GS-9350: A Pharmacoenhancer Without anti-HIV Activity AA Mathias, P German, M Lee, C Callebaut, L Xu, L Tsai, B Murray, H Liu, K Yale, D Warren and BP.

Slides:

Advertisements

Similar presentations

Daniel Everitt, MD; Erica Egizi MPH Global Alliance for TB Drug Development, New York Helen Winter, PhD University of Otago, New Zealand 2012 International.

Advertisements

Nuevos fármacos Pere Domingo Malalties Infeccioses Hospital de la Santa Creu i Sant Pau

VIREAD (Tenofovir DF) Update. Viread Update  Pharmacokinetics  Safety & Tolerability  Efficacy  Virology.

Scott Butler Infection Innovative Medicines Group AstraZeneca R&D, Boston CPTR Workshop, 2012 Arlington, VA AZD5847 Oxazolidinone for the treatment of.

New Antiretrovirals for the Treatment of HIV. Convenience, tolerability, simplicity New & Investigational Agents.

American Conference on Pharmacometics –San Diego, CA; April Population PK modeling incorporating enzyme induction mechanism to guide the design.

Phase 2 of new ARVs TAF (TFV prodrug) - Study Study

Phase 2 of new ARVs BMS (maturation inhibitor)

Phase 2 of new ARVs BMS , prodrug of BMS (attachment inhibitor) - AI Study.

Clinical Pharmacology Overview From the Antiviral Perspective Kellie Schoolar Reynolds, Pharm.D. Pharmacokinetics Team Leader Office of Clinical Pharmacology.

Drug-Like Properties: Optimizing Pharmacokinetics and Safety During Drug Discovery Li Di and Edward H. Kerns ACS Short Course.

Recommendations on integrated safety summaries from Phase 1 studies

“FUTURE CONSIDERATIONS FOR PK/PD RESEARCH” Terrence F. Blaschke, M.D. Professor of Medicine and Molecular Pharmacology Stanford University.

Interchangeability and study design Drs. Jan Welink Training workshop: Training of BE assessors, Kiev, October 2009.

Livalo (Pitavastatin)

Background: Focus on P-gp Questions:

Pharmacokinetic interactions of darunavir/ritonavir, efavirenz, and tenofovir with the HCV protease inhibitor faldaprevir in healthy volunteers John P.

Comparison of NRTI combinations  ZDV/3TC vs TDF + FTC –Study 934  ABC/3TC vs TDF/FTC –HEAT Study –ACTG A5202 Study –ASSERT Study  Comparison of TAF.

Significance of ARV Pharmacokinetics. Data Presentation.

Potent Antiretroviral Effect of MK-0518, a Novel HIV-1 Integrase Inhibitor, in Patients with Triple-class Resistant Virus Potent Antiretroviral Effect.

Comparison of PI vs PI  ATV vs ATV/r BMS 089  LPV/r mono vs LPV/r + ZDV/3TCMONARK  LPV/r QD vs BIDM M A5073  LPV/r + 3TC vs LPV/r + 2 NRTIGARDEL.

Update on Atazanavir and the Early Access Program AIDS Treatment Activists Coalition Seattle, Washington February

Comparison of RTV vs Cobi  GS-US Gallant JE. JID 2013;208:32-9 GS-US  Design  Objective –Non inferiority of COBI compared with RTV.

Pharmacokinetics of Saquinavir hard gel (Invirase) when combined with Atazanavir 8.11 D Prelutsky 1, P Salvato 2, R Falcon 3 1. Washington University School.

Regulatory requirements Drs. Jan Welink Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009.

RESEARCH Lymphatic Targeting of Tenofovir; Intracellular Pharmacokinetics and Viral Dynamics Arnold Fridland, Ph.D, William Lee, Ph.D. Gilead Sciences,

Clinical Aspects of Treatment with Tipranavir Dr Kevin Curry Boehringer Ingelheim, Bracknell, UK.

