Population PK/PD analysis of the bactericidal activity of sutezolid and its major metabolite against intracellular Mtb in whole blood cultures of TB patients.

Slides:

Advertisements

Similar presentations

Dose Escalating Safety Study of a New Oral Direct Thrombin Inhibitor, Dabigatran Etexilate, in Patients Undergoing Total Hip Replacement: BISTRO I Eriksson.

Advertisements

A 23 Variability in the Size of the Fluoroquinolone AUC/MIC for Antibacterial Effect in S.aureus: Impact for Clinical Breakpoints A. R. Noel, K.E. Bowker,

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

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

Safety, tolerability and early bactericidal activity in sputum of PNU (sutezolid) in patients with pulmonary tuberculosis RS Wallis 1, AH Diacon.

QUANTITATIVE ASPECTS OF DRUG ACTIONS DR. SHABANA ALI.

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

Rationale for New Drugs for Tuberculosis 500,000 cases annually of MDR TB – Second line treatment toxic and weak 15% of TB is HIV-related – Drug-drug interactions.

Improvement in Dose Selection Through Clinical Applications of PK/PD in Antimicrobial Drug Development Hartmut Derendorf, Ph.D. University of Florida.

Eccmid 2003 Aminoglycosiden bij neonaten Canisius-Wilhelmina Hospital Nijmegen, The Netherlands Johan W Mouton Relationship between bacterial killing,

Ibrance® - Palbociclib

Plasmids Chromosome Plasmid Plasmid + Transposon Plasmid + integron Plasmid+transposon +intergron Chromosome Chromosome + transposon Chromosome + transposon.

Interim analysis of a double- blind, placebo-controlled study with TMC207 in patients with Multi-Drug Resistant (MDR) Tuberculosis Karel de Beule, CDTL.

Office of Drug Evaluation IV, CDER FDA/IDSA/ISAP Workshop 4/16/04 Overview of PK-PD in Drug Development Programs: FDA Perspective FDA/IDSA/ISAP Workshop.

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

Charge to the Committee Kimberly Struble, Pharm.D. Regulatory Review Officer Division of Antiviral Drug Products.

Persisting long term benefit of genotypic guided treatment in HIV infected patients failing HAART and Importance of Protease Inhibitor plasma levels. Viradapt.

Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 1 Improvement in Dose Selection: FDA Perspective IDSA/ISAP/FDA Workshop.

PK/PD: New Microbial Diseases and Model Systems Tawanda Gumbo, MD Associate Professor of Medicine, Division of Infectious Diseases, University of Texas.

Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 In Vitro/Animal Models to Support Dosage Selection: FDA Perspective.

Carbapenem Activity Against Acinetobacter calcoaceticus-baumanii complex (ACBC) in an In Vitro Pharmacokinetic Bacteremia Model (PKM) Eric G Sahloff, Pharm.D.,

PK/PD of Antibiotics in relation to resistance Otto Cars MD Department of Medical Sciences Infectious diseases Uppsala University Sweden.

CLEARANCE CONCEPTS Text: Applied Biopharm. & PK

1 I4E-MC-JXBA and JXBB Phase 2 Study to Evaluate the PK and Drug-Drug Interaction of Cetuximab and Cisplatin (JXBA) Cetuximab and Cisplatin (JXBB)

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

Application of PK/PD modeling for optimization of linezolid therapy Julia Zayezdnaya Zack.

A New Oral Direct Thrombin Inhibitor, Dabigatran Etexilate, Compared With Enoxaparin for Prevention of Thromboembolic Events Following Total Hip or Knee.

Pharmacodynamics of Antimicrobials in Animal Models William A. Craig, M.D. University of Wisconsin-Madison.

Background Objectives Data Simulation in human Conclusion -F14512, a polyamine-vectorized anti-cancer drug which combines an epipodophyllotoxin core targeting.

EMEA London Pharmacokinetic- pharmacodynamic integration in veterinary drug development: an overview P.L. Toutain National Veterinary School ;Toulouse.

A Pharmacodynamic Model for Cefprozil against Haemphilus influenzae in an in vitro Infection Model across Multiple Regimens Olanrewaju O. Okusanya, Pharm.D,

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.

CR-1 Everolimus Benefit/Risk Assessment Howard J. Eisen, MD Thomas J. Vischer Professor of Medicine Chief, Division of Cardiology Drexel University College.

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

Core Concepts in Pharmacology Chapter 5 Pharmacokinetics.

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

Issues in testing regimens containing multiple novel agents I. Preclinical Testing Jacques Grosset Johns Hopkins University School of Medicine, Baltimore,

1 METHODS FOR DETERMINING SIMILARITY OF EXPOSURE-RESPONSE BETWEEN PEDIATRIC AND ADULT POPULATIONS Stella G. Machado, Ph.D. Quantitative Methods and Research.

Phase I Issues for Novel TB Drugs Dakshina M. Chilukuri, Ph.D. Office of Clinical Pharmacology and Biopharmaceutics, FDA OPEN FORUM ON KEY ISSUES IN TB.

Pharmacodynamics of Antifungals

Issues in development for an MDR TB indication Leonard Sacks MD Division of special pathogens and transplant products FDA.

Relationship between Time to Eradication in vivo & Bactericidal Activity in vitro of Vancomycin for MRSA Infections Pamela A. Moise-Broder Alan Forrest.

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

Organization of statistical research. The role of Biostatisticians Biostatisticians play essential roles in designing studies, analyzing data and.

BIOPHARMACEUTICS.

