Presentation on theme: "Human studies of neurokinin-1 receptor antagonists in HIV-1"— Presentation transcript:
1 Human studies of neurokinin-1 receptor antagonists in HIV-1 Project 4Human studies of neurokinin-1 receptor antagonists in HIV-1PI: 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 4Aim 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.
4 Substance P antagonists have antiviral activity in vitro Effect of CP-96,345 on HIV infection of MDMLai, 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 RegimenBinding of PET tracer to NK1 receptors prior to aprepitant dosing102030405060708090100Brain NK1 Receptor Occupancy (%)Blockade ofNK1 receptors after aprepitant dosing110100100010000Aprepitant Plasma Trough Concentration (ng/mL)Low HighTracer Binding
6 Aprepitant Plasma Concentration (ng/mL) Aprepitant has well-characterized PK that permits once daily dosing in CINV125 mg80 mg80 mgAprepitant Plasma Concentration (ng/mL)N=12Time Postdose (hr)
7 Aprepitant works and it has been tried in large populations. Complete Response: Acute and Delayed PhasesProtocol 052Protocol 054p<0.001p<0.001p<0.001p<0.00189%83%78%75%68%68%56%47%N=259260260260261263260263
8 Clinical Development Program Number of Patients Receiving AprepitantPhase I clinical pharmacology studiesStudies in non-cancer patientsStudies in patients receiving cancer chemotherapyPhase II Phase III 54471111721459Total
9 5. Aprepitant is safe, approved & available. Clinical Adverse Experience SummaryAPR 125/80(N=544) %220.127.116.11.73.7Control (N=550) %67.612.718.104.22.168Adverse experiences (AEs)Drug-related AEsSerious AEsDiscontinuations due to AEsDeathsPercent of Patients with:Phase III: Cycle 1Aprepitant is approved by the FDA for emesisReadily available
10 How do we want to test it? Phase 1b randomized blinded study
11 Main inclusion criteria HIV-1 infectionCD4+ cell count ≥ 350/mm3Plasma HIV-1 RNA of ≥2000 copies/mLStable hepatic, renal, and hematological indicesNot pregnantNo current serious psychiatric disorder (by SCID)
12 Endpoints Primary endpoints Safety and PK HIV-1 RNA compared with baseline.Secondary endpointsCD4+ and CD8+ T-cell counts, T-cell activation, and proliferationIf we demonstrate antiviral activity: check for amino acid substitutionsCCR5 expression in peripheral PBMCsFasting plasma glucose, insulin, HDL, FFA, and TG at 28 days.Fatigue and poor sleep, anxiety and depressed mood; neuropsychiatric measures
14 Sample size justification True Toxicity LevelProb to observe > 1 event w n=13Prob to observe > 1 event w n=26.02.23.41.04.65.06.55.80.08.66.89.22.214.171.124.95.997With a total of 13 subjects in a group, the width of a 95% confidence interval around theD 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 toxicitiesStudy large enough for viral dynamics analysis
15 Project 4Aim 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 isozymeInhibits CYP3A4 with aprepitant regimen (as early as 1 hr after Day 1 dosing)Induces CYP2C9 with aprepitant regimenInduces its own metabolism upon dosing for 2 weeks (autoinduction)
17 Effect of Aprepitant on CYP3A4 Drugs Gastrointestinal Drugs Advisory Committee MeetingMarch 6, 2003
18 Effect of Other Drugs on Aprepitant Gastrointestinal Drugs Advisory Committee MeetingMarch 6, 2003
19 Aprepitant Is a Moderate CYP3A4 Inhibitor Inhibition of CYP3A4 Ranked According to Fold Increase in Oral Midazolam AUCClarithromycinItraconazoleKetoconazoleErythromycinDiltiazemVerapamilGrapefruit juiceWeakModerateStrongDay: 1 5Aprepitant (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 inhibitorMay increase the systemic exposure of antiretroviral drugs metabolized by CYP3A4 which can have a double effect:Positive: increase antiretroviral exposureNegative: increased risk for toxicityPotential impact of antiretrovirals on aprepitant exposure (especially ritonavir)
21 Aprepitant Pharmacology: Summary Novel potential mechanism of actionBlockade of (substance P) NK1 receptorsEffective against both acute and delayed emesis in humans through the same mechanism/s that we are proposing it will work as an antiviralFavorable pharmacokinetics/pharmacodynamicsOnce daily oral dosingNo dose adjustment in special populationsWell characterized drug interaction potentialFurther characterization needed to evaluate interactions with other antiretrovirals (if antiviral activity is confirmed)
22 How are we going to do this? Cross-validate aprepitantLC/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 ModelCovariate ModelError ModelValidation (data splitting or bootstrapping)Individual predicted pop-PK from final model (MAP Bayesian)PD: Exposure-responseSafety Indices(Logistic Regression)PD: Exposure-ResponseViral Dynamics(NLMEM)PD: Exposure-ResponseNK response(NLMEM)PD: Exposure-responsePsychologic 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 4Exploratory Aim 3: To evaluate the potential immunoregulatory role of NK-1R inhibition in HIV infected individualsCCR5 expressionNatural Killer cell function
25 Lai, Jian-Ping et al. (2001) Proc. Natl. Acad. Sci. USA 98, 3970-3975 CCR5 and substance PSubstance P antagonists down- regulate CCR5 expressionCCR5 D32 heterozygosity is associated with slower disease progressionLai, 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 VITROIN VIVOEvaluate 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 withelevated 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 4Exploratory 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 depressionN=117 (66A, 64P)6 weeks40 mg q dayAprepitant had a significant antidepressant effectKramer 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 infectionSymptoms of depressionComplaints of poor sleep and daytime fatigue
33 Questions/future directions Project 4Questions/future directionsShould we include a study that evaluates interactions (both ways) of aprepitant with approved ARVs in patients with fully suppressed virus?orWait until we demonstrate antiviral activity?
34 Questions/future directions Project 4Questions/future directionsObtain pilot data for estimating effect sizes now?orShould we leave neuropsychiatric evaluations for Phase III trials?