Bioequivalence and Bioavailability Forum • EMA: Capecitabine product-specific guidance ♬

EMA: Capecitabine product-specific guidance ♬ [Regulatives / Guidelines]

posted by mittyri – Russia, 2013-12-10 16:33 (4582 d 12:22 ago) – Posting: # 12030
Views: 32,004

Dear Helmut & all,

Could you explain, why does Capecitabine draft have no scaling at least for Cmax?

❝ Acceptance Range (AR) 80.00–125.00% for AUC_t and C_max (no scaling, “critical dose” drug).

According to the Cassidy J, Twelves C, Cameron D, et al. (Bioequivalence to two tablet formulations of capecitabine) capecitabine Cmax has high variability and low clinical significance:

The maximum tolerated dose (MTD) of 3000 mg/m2 per day for an intermittent dosing schedule produced a mean Cmax of 13.4 lg/ml for 5-DFUR, which is greater than the value of 6.1 lg/ml obtained at the MTD of 1657 mg/m2 per day following a continuous dosing schedule. Thus, safety in humans does not correlate with Cmax values.
Preclinical experiments in mice have shown that the antitumor activity is similar when the same daily dose of capecitabine is administered once or twice daily (H. Ishitsuka). Therefore, this suggests that AUC and not Cmax correlates with antitumor activity in mice.
In vitro studies investigating the cell killing effect of 5-FU have shown that 5-FU is an 'AUC-dependent drug', that is, short exposure requires high concentrations to obtain the cell killing eect whereas the same effect can be obtained with longer exposure to lower concentrations.
In the clinical use of cytotoxic agents, efficacy generally correlates better with AUC rather than with Cmax.

—
Kind regards,
Mittyri

Complete thread:

Bioequivalence Recommendations for Specific Products cr.maroj 2013-09-19 11:00
- Bioequivalence Recommendations for Specific Products Ohlbe 2013-09-19 11:45
  - EMA: Draft product-specific guidances ♬ Helmut 2013-11-15 15:45
    - EMA: Draft product-specific guidances ♬ luvblooms 2013-11-19 06:35
    - EMA: Capecitabine product-specific guidance ♬mittyri 2013-12-10 15:33
      - EMA: Capecitabine product-specific guidance ♬ Helmut 2013-12-10 16:11
        
        Russian GL 2013: harmonisation to EMA mittyri 2013-12-14 11:57
    - EMA: Draft product-specific guidances ♬ pash413 2013-12-18 12:35
      - EMA: Use of AUC72 not dependent on t½ Helmut 2013-12-18 14:35
    - End of consultation approaching‼ Helmut 2014-02-10 18:33
      - End of consultation approaching‼ Dr_Dan 2016-01-28 09:27
        
        Guesstimates Helmut 2016-01-28 13:32
- EMA: generally no product-specific GLs Helmut 2013-09-19 11:48
  - Thank you cr.maroj 2013-09-19 13:03
  - EMA: generally no product-specific GLs The Outlaw Torn 2013-09-20 07:52
    - EMA: parent whenever possible Helmut 2013-09-20 09:02
      - EMA: parent whenever possible cr.maroj 2013-09-20 10:14
        
        EMA: parent whenever possible Helmut 2013-09-20 12:53
        
        EMA: parent whenever possible Ohlbe 2013-09-20 13:52
        
        EMA: parent whenever possible mittyri 2013-09-20 14:55
        
        EMA vs. Russia Helmut 2013-09-20 19:21
        
        FDA: Prasugrel intuitivepharma 2013-12-20 07:36
        
        FDA: Prasugrel Helmut 2013-12-20 13:46
        
        FDA: Prasugrel intuitivepharma 2013-12-24 06:38
        
        FDA: Alternative approaches… Helmut 2013-12-24 14:15
        
        FDA: Alternative approaches… intuitivepharma 2013-12-26 05:11
        
        FDA: RTR Helmut 2013-12-26 14:35
        
        FDA: RTR intuitivepharma 2013-12-31 05:34
        FDA: RTR meghalvakil20 2015-07-23 16:32
        
        WayBack Machine Helmut 2015-07-23 16:58
        
        WayBack Machine meghalvakil20 2015-07-23 17:03
        
        Old stuff Helmut 2015-07-23 17:28
        
        EMA: parent whenever possible ElMaestro 2013-09-20 19:35
        
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