PK/PD: New Microbial Diseases and Model Systems Tawanda Gumbo, MD Associate Professor of Medicine,...
-
Upload
octavia-cross -
Category
Documents
-
view
215 -
download
0
Transcript of PK/PD: New Microbial Diseases and Model Systems Tawanda Gumbo, MD Associate Professor of Medicine,...
![Page 1: PK/PD: New Microbial Diseases and Model Systems Tawanda Gumbo, MD Associate Professor of Medicine, Division of Infectious Diseases, University of Texas.](https://reader030.fdocuments.net/reader030/viewer/2022032707/56649e4b5503460f94b3f9b0/html5/thumbnails/1.jpg)
PK/PD: New Microbial Diseases and Model Systems
Tawanda Gumbo, MD
Associate Professor of Medicine,Division of Infectious Diseases,
University of Texas Southwestern Medical Center, Dallas, Texas
![Page 2: PK/PD: New Microbial Diseases and Model Systems Tawanda Gumbo, MD Associate Professor of Medicine, Division of Infectious Diseases, University of Texas.](https://reader030.fdocuments.net/reader030/viewer/2022032707/56649e4b5503460f94b3f9b0/html5/thumbnails/2.jpg)
• Log-phase growth bacilli (LPG): Killed rapidly by INH during early bactericidal activity. Termed BACTERICIDAL effect.
• Slowly replicating bacilli under acidic conditions (SRB): Killed by PZA during ~8 weeks of therapy. Believed mostly in macrophages
• Non-replicating persistent bacilli (NRP): Killed by rifamycins during short bursts of metabolism but needs up to 6 months to be eradicated. Size SRB>>NRP
Mitchison’s three population model hypothesis
Mitchison DA. The basic mechanisms of chemotherapy. Chest 1979; 76: 771-81
![Page 3: PK/PD: New Microbial Diseases and Model Systems Tawanda Gumbo, MD Associate Professor of Medicine, Division of Infectious Diseases, University of Texas.](https://reader030.fdocuments.net/reader030/viewer/2022032707/56649e4b5503460f94b3f9b0/html5/thumbnails/3.jpg)
Models for PK/PD work in TB
• Require that one of each of the three Mtb populations be emulated
• Require that free drug pharmacokinetics of anti-TB at site of infection be correctly recapitulated
• Mouse models traditionally used. However, it is becoming clear that the bacillary populations in mice are different from cavitary TB
![Page 4: PK/PD: New Microbial Diseases and Model Systems Tawanda Gumbo, MD Associate Professor of Medicine, Division of Infectious Diseases, University of Texas.](https://reader030.fdocuments.net/reader030/viewer/2022032707/56649e4b5503460f94b3f9b0/html5/thumbnails/4.jpg)
M. tuberculosis in the hollow fiber system
Gumbo T, et al. J Infect Dis 2006;195:194-201
![Page 5: PK/PD: New Microbial Diseases and Model Systems Tawanda Gumbo, MD Associate Professor of Medicine, Division of Infectious Diseases, University of Texas.](https://reader030.fdocuments.net/reader030/viewer/2022032707/56649e4b5503460f94b3f9b0/html5/thumbnails/5.jpg)
0
2
4
6
8
0 10 20 30 40
Time (Days)
Lo
g10
CF
U/m
L
GROWTH OF MYCOBACTERIUM TUBERCULOSIS IN THE HOLLOW FIBER SYSTEM: log-phase growth population
• 5 week experiment
• 104 initial inoculum
• Log-phase growth pattern during days 1 through 8
• Bacterial burden relatively stable thereafter
![Page 6: PK/PD: New Microbial Diseases and Model Systems Tawanda Gumbo, MD Associate Professor of Medicine, Division of Infectious Diseases, University of Texas.](https://reader030.fdocuments.net/reader030/viewer/2022032707/56649e4b5503460f94b3f9b0/html5/thumbnails/6.jpg)
• Isoniazid has the greatest bactericidal activity, but ceases to kill after 2-3 days, believed due to depleting M. tuberculosis in log phase growth
ISONIAZIDBackground
![Page 7: PK/PD: New Microbial Diseases and Model Systems Tawanda Gumbo, MD Associate Professor of Medicine, Division of Infectious Diseases, University of Texas.](https://reader030.fdocuments.net/reader030/viewer/2022032707/56649e4b5503460f94b3f9b0/html5/thumbnails/7.jpg)
Is the cessation of isoniazid microbial kill due to depletion of M. tuberculosis in
exponential growth phase?