IAC 2006 Abs# THLB0214 Potent Antiretroviral Effect of MK-0518, a Novel HIV-1 Integrase Inhibitor, as part of Combination ART in Treatment -Naïve HIV-1.

1 Axcan Public Presentation for the FDA Pharmaceutical Science and Clinical Pharmacology Advisory Committee Meeting July 23, 2008.

1 Atazanavir (ATV) With Ritonavir (RTV) or Saquinavir (SQV) vs Lopinavir/Ritonavir (LPV/RTV) in Patients With Multiple Virologic Failures 24-Week Results.

Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November |1 | Prequalification programme: Priority.

Objective: To utilize preclinical and phase I PK/PD data from a new quinolone (Q) and relevant public domain data to develop an exposure-response model.

INJECTAFER Pharmacokinetics (PK) and Pharmacodynamics (PD) Christy S. John, Ph.D Division of Clinical Pharmacology V Office of Clinical Pharmacology Division.

Reesink H, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/28/09.

The effect of fluvoxamine on the pharmacokinetics, and safety of ivabradine in healthy subjects Adina Popa 1, Laurian Vlase 2, Maria Neag 3, Dana Muntean.

PO 2726; IAS; Vicriviroc (formerly SCH ): Antiviral Activity of a Potent New CCR5 Receptor Antagonist D. Schuermann, C. Pechardscheck, R. Rouzier,

Rivaroxaban Has Predictable Pharmacokinetics (PK) and Pharmacodynamics (PD) When Given Once or Twice Daily for the Treatment of Acute, Proximal Deep Vein.

© Copyright 2015 Galapagos NV Safety, tolerability and pharmacokinetics of a novel CFTR potentiator GLPG1837 in healthy volunteers F.P. Vanhoutte 1, M-H.

Grade Statistics without Bonus with Bonus Average = 86 Median = 87 Average = 88 Median = 89 Undergraduates Average=88 MS Average=92.

May 19, 2005FDA Antiviral Drugs Advisory Committee Meeting 1 Tipranavir NDA Drug Interactions Yuanchao (Derek) Zhang, Ph.D. Clinical Pharmacology.

Agenda  Update on Darunavir: Perry Mohammed  Update on Etravirine: Rekha Sinha  Update on TMC278: Peter Williams  Update on TMC207: Karel De Beule.

 Treatment regimens –Co-formulated ombitasvir (OBV)/paritaprevir (PTV)/rironavir (r) : 25/150/100 mg QD = 2 tablets –Dasabuvir (DSV) : 250 mg BID –RBV.

Overview of Drug Interactions Between Brecanavir (BCV) and Other HIV Protease Inhibitors (PIs) M Shelton, S Ford, M Anderson, S Murray, J Ng-Cashin XVI.

Comparison of PI vs PI  ATV vs ATV/r BMS 089  LPV/r mono vs LPV/r + ZDV/3TCMONARK  LPV/r QD vs BIDM M A5073  LPV/r + 3TC vs LPV/r + 2 NRTIGARDEL.

1 The Role of Exposure-Response Evaluation in Drug Development and Regulatory Decisions Case Study: Rosuvastatin Hae-Young Ahn, Ph.D. Office of Clinical.

Design of the RESIST Study Program Dr Kevin Curry Boehringer Ingelheim, Bracknell, UK.

항바이러스제 Ritonavir 양혜란. Ritonavir 화학명 1,3-Tiazol-5-ylmethyl[3-hydroxy-5-[3-methyl-2-[methyl-[(2-propan-2- yl-1,3-thiazole-4-yl)methyl]carbamoyl]-aminobutanoyl]amino-1,6-

Interchangeability and study design Drs. Jan Welink Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009.

Comparison of RTV vs Cobi  GS-US Gallant JE. JID 2013;208:32-9 GS-US  Design  Objective –Non inferiority of COBI compared with RTV.

