Which drugs do we need to learn more about interactions, PKPD and how might we do it

1
Which drugs do we need to learn more about
interactions, PK/PD and how might we do it?

• William Burman
• Denver Public Health
• TBTC / ACTG

2
Tuberculosis drug discovery/development
PZA
Strep
INH
EMB
RPT
Rifampin
1944
1952
1956
1965
1968
1998
2007
3
TB trends in Africa, 1980-2002HIV driving the TB
epidemic
Zimbabwe
Kenya
Notification Rates (x100,000)
Malawi
UR Tanzania
Côte dIvoire
Global Tuberculosis Control. WHO Report 2003.
WHO/HTM/TB/2004.331
4
Effect of rifampin on plasma concentrations of
HIV-1 protease inhibitors
With 100 mg RTV


Clin Infect Dis 1999 28 419-30
12th CROI, abstract 657
5
Side effects of directly-observed therapy with
INH, RIF, PZA, EMB
Unpublished data Denver Public Health
6
Percentage of patients not completing treatment
for active TB Hlabisa, South Africa
Int J Tuberc Lung Dis 199931081-7
7
From ANTI-TUBERCULOSIS DRUG RESISTANCE IN THE
WORLD WHOThird Global Report
8
450,000 incident cases of MDR/year 1.2 million
prevalent cases
From ANTI-TUBERCULOSIS DRUG RESISTANCE IN THE
WORLD WHOThird Global Report
9
DOTS is good, but far from perfect

• Problems with current DOTS regimens
• Rifampin-related drug interactions, particularly
  for patients with HIV
• Bothersome side effects are common serious side
  effects are not rare
• Short-course is still long 6-month duration
  of therapy decreases treatment completion, makes
  treatment relatively expensive
• Rising rates of drug resistance threaten the
  effectiveness of TB control in some parts of the
  world

10
A time of unprecedented need a time of
unprecedented opportunities

• Fluoroquinolones
• Higher-dose rifamycins (rifampin or rifapentine)
• Novel drugs currently in clinical trials
• TMC207 an inhibitor of mycobacterial ATP
  synthesis
• OPC67683, PA824 nitro-imidazole derivatives
• SQ109 an ethambutol derivative

11
Activity of moxifloxacin in combination therapy
in a mouse model of TB
2.5 logs
Am J Respir Crit Care Med 2004 164421-6
12
Bactericidal activity of daily R10HZ, R10MZ, and
P10MZ for 8 weeks against M. tuberculosis in
mice (I. Rosenthal, E. Nuermberger, J. Grosset)
2 logs
4 logs
?
R, rifampin H, isoniazid Z, pyrazinamide M,
moxifloxacin P, rifapentine
13
The effect of rifampin dose on early bactericidal
activity
Antimrob Agents Chemother 2007512994-6
14
Activity of TMC207 (J) in the mouse model
Yellow CFU at 1 month Blue CFU at 2 months
standard
R rifampin J TMC207 H INH Z PZA
Science 2005307223-7
15
The activity of OPC67683, PA-824 in the mouse
model
PLoS Med 2006e466
16
TB drug development - 2007

• Greater need for new drugs
• Burden of HIV-TB
• Rise of XDR-TB
• Greater promise than at any time since 1960s -
  regimens on the immediate horizon
• 3 month, 12-dose regimen for treatment of latent
  TB
• 3 month regimen for active, drug-susceptible TB
• Highly-effective regimens for MDR/XDR TB

17
Estimated 2006 NIH funding for selected
diseases/purposes and their global burden
Global burden

• Disease
• Anthrax
• Biodefense
• HIV/AIDS
• Malaria
• Tuberculosis

• Funding (millions)
• 177
• 1694
• 2933
• 92
• 140

Limited funding for TB clinical trials means we
have to collaborate
18
Overview of an agenda for PK studies to support
new drug development in TB

• Initial Phase 1 and 2 PK studies of new drugs
• Key drug interactions - especially with ART drugs
• Evaluation of PK of new drugs in special
  populations
• AIDS
• Hepatic / renal insufficiency
• Pregnancy
• Children
• Evaluation of PD of new drugs
• Evaluation of pharmacogenomics of new drugs

19
Drug-drug interaction studies

• New TB drugs with old TB drugs especially the
  rifamycins
• TB drugs and ART drugs

Rifapentine Higher-dose rifampin 2nd-line TB
drugs New TB drugs
Efavirenz Boosted PI Raltegravir Tenofovir
20
Needed interaction studies rifamycins and ART

• Rifapentine
• Efavirenz
• Boosted PI
• Raltegravir
• Rifampin
• Effect of higher dose rifampin on efavirenz
• Higher-dose raltegravir
• Super-boosted atazanavir
• Rifabutin
• Raltegravir

21
Likelihood of drug interactions between ART drugs
and 2nd line TB drugs

• Fluoroquinolones
• Aminoglycosides
• Ethionamide
• Cycloserine
• Linezolid
• PAS

• Moxi decreased by RIF - ? EFV
• Unlikely
• Possible hepatic interactions
• Unlikely renal excretion
• Unlikely not CYP metabolized
• Unlikely with current formulation

Limited need for interaction studies with
2nd-line TB drugs
22
Possible study designs for exploring drug-drug
interactions
Sample sizes 12 20 12 100 50 - 200

• Initial step studies in healthy volunteers
• Follow-up studies in TB patients for key
  interactions
• Pharmacodynamic studies for key interactions

23
New TB drugs and ART drugs

• New TB drugs for which interaction studies with
  ART drugs are needed
• TMC207 CYP3A4 substrate
• OPC67683 not metabolized in liver
• SQ109 CYP2D6, CYP2C19 substrate
• Rifapentine potent CYP3A4 inducer, not a 3A4
  substrate

24
Getting PK data on key sub-populations

• Usual PK study great data on a highly-biased
  population
• Unlikely to enroll those most likely to have
  highly abnormal PK severely ill, young
  children, hepatic and renal dysfunction, pregnant
  women
• Requirements for PK/PD studies in key
  sub-populations
• Flexible study design
• Improvements in PK sampling techniques

25
Tools needed to facilitate PK/PD studies, studies
in key-sub-populations in HIV-TB

• Simpler PK sampling methods
• Sparse sampling schemes
• Small volume sampling that does not require
  venipuncture
• Simpler specimen processing and storage
• Flexible trial designs PACTG and ART during
  pregnancy
• Compatible data collection allowing
  cross-protocol analyses
• Better biomarker of activity against M.
  tuberculosis

26
Goals for this meeting

• Ongoing conversation on PK/PD studies in HIV-TB
• Prioritized agenda of needed studies
• Ask for necessary resources
• Coordinate PK / PD / pharmacogenomics studies
  ACTG, IMPAACT, TBTC, industry, other
  investigators
• Harmonize data collection to allow cross-protocol
  analyses