ISONIAZIDQuestions
![Page 8: PK/PD: New Microbial Diseases and Model Systems Tawanda Gumbo, MD Associate Professor of Medicine, Division of Infectious Diseases, University of Texas.](https://reader030.fdocuments.net/reader030/viewer/2022032707/56649e4b5503460f94b3f9b0/html5/thumbnails/8.jpg)
• Slow and fast acetylators simulated
• Doses studied for each acetylation phenotype:
– 0, 25, 100, and 300 mg a day
• In addition, a dose of 600 mg a day for fast acetylators
ISONIAZID AGAINST M. TUBERCULOSISExperimental Design
![Page 9: PK/PD: New Microbial Diseases and Model Systems Tawanda Gumbo, MD Associate Professor of Medicine, Division of Infectious Diseases, University of Texas.](https://reader030.fdocuments.net/reader030/viewer/2022032707/56649e4b5503460f94b3f9b0/html5/thumbnails/9.jpg)
ISONIAZID AGAINST M. TUBERCULOSIS Resistance, Not Extinction Responsible For Effect Cessation
Gumbo T, Louie A, Liu W, Bhavnani S, Ambrose P,Brown D, Drusano GL. (2006). Journal of Infectious Diseases 195:194-201
0 20 40 60 80 100 1200
1
2
3
4
5
6
Simulated total population
Simulated isoniazid-susceptible population
Simulated isoniazid-resistant population
Observed total population
Observed isoniazid-resistant population
Time in hours
M. t
uber
culo
sis
dens
ity
(log
10C
FU/m
l)
![Page 10: PK/PD: New Microbial Diseases and Model Systems Tawanda Gumbo, MD Associate Professor of Medicine, Division of Infectious Diseases, University of Texas.](https://reader030.fdocuments.net/reader030/viewer/2022032707/56649e4b5503460f94b3f9b0/html5/thumbnails/10.jpg)
PZA dose-effect & dose scheduling studies• All media acidified to pH 5.8 for entire study, and Mtb
grew slowly in the HFS, to simulate SRB under acidic conditions
• Half-life =11hr
• Doses mimicked: 0, 7.5, 15, 30, 60, 90, 120 mg/kg daily for 28 days (dose effect)
• EC20, EC40, EC60 then examined in dose-scheduling studies
• Checked microbial kill and actual PK parameters achieved
![Page 11: PK/PD: New Microbial Diseases and Model Systems Tawanda Gumbo, MD Associate Professor of Medicine, Division of Infectious Diseases, University of Texas.](https://reader030.fdocuments.net/reader030/viewer/2022032707/56649e4b5503460f94b3f9b0/html5/thumbnails/11.jpg)
Relationship between PZA AUC/MIC and kill
• The PK/PD index most closely associated with pyrazinamide sterilizing effect was AUC/MIC
• E=6.52-(2.89 x AUC/MIC1.21 34.22 1.2 +AUC/MIC1.21
r2 =0.93; p<0.01
![Page 12: PK/PD: New Microbial Diseases and Model Systems Tawanda Gumbo, MD Associate Professor of Medicine, Division of Infectious Diseases, University of Texas.](https://reader030.fdocuments.net/reader030/viewer/2022032707/56649e4b5503460f94b3f9b0/html5/thumbnails/12.jpg)
BIG QUESTION
• Where in pulmonary lesions is this large population that PZA kills?– The majority, starting with Mackeness &
McDermott in the 1950s and 1960s believe it is within macrophages
• Few voices here and there: extra-cellular
![Page 13: PK/PD: New Microbial Diseases and Model Systems Tawanda Gumbo, MD Associate Professor of Medicine, Division of Infectious Diseases, University of Texas.](https://reader030.fdocuments.net/reader030/viewer/2022032707/56649e4b5503460f94b3f9b0/html5/thumbnails/13.jpg)