Systemic Exposure of Topical Tacrolimus Veneeta Tandon, Ph.D. Pharmacokinetics Reviewer Division of Pharmaceutical Evaluation III Office of Clinical Pharmacology.

Antibiotic Resistance Emerging antibiotic resistance is a major health concern. 2 million people in the U.S. infected with antibiotic resistant bacteria.

Serum levels of aripiprazole and dehydroaripiprazole, clinical response and side effects Linas Martinaitis Erasmus =)

BIOSTATISTICS Lecture 2. The role of Biostatisticians Biostatisticians play essential roles in designing studies, analyzing data and creating methods.

Acute Bacterial Otitis Media Summary and Charge to the Committee Renata Albrecht, M.D. Division of Special Pathogen and Immunologic Drug Products ODEIV,

PHT 415 BASIC PHARMACOKINETICS

Improvement in Dose Selection Through Clinical PK/PD in Antimicrobial Drug Development: Perspective of an Industry PK/PD Scientist Gregory A. Winchell,

Pharmacokinetics (PK) and Pharmacodynamics (PD) of Rivaroxaban: A Comparison of Once- and Twice-daily Dosing in Patients Undergoing Total Hip Replacement.

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

Effect of Four Different Meal Types on the Population Pharmacokinetics of Single Dose of Rifapentine in Healthy Male Volunteers Simbarashe P. Zvada 1,

MULTIPLE DOSAGE REGIMEN

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

Lenalidomide plus dexamethasone is more effective than dexamethasone alone inpatients with relapsed or refractory multiple myeloma regardless of prior.

Fadiea Al-Aieshy PhD-student, MSc Pharm

Chapter 8 BIOAVAILABILITY & BIOEQUIVALENCE

Identification of optimal dose and dosing regimen of clofazimine for the treatment of multi-drug resistant tuberculosis (MDR-TB) based on pharmacokinetic.

Pharmacokinetic Modeling (describing what happens)

Pharmacodynamics of novel Mycobacteria tuberculosis DNA gyrase inhibitors EMMANUEL MOYO.

W.W. Hope, G.L. Drusano Clinical Microbiology and Infection

Activities of antistaphylococcal antibiotics towards the extracellular and intraphagocytic forms of Staphylococcus aureus isolates from a patient with.

Antibiotic Resistance Emerging antibiotic resistance is a major health concern. 2 million people in the U.S. infected with antibiotic resistant bacteria.

Activities of antistaphylococcal antibiotics towards the extracellular and intraphagocytic forms of Staphylococcus aureus isolates from a patient with.

Selected Bioavailability and Pharmacokinetic Calculations

Hollow Fiber Infection Model for Antibiotic PK/PD

MDR-TB Clinical Trials Landscape Overview: Current and Future Trials

Presentation transcript:

Population PK/PD analysis of the bactericidal activity of sutezolid and its major metabolite against intracellular Mtb in whole blood cultures of TB patients Tong Zhu 1, Sven Friedrich 2, Andreas Diacon 2, and Robert Wallis 1 1 Pfizer, Groton CT; 2 Stellenbosch University, Cape Town, South Africa

Sutezolid First oxazolidinone developed for TB Parent: PNU or U-480 Metabolite: PNU or U-603 MICs are similar when tested on agar After oral dosing, plasma concentrations of metabolite are several fold higher than parent Louie & Drusano found killing of extracellular Mtb in hollow fibers mainly due to the metabolite Converse & Nuermberger found killing of intracellular Mtb in cell culture models mainly due to the parent

Objective To develop a PK/PD model describing the relative contributions of sutezolid and its metabolite against intracellular Mtb in vivo in patients with pulmonary tuberculosis.

Methods Data (plasma concentrations of U-480 and U-603, and corresponding whole blood bactericidal activity [WBA]) came from patients treated with sutezolid 600 mg BID (N=25) or 1200 mg QD (N=25) enrolled the sutezolid EBA trial (B ). A 4 parameter sigmoid curve was used to describe the concentration-activity relationship, based on prior observations that killing was concentration-dependent at low concentrations, but did not increase further once a maximal response (Imax) was reached. The activities of U-480 and U-603 were assumed competitive, based on prior observations that U-603 did not further increase the activity of optimal concentrations of U-480.

Equations Predicted result Value in the absence of drug Maximal effect Fraction of IC 50 Shape (Hill) factor Dilution factor

Data set 690 PK and 345 WBA determinations at 0, 1, 2, 3, 6, 8, and 12 hrs post dose measured on days The median ratio of U-603/U-480 plasma concentrations was 7.1 (range, 1 to 28). High ratios mainly occurred at late time points in the dosing interval. The wide range of values facilitated modeling of the relative contributions of parent and metabolite.

Diagnostic plots

Parameters ParameterEstimate90% CI Fixed effects WBA to I max to IC ng/mL to 84.9 IC ng/mL to 2960  to 3.2  603 (0.94)- Random effects WBA 0 (%) to 35.2 Sigma (%) to x 2x

Predicted drug activity (in vitro) 11x

Predicted drug activity (in vivo) Discrete timepoints Cumulative activity 80% of activity due to parent BID superior to QD

Conclusions Killing of intracellular Mtb by oral sutezolid is mainly due to the parent, despite the higher plasma concentrations reached by the metabolite. Intracellular drug accumulation may account for this Mtb subpopulations have distinct roles in TB: Extracellular: resistance and treatment failure Intracellular: persistence and relapse Factors that differentially affect exposure to parent and metabolite (e.g., dosing schedules, induction of metabolism) may have different effects on these 2 outcomes.