Bioequivalence and Bioavailability Forum

Dear Ratnakar!

❝ […] what all primary and secondary PK parameters and criteria for BE should be considered for steady state study for a modified released tablet for EU submission? As per current EU guideline it only mentions about AUC0-tau to be considered as the additional parameter for bioequivalence.

Unfortunately the MR NfG is quite old (1999) and somewhat ambiguous:

4.1 Bioavailability studies
The purpose of these studies is to characterise the modified drug formulation in vivo by investigating

• the rate and extent of absorption
  
• fluctuations in drug concentrations

4.1.1. Rate and extent of absorption, fluctuation
Rate and extent of absorption from a modified release formulation should be evaluated by comparison with an immediate release formulation following single and repeated dosing. Fluctuations in drug concentrations should be studied following repeated dosing. It should be demonstrated that the modified release formulation has the claimed release characteristics, produces similar or less fluctuations as the immediate release product and comparable total systemic exposure that is acceptable in comparison to that of the immediate release product. The pharmacokinetic parameters of interest are AUC, C_max and C_min or other means reflecting fluctuation.

5.1 Prolonged release formulations
Assessment of bioequivalence will be based on AUC_τ, C_max and C_min applying similar statistical procedures as for the immediate release formulations.

5.2 Delayed release formulations
Bioequivalence is assessed using the same main characteristics and statistical procedures as for immediate release formulations with emphasis on the delayed release characteristics.

Interesting points:

• Neither %PTF nor Swing are mentioned explicitly; only ‘or other means reflecting fluctuation’ (as an alternative to C_max and C_min). But don’t take this literally. C_max is required anyhow (4.1, 5.1/5.2). C_max & %PTF worked in almost all of my studies (got some deficiency letters asking for C_min). Never submitted Swing and was also never asked.
  
• Fluctuation: No equivalence to IR, but non-superiority!
  
• No testing of C_min / fluctuation for DR (no or only minor accumulation expected). Could refer to the current IR guideline and the Overview of comments:
  “By C_min,ss we mean the concentration at the end of the dosage interval, i.e. C_trough. However, in bioequivalence studies for immediate release formulations there is no need to report C_trough and fluctuation. The guideline has been revised. We see no need to include swing […]”
  
• The MR GL is under revision (draft expected by the end of QII/2012). What I would expect / hope for:
  ■ No MD studies if no accumulation (SD AUC_t/AUC_∞ >80%).
  ■ For others C_min,ss mandatory (if clinically relevant?), %PTF supportive.
  ■ Partial AUCs for pulsatile/biphasic products (see this thread).
  ■ Scaling for C_max,ss and C_min,ss.

❝ Whereas for Steady State study for immediate release formulations it mentions parameters like AUC0-tau, Cmax,ss and Tmax,ss also.

T_max – where?

❝ But as per FDA we do consider Cmin, Cav, degree of fluctuation [(Cmax-Cmin)/Cav], and swing [(Cmax-Cmin)/Cmin].

Not relevant here. BTW, I can’t imagine that FDA rejects a study based on failing Swing if all other metrics pass. Swing is a lousy metric, since you divide by the one concentration with the largest variability of the entire profile.