Challenges in Infectious Diseases Lessons from tuberculosis Gerry - - PowerPoint PPT Presentation
Challenges in Infectious Diseases Lessons from tuberculosis Gerry Davies Senior Lecturer in Infection Pharmacology Institutes of Global Health and Translational Medicine Consortium for Pharmacokinetics & Pharmacodynamics of Infectious
Lessons from tuberculosis
Gerry Davies
Senior Lecturer in Infection Pharmacology Institutes of Global Health and Translational Medicine
Consortium for Pharmacokinetics & Pharmacodynamics of Infectious Agents
More than one biological system/entity Combination therapy routine Complex patterns of pharmacodynamic response Persistence and resistance Microbiological versus clinical response Important events below LOD Empirical versus mechanistic approaches
What's so different about infectious diseases ?
2 billion latent infections
26% of avoidable adult deaths in developing world 2 million deaths /yr
8-10 million new cases/yr
Short Course treatment for TB
SHR HR SHRZ/TH SHRZ/SHZ
Relapse 6 months 2 months
10 20 30 40 Percent Positive
SHRZ/HRZ SHRZ/HR SHRZ/HZ SHRZ/H HRZ/H
Relapse 6 months 2 months
10 20 30 40 Percent Positive
N=953 ~240 per arm N=696 ~130 per arm
THE LANCET, NOVEMBER 9, 1974 CONTROLLED CLINICAL TRIAL OF FOUR SHORT- COURSE (6-MONTH) REGIMENS OF CHEMOTHERAPY FOR TREATMENT OF PUMONARY TUBERCULOSIS
SECOND EAST AFRICAN / BRITISH MEDICAL RESEARCH COUNCIL STUDY
THE LANCET, AUGUST 12, 1978 CONTROLLED CLINICAL TRIAL OF FIVE SHORT-COURSE (4-MONTH) CHEMOTHERAPY REGIMENS IN PULMONARY TUBERCULOSIS
First Report of 4th Study
EAST AFRICAN AND BRITISH MEDICAL RESEARCH
COUNCILS
TB pandemic 2010
80% in 22 high burden countries 30% in India & China
New anti-tuberculosis drugs
Rifabutin Rifapentine Levo/ofloxacin Moxifloxacin Gatifloxacin PA-824 OPC-67683 TMC-207
15 BMRC trials 6974 participants 37 treatment comparisons
Bacteriological biomarkers are useful surrogate endpoints
Phillips PJ et al IUATLD Cape Town 2007
Phillips P and Fielding K 2008 IUATLD Conference Paris
0.1 0.2 0.3 0.4 0.5 0.6 1 10 100 1000 10000
Log Dose (mg) EBA
0-2 (Log 10 CFU/ml/day) H R Rb Rp Cp S
Early Bactericidal Activity
Bacillary elimination is biphasic
Nairobi SHRZ N=46 Durban HRZE N=50 Bangkok HRZE N=44 Davies G Tuberculosis (Edinb). 2010 90(3):171-6
Modelling Phase II trials
Predictions from unadjusted model
Rustomjee R et al . Int J Tuberc Lung Dis. (2008) 12(2):128-38
Limit of detection
N=159
NONMEM M3 Method WinBUGS I() Method
Davies Gordon Conference on TB drug development 2011
Power advantages of NLME
Randomize d treatment allocation in blocks of 10 Generate profiles of bacillary load from day 7 -56 Generate individual day 7 intercept and slope from random effect distributions Censor at limits of detection Generate datasets for each form of analysis Store effect sizes, p-values, culture conversion rates N >
simulations ? Compute power and plot diagnostics Compute summary statistics and perform analyses
N+1
N=31 N=31
p=0.010 p=0.635
Detection of PK-PD relationships
Isoniazid Rifampicin
Abstract OI-106 CROI 2008
Patterns of PD response
Bedaquiline (TMC-207) Delaminid (OPC-67683)
Diacon AH 2011 IJTLD 15(7):949–954 Rustomjee R 2008 AA&C 52(8):2831-5
Fast Slow
Speed of bacterial growth
A CONTINUOUS GROWTH
D DORMANT B ACID INHIBITION C SPURTS OF METABOLISM
H (R, S) Z R
The Subpopulations hypothesis
Mitchison 1978 Canetti 1969
Persister phenotype in sputum
Garton NJ PLoS Med 2008 5(4):e75 Schoolnik Keystone 2009
334 genes down- regulated in both NRP2 and sputum 182 genes up- regulated in both NRP2 and sputum
icl,hspX,whiB6 fadD & E families, other members
rpl, rps, atp, nuo, inhA, fas,whiB1, sigH, sigD
Semi-mechanistic PD model
Davies GR Tuberculosis (Edinb). 2010 90(3):171-6
Disease modelling in TB
Summary
A PK-PD approach promises more rational clinical development of new combination therapies for tuberculosis Efficient proof-of-concept, screening of combinations and dose-finding may be possible using model-based designs Mechanistic modelling of the underlying mechanisms of sterilization may be the only way to correctly interpret the results of future early phase clinical trials
Acknowledgements
Mahidol-Wellcome-Oxford SEA Unit
Nick White Kasia Stepniewska Wirongrong Cheirakul
St George’s / InterTB
Dennis Mitchison Amina JIndani David Coleman
Training fellowship GR067910MA PKPDia Programme grant
University of Liverpool
Saye Khoo Dave Back Andrew Owen
CAPKR, University of Manchester
Leon Aarons
South African Medical Research Council, Durban
Roxana Rustomjee Jonathan Levin Jenny Allen Alex Pym
Bamrasnaradura Infectious Diseases Institute Nartpratou Saguenwong
Boonchuay Eompokalap
Siriraj Hospital, Faculty
Nitipatana Cheirakul Angkana Chaiprasert
Oflotub Consortium
Christian Lienhardt
Tom Kanyok John Horton
Harvard University & Socios en Salud
Carol Mitnick
CDC TB trials consortium
Chad Heilig Andy Vernon
Liverpool School of Tropical Medicine
Steve Ward Bertie Squire Andy Ramsay