate aprepitant
LC/MS/MS method
(Constanzer et. al., 2004)
PK (NCA) of aprepitant in HIV-infected patients
(2-stage approach/ subgroup analysis)
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
Viral Dynamics
(NLMEM)
PD: Exposure-Response
NK response
(NLMEM)
PD: Exposure-response
Psychologic Disturbances
(Categorical Analysis)
Clinical Trial Simulation Model for Proof-of-Concept Phase IIA Trial

23. How are we going to do this?
Transfer aprepitant bioanalytical method to Core C.
Summarize basic PK of aprepitant in HIV-infected patients via standard noncompartmental methods.
Develop and validate population-based PK model to explain sources of variation in aprepitant exposure in HIV-infected patients.
Construct exposure-response relationships via PK/PD modeling for both safety and activity (psychologic disturbances, viral dynamics and NK response) in HIV-infected patients.
Develop clinical trial simulation model from which a Phase IIA proof-of-concept trial may be

24. CCR5 expression Natural Killer cell function
Project 4
Exploratory Aim 3: To evaluate the potential immunoregulatory role of NK-1R inhibition in HIV infected individuals
CCR5 expression
Natural Killer cell function

25. Lai, Jian-Ping et al. (2001) Proc. Natl. Acad. Sci. USA 98, 3970-3975
CCR5 and substance P
Substance P antagonists down- regulate CCR5 expression
CCR5 D32 heterozygosity is associated with slower disease progression
Lai, Jian-Ping et al. (2001) Proc. Natl. Acad. Sci. USA 98,
de Roda Husman, A.-M. et. al. Ann Intern Med 1997;127:

26. How are we going to do this?
IN VITRO
IN VIVO
Evaluate the effect of SP upon cytotoxicity (extend to fresh cells). Determine effect of SP on NK binding to target cells.
Determine effect of SP upon the cytotoxic activity and Ca++ flux induced by ligation of specific activating receptors.
Determine the effect of SP upon the expression of NK cell activating receptors including the NCRs.
Determine the effect of SP upon NK cell cytokine production.
Samples obtained from HIV-infected patients on 3 separate occasions prior to the initiation of aprepitant.
Absolute NK cell count.
NK cell percentage of total lymphocytes.
K562 lytic units per NK cell.
Expression of NCRs on NK cells.

27. Natural Killer cells and SP in HIV infection
Natural killer cell number and function reduced in HIV (Ullum H et al J. Exp. Med. 182: )
Natural killer number and function further diminished in HIV+ depressed subjects (Evans, Ten Have, Douglas et al Am. J. Psychiatry 159: )
3. Reduced natural killer activity is correlated with
elevated SP levels in HIV-infected men (Douglas, Ho, Evans, Cnaan AIDS 15: )

28. Function of Aprepitant in natural killer cell: in vitro studies

29. Function of Aprepitant in natural killer cell: ex vivo studies

30. Project 4
Exploratory Aim 4: Evaluation of the potential link between immune cell function and indices of neuropsychiatric disturbance: Depression, anxiety, fatigue, sleep quality, and neurocognitive function (Phase 1B study in Aim 1)

31. Aprepitant as an antidepressant
Major depression
N=117 (66A, 64P)
6 weeks
40 mg q day
Aprepitant had a significant antidepressant effect
Kramer MS, Winokur A, Kelsey J, et al.: Demonstration of the efficacy and safety of a novel Substance P (NK1) receptor antagonist in major depression. Neuropsychopharmacology (2004) 29,

32. Why and how to evaluate psychiatric symptoms in Project 4?
Aprepitant has been studied in depressed and anxious patients.
This is the first time aprepitant will be studied in HIV patients.
Pilot data will be needed on aprepitant effects on symptoms.
We will evaluate the effects of aprepitant in all participants (before and after dosing) on:
Neuropsychological functions using tests sensitive to HIV infection
Symptoms of depression
Complaints of poor sleep and daytime fatigue

33. Questions/future directions
Project 4
Questions/future directions
Should we include a study that evaluates interactions (both ways) of aprepitant with approved ARVs in patients with fully suppressed virus? or
Wait until we demonstrate antiviral activity?

34. Questions/future directions
Project 4
Questions/future directions
Obtain pilot data for estimating effect sizes now? or
Should we leave neuropsychiatric evaluations for Phase III trials?