2005 4139S1 09 FDA Zheng by w19Vz8H

VIEWS: 4 PAGES: 8

									           Tipranavir NDA 21-814:
      Exposure Response Analysis

                         Jenny J Zheng, Ph.D.
                       Pharmacometrics Reviewer

                Office of Clinical Pharmacology and
                          Biopharmaceutics
                             CDER, FDA


May 19, 2005   FDA Antiviral Drugs Advisory Committee Meeting   1
The measurement of tipranavir
cmin and viral IC50 as an option
  for the individualization of
  tipranavir/ritonavir dosing
TPV Cmin, IC50, T20 co-administration
significantly influence viral response
                                                                            IQ effect: p<0.001
                                 80% 100%                                   T20 effect: p<0.001
        Percent of Responders at Week 24
                   40%   60%




                                                                   phase 3 without T20 (n=200)
                                                                   phase 3 with T20 (n=91)
                                                                   phase 2 (n=160)
           20%




                                                                                     Control+T20
                                                                                     Control
     0%




                                            0   200     400        600         800         1000
                                                      Inhibitory Quotient

For IQ ≥ 100, 54% responded to TPV and 73% responded to TPV+T20
For IQ < 100, 21% responded to TPV and 52% responded to TPV+T20
Cmin in Phase 2 and Phase 3 at
        Different Doses
                         100 120
 Trough Concentration in ug/mL
 20    40   60     80
                   0




                                     500/200     500/200    750/200
                                   Study 12/48   Study 52   Study 52
Inhibitory quotient displays high
   between-patient variability

   500 1000 1500 2000 2500
       Inhibitory Quotient
                0




                               500/200     500/200    750/200
                             Study 12/48   Study 52   Study 52


Inhibitory quotient = Cmin / corrected IC50
Probability of grade 3 or 4 ALT toxicity
 increases with higher tipranavir Cmin
     Percent of Patients with Grade 3/4 ALT Toxicity
                                      80% 100%

                                                                      Study 52 (N=210)
      0%      20%     40%      60%




                                                       10   20          30       40      50
                                                                 Cmin in ug/mL
Possible Therapeutic Drug Monitoring Strategy
                                Measure IC50
                                 at baseline


                               Determine
                            Cmin at wk 1,2 or 3



                        No/No    Is IQ>100? Yes/Yes
Alternative treatment                               Continue 500/200 mg
                                Is tolerable?

                  Yes/No                          No/Yes



                Dose                             Dose ↑
The measurement of tipranavir cmin
 and viral IC50 as an option for the
        individualization of
    tipranavir/ritonavir dosing

								
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