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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,

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Presentation on theme: "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,"— Presentation transcript:

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 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. Project 4

3 Rationale for the selection of Aprepitant

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

5 2.Aprepitant Blocks Brain NK 1 Receptors in Humans Binding of PET tracer to NK 1 receptors prior to aprepitant dosing Blockade of NK 1 receptors after aprepitant dosing Aprepitant Plasma Trough Concentration (ng/mL) Brain NK 1 Receptor Occupancy (%) Mean (± SD) Plasma Trough Concentrations of the Aprepitant 3-Day Regimen Low High Tracer Binding

6 3.Aprepitant has well-characterized PK that permits once daily dosing in CINV 125 mg80 mg Time Postdose (hr) N=12 Aprepitant Plasma Concentration (ng/mL)

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

8 Number of Patients Receiving Aprepitant Phase I clinical pharmacology studies Studies in non-cancer patients Studies in patients receiving cancer chemotherapy Phase II915 Phase III Total 3342 Clinical Development Program

9 APR 125/80 (N=544) % Control (N=550) % Adverse experiences (AEs) Drug-related AEs Serious AEs Discontinuations due to AEs Deaths Percent of Patients with: Phase III: Cycle 1 5. Aprepitant is safe, approved & available. Clinical Adverse Experience Summary Clinical Adverse Experience Summary Aprepitant is approved by the FDA for emesisAprepitant is approved by the FDA for emesis Readily availableReadily 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) 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 EndpointsEndpoints 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 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 With a total of 13 subjects in a group, the width of a 95% confidence interval around the  log 10 viral load, with 90% coverage, will be 1.5 s.d.’s of the  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 With a total of 13 subjects in a group, the width of a 95% confidence interval around the  log 10 viral load, with 90% coverage, will be 1.5 s.d.’s of the  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 True Toxicity Level Prob to observe > 1 event w n=13 Prob to observe > 1 event w n=

15 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. Project 4

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

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) 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) NK 1 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) Novel potential mechanism of action –Blockade of (substance P) NK 1 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 Cross-validate aprepitant LC/MS/MS method (Constanzer et. al., 2004) PK (NCA) of aprepitant in HIV-infected patients (2-stage approach/ subgroup analysis) Individual predicted pop-PK from final model (MAP Bayesian) PD: Exposure-response Psychologic Disturbances (Categorical Analysis) PD: Exposure-Response Viral Dynamics (NLMEM) PD: Exposure-Response NK response (NLMEM) PD: Exposure-response Safety 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 How are we going to do this?

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

25 Substance P antagonists down- regulate CCR5 expression CCR5  32 heterozygosity is associated with slower disease progression Substance P antagonists down- regulate CCR5 expression CCR5  32 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: CCR5 and substance P

26 How are we going to do this? 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. 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. IN VIVO IN VITRO

27 Natural Killer cells and SP in HIV infection 1.Natural killer cell number and function reduced in HIV (Ullum H et al J. Exp. Med. 182: ) 2.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 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) Project 4

31 Aprepitant as an antidepressant 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, Major depression N=117 (66A, 64P) 6 weeks 40 mg q day Aprepitant had a significant antidepressant effect Major depression N=117 (66A, 64P) 6 weeks 40 mg q day Aprepitant had a significant antidepressant effect

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 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 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? 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? Project 4

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


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