Trough Concentration Cmin Virologic Success RNA 400 copiesmL Analysis

1
Trough Concentration (Cmin) Virologic Success
(RNA lt400 copies/mL) Analysis

• Review team
• Pravin Jadhav Jenny Zheng
• Shashi Amur Kellie Reynolds
• Joga Gobburu John Lazor
• OFFICE OF CLINICAL PHARMACOLOGY (OCP)

2
Major aims

• Is the proposed dosing regimen (150mg BID with PI
  or 300mg BID w/o PI) acceptable?
• What is the utility of Cmin-Virologic success
  relationship?

3
Summary of Cmin-Virologic Success Analysis

• Patients with Cmin 50-75 ng/mL have a better
  chance of virologic success.
• In addition to Cmin, the probability of success
  is also influenced by other factors such as
  baseline CD4 count, baseline viral load and OSS.
  
• With the proposed doses (150mg BID and 300mg BID)
  60 patients will be 75 ng/mL compared to the
  QD dosing (18).
• The maraviroc concentrations could be important
  to
• Help explain lack of response.
• Help assess compliance.
• Help assess a need to dose adjust to increase
  virologic success.
• For example, in patient population with Cmin lt75
  ng/mL, by doubling dose the probability of
  success is increased to 62 (vs 56 at the
  proposed dosing). In overall population this
  probability is 69 vs. 67.

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Data from studies A4001027, A4001028 were used

• 973 patients were included in the analyses
• 76 patients were ignored due to unavailability of
  covariate information
• Plasma trough concentrations (Cmin) were used as
  an exposure variable
• Virologic success was defined as RNA lt400
  copies/mL
• Important predictors Baseline viral load,
  Baseline CD4 count, Baseline tropism, OSS etc.

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Is virologic success dependent on maraviroc Cmin?
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The probability of virologic success increases
with maraviroc concentration

• Other endpoints
• lt50 RNA copies/mL at week 24
• protocol defined failure
• at least 1 log drop at week 4
• also exhibit consistent relationship

Week 24 analysis
Virologic success was determined in each Cmin
quartile from 777 maraviroc patients and 196
placebo patients
7
Baseline CD4 count, OSS, Cmin and baseline viral
load are important predictors of virologic success
Overall susceptibility score (OSS) Baseline
Tropism Time since diagnosis, years Time since
first treatment, years
Number of NRTIs in the OBT Presence of
tipranavir Presence and sensitivity to
T20 Previous exposure to T20
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Maximum benefit is achieved at 50-75 ng/mL
Cmin Higher Cmin offers minimal additional
benefit
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The proposed BID dosing is consistent with the
Cmin-Virologic success relationship
With the proposed doses (150mg BID and 300mg BID)
60 patients will be 75 ng/mL compared to the
QD dosing (18).
(w/o PI )
(with PI )
10
What are the important predictors for lower Cmin?
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28 (150mg BID), 77 (300mg BID) of patients have
Cmin lt 75 ng/mL
(with PI )
(w/o PI)
Median
75 ng/mL
12
No baseline extrinsic/intrinsic factor explains
Cmin variability well
n 5 n 7 n 48 n 339
BID regimen
13
What is the utility of Cmin-Virologic success
relationship?
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Utility of Cmin-Virologic Success Relationship

• In clinical practice, in addition to intrinsic
  pharmacokinetic variability, there are several
  factors (such as compliance, concomitant
  medications etc.) that could lead to lower
  concentration
• Controlling these factors becomes important to
  achieve the benefit shown in the controlled
  trials.
• Maraviroc concentrations could be important to
• Help explain lack of response
• Help assess compliance
• Help assess a need to dose adjust to increase the
  probability of success while not increasing the
  exposure related risk

15
Evaluation of the added benefit of, for instance,
doubling dose in patients with lower Cmin

• Based on the final model, simulations were
  conducted to assess the effect of doubling the
  dose in patients with Cmin below the defined
  threshold.
• A total of 399 patients from studies A4001027 and
  A4001028 who received maraviroc 300mg or 150mg
  BID.
• Doubling of dose in patients with efavirenz or
  nevirapine in OBT.
• Doubling of dose if Cmin was below the defined
  threshold- 10, 25, 50, 75 or 100 ng/mL.
• Only one doubling of the dose was permitted.

16
Doubling of dose could lead to 62 (vs 56)
success in patient population with Cmin lt75
ng/mL. In overall population this probability is
69 vs. 67
399 Patients were evaluated 146 Patients with lt75
ng/mL In 146 patients the current probability of
virologic success is 56. Doubling of dose could
increase the probability to 62. At overall
population level the benefit translates to 2
17
Practical aspects of individualized dosing

• Cmin in 8 (150mg BID) and 33 (300mg BID)
  patients is lt 25 ng/mL.
• Doubling dose will not ensure Cmin 75 ng/mL
• Safety experience at higher doses is limited
• Individualization of treatment will need to
  consider tropism, OSS, viral load change, in
  addition to Cmin.

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Summary of Cmin-Virologic Success Analysis

• Patients with Cmin 50-75 ng/mL have a better
  chance of virologic success.
• In addition to Cmin, the probability of success
  is also influenced by other factors such as
  baseline CD4 count, baseline viral load and OSS.
  
• With the proposed doses (150mg BID and 300mg BID)
  60 patients will be 75 ng/mL compared to the
  QD dosing (18).
• The maraviroc concentrations could be important
  to
• Help explain lack of response.
• Help assess compliance.
• Help assess a need to dose adjust to increase
  virologic success.
• For example, in patient population with Cmin lt75
  ng/mL, by doubling dose the probability of
  success is increased to 62 (vs 56 at the
  proposed dosing). In overall population this
  probability is 69 vs. 67.