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 Agents
What's so different about infectious diseases ? 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
2 billion latent infections 8-10 million new cases/yr 2 million 26% of avoidable deaths /yr adult deaths in developing world
Short Course treatment for TB THE LANCET, NOVEMBER 9, 1974 THE LANCET, AUGUST 12, 1978 CONTROLLED CLINICAL TRIAL OF FOUR SHORT- CONTROLLED CLINICAL TRIAL OF FIVE COURSE (6-MONTH) REGIMENS OF SHORT-COURSE (4-MONTH) CHEMOTHERAPY CHEMOTHERAPY FOR TREATMENT OF REGIMENS IN PULMONARY TUBERCULOSIS PUMONARY TUBERCULOSIS First Report of 4 th Study E AST AFRICAN AND BRITISH MEDICAL RESEARCH SECOND EAST AFRICAN / BRITISH COUNCILS MEDICAL RESEARCH COUNCIL STUDY N= 696 N=953 ~130 per arm ~240 per arm 40 40 Percent Positive 30 Percent Positive 30 20 20 10 10 2 months 2 months 6 months 6 months 0 0 Relapse Relapse SHRZ/HRZ SHR SHRZ/HR HR SHRZ/HZ SHRZ/TH SHRZ/H SHRZ/SHZ HRZ/H
TB pandemic 2010 80% in 22 high burden countries 30% in India & China
New anti-tuberculosis drugs Levo/ofloxacin PA-824 Rifabutin OPC-67683 Moxifloxacin Rifapentine Gatifloxacin TMC-207
Bacteriological biomarkers are 15 BMRC trials 6974 participants 37 treatment comparisons useful surrogate endpoints Phillips P and Fielding K 2008 IUATLD Conference Paris Phillips PJ et al IUATLD Cape Town 2007
Early Bactericidal Activity 0.6 H R 10 CFU/ml/day) 0.5 Rb Rp 0.4 Cp S 0.3 0.2 0-2 (Log 0.1 EBA 0 1 10 100 1000 10000 -0.1 -0.2 Log Dose (mg)
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 individual day 7 intercept and slope from random effect distributions Generate profiles of bacillary load from day 7 -56 Censor at limits of detection N+1 Generate datasets for each form of analysis Compute summary statistics and perform analyses Store effect sizes, p-values, culture conversion rates N > No. of simulations ? Compute power and plot diagnostics
Detection of PK-PD relationships Isoniazid Rifampicin N=31 N=31 p=0.635 p=0.010 Abstract OI-106 CROI 2008
Patterns of PD response Delaminid (OPC-67683) Bedaquiline (TMC-207) 0 0 Rustomjee R 2008 AA&C 52(8):2831-5 Diacon AH 2011 IJTLD 15(7):949–954
The Subpopulations hypothesis H Fast (R, S) A Z R CONTINUOUS Speed of GROWTH bacterial growth B C ACID SPURTS OF INHIBITION METABOLISM D DORMANT Slow Canetti 1969 Mitchison 1978
Persister phenotype in sputum 334 genes down- regulated in both NRP2 and sputum rpl, rps, atp, nuo, inhA, fas,whiB1, sigH, sigD 182 genes up- regulated in both NRP2 and sputum icl,hspX,whiB6 fadD & E families, other members Garton NJ PLoS Med 2008 5(4):e75 Schoolnik Keystone 2009 of dosR regulon
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 South African Medical Bamrasnaradura Infectious Siriraj Hospital, Faculty Oflotub Consortium Research Council, Durban Diseases Institute of Medicine Christian Lienhardt Roxana Rustomjee Nartpratou Saguenwong Nitipatana Cheirakul Tom Kanyok Jonathan Levin John Horton Angkana Chaiprasert Jenny Allen Boonchuay Eompokalap Alex Pym Mahidol-Wellcome-Oxford Dept. of Pharmacology, Liverpool School of St George’s / InterTB SEA Unit University of Liverpool Tropical Medicine Dennis Mitchison Nick White Saye Khoo Steve Ward Amina JIndani Dave Back Bertie Squire Kasia Stepniewska David Coleman Andrew Owen Andy Ramsay Wirongrong Cheirakul CDC TB trials Harvard University CAPKR, University of Training fellowship GR067910MA consortium & Socios en Salud Manchester PKPDia Programme grant Chad Heilig Carol Mitnick Leon Aarons Andy Vernon
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