Copyright © 2008 Merck & Co., Inc., Whitehouse Station, New Jersey, USA All rights Reserved Pharmacokinetic/Pharmacodynamic (PK/PD) Analyses for Raltegravir.

Lack of Pharmacokinetic Interaction Between Ritonavir-Boosted GS-9137 (Elvitegravir) and Tipranavir/r Anita A. Mathias 1, John Hinkle 1, Jeff Enejosa 1,

Slideset on: Gathe J, da Silva BA, Cohen DE, et al. A once-daily lopinavir/ritonavir-based regimen is noninferior to twice-daily dosing and results in.

Clinicaloptions.com/hepatitis Effect of Telaprevir on the Pharmacokinetics of Cyclosporine and Tacrolimus Slideset on: Garg V, van Heeswijk R, Lee JE,

Antiviral Activity of RDEA806, a Novel HIV Non-Nucleoside Reverse Transcriptase Inhibitor, in Treatment of Näive HIV Patients G. Moyle, M. Boffito, K.

Figure 1: Mean comparative midazolam plasma concentration-time plot

Comparison of INSTI vs INSTI

Pharmacokinetics.

…driving discovery An improved potent direct thrombin inhibitor shows efficacy with low bleeding risk Anirban Datta et al.

Senior Medical Director, Cardiovascular

Pharmacokinetics and Drug Interactions in the new HCV Clinical Management SOC.

TAK-715 p38MAPK inhibitor Summary

Switch to E/C/F/TAF + DRV

Comparison of NRTI combinations

Comparison of PI vs PI ATV vs ATV/r BMS 089

AChE (Acetylcholinesterase) inhibitor

Comparison of PI vs PI ATV vs ATV/r BMS 089

Comparison of INSTI vs INSTI

Comparison of NRTI combinations

NGM282 in NASH: 3 mg QD (phase 2)

Safety and Antiviral Activity Over 10 Days Following a Single Dose of Subcutaneous GS-6207, a First-in-Class, Long-Acting HIV Capsid Inhibitor in People.

Presentation transcript:

GS-9350: A Pharmacoenhancer Without anti-HIV Activity AA Mathias, P German, M Lee, C Callebaut, L Xu, L Tsai, B Murray, H Liu, K Yale, D Warren and BP Kearney Gilead Sciences Foster City, CA, USA

Potent, irreversible (mechanism-based) inhibition of CYP3A No anti-HIV activity Keys to Pharmacoenhancement GS-9350RTV k inact (min -1 ) K I (µM) mean of 5 experiments Antiviral Assay EC 50 (  M) GS-9350RTVFold-difference - w/o human serum - 40% human serum > 30 > > 2000 > 1500 mean of > 5 experiments

Greater CYP450 enzyme inhibition specificity Less induction of drug metabolizing enzymes and transporters Keys to Pharmacoenhancement CYP450 enzyme IC 50 (µM) 1A22B62C82C92C192D63A* GS-9350> > RTV> > * midazolam 1’-hydroxylase (no preincubation) mean of 3 experiments conducted in duplicate

Reduced potential for lipid abnormalities Improved physicochemical properties Keys to Pharmacoenhancement Drug Adipocyte Function Assays Inhibition of Normal Lipid Accumulation (EC 50 µM) % Inhibition of Glucose 10µM RTV1655 GS-9350> ATV> Aqueous Solubility (  g/mL) GS-9350RTVFold-difference pH 7.475~ pH 2.2> > 2100 mean of 5 experiments /assay mean of 2 experiments conducted in duplicate

