Tuberculosis Trials Consortium Pharmacology Studies and Capacity

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Tuberculosis Trials Consortium Pharmacology
Studies and Capacity
Marc Weiner, M.D. VAMC and University of Texas
Health Science Center at San Antonio
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(No Transcript)
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PK cases by TBTC site
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TBTC Study 22 and 22PK

• The long half life of rifapentine vs. rifampin
  supported a treatment simplification with once
  weekly therapy
• The Phase III RCT in patients with
  drug-susceptible pulmonary TB who had completed 2
  months of a 6-month treatment regimen
• The primary objective was a comparison in
  continuation-phase therapy of rifapentine/INH
  once weekly with rifampin/INH BIW

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Study 22 Rates of relapse, by treatment arm and
by month after therapy
4.8
10.6
Log rank, P-value 0.0110
TBTC 22 Lancet 2002 360528-34.
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A PK/PD sub study evaluated
INH, rifapentine and rifampin

• Outcome in 133 HIV(-) cases
• RPT (76) cure (53), failure (3), and relapse
  (20)
• RIF (57) cure (40), failure (2), and relapse
  (15)
• Genotyping identified C481T, G590A and G857A NAT2
  polymorphic sites

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INH AUC lower with failure/relapse in cases
treated with INH/RPT once/wk but not with INH/RIF
twice/week
p .005 p .65
? Failure/relapse ? Cure
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22PK Conclusions

• Decrease in INH AUC found with failure/relapse
  only with once-weekly therapy
• In MVA, the association remained after adjustment
  for clinical risk factors for treatment failure
• INH acetylation was more rapid by NAT2 genotype
  with failure/relapse treated with once-weekly
  therapy
• The effect of INH was dependent on the
  co-administered rifamycin and/or frequency of
  drug administration

TBTC 22PK Am J Respir Crit Care Med 2003
1671341-7
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Study 23 In patients with HIV-TB, low drug
exposures found

• 169 patients with HIV-TB treated with rifabutin
  based regimen
• Intensive phase RBT-based regimen
• Continuation phase RBT (300 mg) INH (15
  mg/kg) BIW
• RBT doses adjusted for HAART
• Outcomes
• Treatment failure or relapse in 9 (5.3) / 169
• Failure or relapse with acquired rifamycin
  resistant MTB in 8 (89) / 9 cases
• 102 patients with PK/PD evaluations

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Rifabutin and INH AUC were lower in patients with
failure/relapse with ARR MTB vs. cure median
rifabutin AUC 3.3 vs. 5.2 mghr/ml median INH
AUC 20.6 vs. 29.0 mghr/ml

• ? ARR fail/relapse
• Cure

? ARR fail/relapse ? Cure
TBTC 23PKa Clin Infect Dis 2005 401481-91
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Analyses of data across several studies -INH AUC
and Cmax significantly lower in 136
patients with HIV-TB versus
156 TB patients without HIV
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INH acetylator status by NAT2 genotype did not
differ between HIV serologic groups
Int J Tuberc Lung Dis 2005 Nov9S238
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TBTC 22, 23 and PK Studies

• Patients with failure/relapse with ARR MTB
• had low concentrations of INH and rifabutin
• had CD4 cell count lt 100
• treated with twice weekly TB regimens
• Impact on TB treatment - Many TB programs now use
  2 months daily therapy, followed by 4-7 months
  thrice weekly

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Drug-drug interactions in patients with
HIV-TB23C - rifabutin-efavirenz

• Bi-directional drug-drug interactions mediated by
  CYP450 occur between rifamycins and PI / NNRTI
• Induction effect on CYP450 of rifabutin (RBT) lt
  rifampin
• In normal volunteer studies, RBT 300 mg daily
  appeared to have minimal effect on EFV
  concentrations
• However, RBT AUC was reduced 37 by daily EFV
• Objectives
• To compare RBT exposure of
• RBT 300 mg 2/wk without HAART to
• RBT 600 mg 2/wk with daily EFV (600 mg) based
  HAART
• To compare AUC of EFV 600 mg daily RBT to
  AUC of EFV 600
  mg daily in historical HIV controls
• Design two period, one sequence

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Mean RBT concentrations at steady state vs. time
of RBT 300 mg (-?-) vs.
RBT 600 mg with EFV-based ART (-?-)
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Mean EFV concentrations at steady state versus
time
EFV co-administered with RBT 600 mg
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TB murine models identify sterilizing activity
and effects of multidrug regimens