Rates of sterilizing effect with standard dosing
• Standard dose of 2grams PZA per day in patients produces 0.1 log10CFU/ml/day in 90% of patients
• From our inhibitory sigmoid Emax relationship, the AUC0-24/MIC associated with such a kill rate of 0.1log10CFU/ml/day is 120
![Page 14: PK/PD: New Microbial Diseases and Model Systems Tawanda Gumbo, MD Associate Professor of Medicine, Division of Infectious Diseases, University of Texas.](https://reader030.fdocuments.net/reader030/viewer/2022032707/56649e4b5503460f94b3f9b0/html5/thumbnails/14.jpg)
Population PK data• 100,000 patients simulated using ADAPT II & ADAPT
5
• Pop PK: Wilkins J et al. Eur. J Clin. Pharmacol. 2006; 62:727-735.
– Serum clearance= 3.4 L/h, Volume=30 L.
• PZA penetration in ELF and alveolar macrophages Conte et al. Antimicrob. Agents Chemother. 1999; 43, 1329-1333
Alveolar macrophage/serum ratio=0.52 to 1.14 Epithelial lining fluid/serum ratio=13.9-21.7
• MICs at pH 5.8: Salfinger M & Heifets LB. Antimicrob Agents Chemother 1988;32:1002-4
.
![Page 15: PK/PD: New Microbial Diseases and Model Systems Tawanda Gumbo, MD Associate Professor of Medicine, Division of Infectious Diseases, University of Texas.](https://reader030.fdocuments.net/reader030/viewer/2022032707/56649e4b5503460f94b3f9b0/html5/thumbnails/15.jpg)
Monte Carlo simulation assuming intracellular location
• MCS targeting alveolar macrophage PZA concentration associated with AUC0-24/MIC of 120.
• Processing….• Processing….• Processing… • Processing….
• …..in 0.07% of patients!
• But we know that 2G of pyrazinamide has good sterilizing effect rates in patients.
![Page 16: PK/PD: New Microbial Diseases and Model Systems Tawanda Gumbo, MD Associate Professor of Medicine, Division of Infectious Diseases, University of Texas.](https://reader030.fdocuments.net/reader030/viewer/2022032707/56649e4b5503460f94b3f9b0/html5/thumbnails/16.jpg)
Monte Carlo simulation assuming extracellular location
• MCS targeting ELF associated with AUC0-24/MIC of 120.
• Processing….• Processing….• Processing… • Processing….
• …..in 80.0-90.0% of patients!• Match!
![Page 17: PK/PD: New Microbial Diseases and Model Systems Tawanda Gumbo, MD Associate Professor of Medicine, Division of Infectious Diseases, University of Texas.](https://reader030.fdocuments.net/reader030/viewer/2022032707/56649e4b5503460f94b3f9b0/html5/thumbnails/17.jpg)
PZA conclusions
• Based on these simulations, seems that the majority opinion is in this case likely incorrect
• In fact, in reviewing Robert Koch’s autopsy reports that he published, he commented that most Mtb in pulmonary cavities was extracellular
![Page 18: PK/PD: New Microbial Diseases and Model Systems Tawanda Gumbo, MD Associate Professor of Medicine, Division of Infectious Diseases, University of Texas.](https://reader030.fdocuments.net/reader030/viewer/2022032707/56649e4b5503460f94b3f9b0/html5/thumbnails/18.jpg)
Wasana Siyambalapitiyage, Crystal Norton, Sandirai Musuka, Shashikant Srivasatava, Carleton Sherman