Study GS Evaluate GS-9350 safety, tolerability, PK and PD (anti-CYP3A activity) – Double-blind, double-dummy, active and placebo controlled study in HIV(-) subjects 3 dose-escalation cohorts: 50, 100 and 200mg tablets (N = 12 /cohort) RTV 100mg & dual placebo (each N = 3 /cohort) –Single and multiple dose PK, safety and tolerability –Steady-state PD: change from pre-treatment PK of “metabolic probe” oral midazolam 50 mg Single Dose PK 50 mg x 14 Days PK/PD 100 mg Single Dose PK 100 mg x 14 Days PK/PD 200 mg X 14 Days PK/PD Pre-treatment safety and PD assessments Study drugs administered with food

PK/PD Results GS-9350 exhibited non-linear increases in exposure with dose and time –Time- and dose-dependent PK consistent with mechanism-based inhibition GS-9350 achieved potent inhibition of CYP3A activity –Near-maximal inhibition achieved at ≥ 100mg

Study GS Evaluate the relative bioavailability, PK and safety of EVG/FTC/TDF/GS-9350 FDC tablet vs. EVG/r and FTC + TDF –Open-label, partially-randomized, adaptive study design in HIV(-) subjects (N = 44) 100 mg starting GS-9350 dose → 75 or 150 mg GS-9350 containing FDC EVG/FTC/TDF/GS /200/300/100mg EVG + RTV 150mg + 100mg FTC + TDF 200mg + 300mg EVG/FTC/TDF/GS /200/300/100mg EVG + RTV 150mg + 100mg EVG/FTC/TDF/GS /200/300/150mg Real-time GS-9350 & EVG PK analysis Study drugs administered with food

Mean (CV%) EVG PK (n = 42) GS mg FDCGS mg FDCEVG + RTV 100mg AUC tau (ng.hr/mL)21100 (25.4)27000 (29.4)22500 (23.4) C max (ng/mL)2250 (26.3)2660 (27.6)2500 (32.1) C tau (ng/mL)282 (60.4)490 (52.9)409 (40.5) Elvitegravir PK GS-9350 effectively boosts EVG within FDC tablet High EVG trough concentrations maintained w/ GS mg –11-fold above the protein binding-adjusted IC 95 (44.5 ng/mL) –Low within-subject variability (15% CV)

FTC and TFV exposures clinically equivalent –FTC exposures increased 20% as FDC vs. FTC capsule –TFV AUC bioequivalent as FDC or TDF tablet EVG/FTC/TDF/GS mgFTC + TDF Mean (CV%) PK (n = 42) FTCTFVFTCTFV AUC tau (ng.hr/mL) (19.3)3010 (20.4)9330 (22.1)2550 (22.6) C max (ng/mL)1850 (22.5)332 (28.9)1600 (26.1)252 (24.9) C tau (ng/mL)101 (26.8)65.0 (26.0)80.1 (25.9)52.0 (25.4) FTC/TDF PK

Safety Summary GS-9350 first-in-man, dose-ranging study –Single and multiple doses up to 200 mg well tolerated –No drug-related Grade 3/4 laboratory abnormalities –Single Grade 3 adverse event of discoordination (GS mg) –No changes or differences observed in serum lipids across treatments over 14 days Integrase FDC “Quad” tablet study –All treatments well tolerated –Two Grade 3 adverse events Single subject with drug-related ALT elevation (GS mg FDC) One subject with acute appendicitis –No other drug-related Grade 3/4 laboratory abnormalities

Conclusions GS-9350 is a potent, selective, mechanism-based CYP3A inhibitor that lacks anti-HIV activity and has limited effects on adipocyte function in vitro GS-9350 boosts CYP3A substrates comparable to RTV in humans EVG/FTC/TDF/GS-9350 FDC tablet achieves desired exposures of EVG, FTC and TFV

GS-9350 & Ritonavir PK Mean (CV%) PK (n = 42) GS mg FDCGS mg FDCRTV 100mg AUC tau (ng.hr/mL)5150 (31.7)10400 (35.2)5750 (38.4) C max (ng/mL)855 (27.6)1570 (29.7)1030 (47.8) C tau (ng/mL)7.6 (124)22.7 (107)37.6 (52.2)