• Murine models have been predictive of results in
  humans if treatments are equipotent
• Utility to guide Phase II MTB clinical trials
• Caveat - Does not model high-risk
  sub-populations (e.g., pulmonary cavitation)

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Phase II Study 27 Factorial design to evaluate
drug effect and treatment
frequency

• Double-blind substitution of moxifloxacin for
  ethambutol
• Randomization stratified by presence of
  cavitation and by region Africa vs. N. America
• There was no significant difference in sputum
  conversion at 8 weeks with moxifloxacin vs.
  ethambutol
• Surprisingly low culture conversion rate among
  African patients compared to patients in North
  America not explained by cavitation, HIV
  co-infection
• Study 27/28 PK in patients with TB to evaluate
  moxifloxacin-rifampin interaction and regional
  differences

TBTC 27 Amer J Resp Crit Care Med 2006 174331-8
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27PKa Moxifloxacin-rifampin interaction
in normal volunteers

• Background
• Rifampin may induce enzymes that transport and
  metabolize moxifloxacin
• Phase II biotransformation enzymes
• Sulfation - M1 conjugate 38 of the oral dose
• Glucuronidation - M2 conjugate 14 of the oral
  dose
• P-glycoprotein plays an important role in
  absorption, distribution and elimination of
  xenobiotics
• Objectives
• Evaluate a possible interaction between
  moxifloxacin and rifampin
• Investigate the effects the multidrug resistance
  gene C3435T polymorphism on moxifloxacin PK
  values
• Design
• Two period, one-sequence in 16 volunteers

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Mean moxifloxacin concentrations at steady state
versus time from moxifloxacin (400 mg) without
(-?- ) and with (-?-) rifampin
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Mean moxifloxacin metabolite M1 (left) and M2
(right) concentrations at steady state versus
time from moxifloxacin (400 mg)
without (-?- ) and with (-?-) rifampin
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Mean moxifloxacin concentrations at steady state
(co-administered with rifampin) versus time
divided by MDR1 3435 genotype cc (?) vs. others
(?)
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Moxifloxacin-rifampin interaction in healthy
volunteers

• Rifampin administration results in a 27 decrease
  in moxifloxacin AUC
• Genetic variations in the MDR1 gene may modify
  moxifloxacin PK values
• Additional studies are required to determine
  whether this difference is clinically relevant
• Study 27/28 PK in patients with TB has completed
  enrollment

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Murine TB model demonstrates greater activity
with higher rifamycin dosages -
rifapentine from 5 to 20
mg/kg
Rosenthal et al Amer J Resp Crit Care Med
200617494-101
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25PK - Dose ranging Mean rifapentine AUC
increased significantly with dose (296, 410 and
477 mghr/ml with 600, 900 and 1,200
mg doses)
29 and 29PK in patients with TB to evaluate high
dose rifapentine vs. standard rifampin-based
control regimen
N 35
TBTC 25PK Am J Respir Crit Care Med 2004
1691191-7
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Summary

• Pharmacokinetic, pharmacodynamic and
  pharmacogenomic studies are integrated into TBTC
  structure and trials
• Capacity at TBTC sites is robust with enrollments
  of 1,000 subjects into completed, active or
  planned studies

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Challenges

• Because treatment consists of combination
  therapy, PK/PD studies must
• distinguish the role of individual agents in the
  activity of a 3-4 drug regimens
• adjust for the important covariates of disease
• Simplified PK/PD logistics
• to decrease the number of specimens collected
• to determine optimal times for specimen
  collection for regimens of multiple drugs
• to provide for specimen acquisition and storage
  by simple techniques without sophisticated
  laboratory or logistical support
• Development of a robust surrogate endpoint for
  sterilizing activity for TB

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Pharmacokinetic Work Group of the
Tuberculosis Trials
Consortium
Marc Weiner, M.D., Chair VAMC San
Antonio William Burman, M.D. - Denver Public
Health Charles Peloquin, Pharm.D. - National
Jewish Medical Center Debra Benator, M.D. -
George Washington U. Medical Center William Mac
Kenzie, M.D. - Project Officer, DTBE /CDC Melissa
Engle, C.C.R.C. - VAMC San Antonio Nong Shang,
Ph.D. - Statistics/DTBE /CDC Beth Jeffries -
Westat Andrew Vernon, M.D. - DTBE /CDC