Bioequivalence and Bioavailability Forum

❝ Dear Sir,

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Hi Sam,
I called you “Madam” in my last post as a joke. I don’t know your sex. When you call me Sir, that’s fine. But in a first post to all members of the forum, please avoid a sex-specific salutation in the future. The forum is not a “males only” club.

❝ You have clearly stated all the recommendations given by the USFDA and it is not very clear to me.

In which respect? FDA’s guidance is comprehensive. Two studies, fasting + fed.

❝ Sir I have one doubt that in case of fasting study the ratio is very good and it is around 100 for all the three parameters like AUCs and Cmax. But in case of the Fed study the ratio for AUCs are good and it is around 100 but the ratio of Cmax is very abrupt which is 130. Ideally if the ratio changes, it should change in all the parameters but in my case all the parameters are coming in range but the Cmax is only outside the range.

↑ This is a misconception. C_max is a surrogate for the rate of absorption (k_a). Did you see a sub­stantial difference in t_max between T and R? Imagine a situation where both the absorption rate and fraction absorption (f) of test and reference are different.
Example (one-compartment, no lag time, k_a 0.6 h^-1 (R) and 3.905 h^-1 (T), f 1 (R) and 0.85552 (T); linear trapezoidal rule for simplicity):
time      C(R)     C(T)
 0.00      BQL      BQL
 0.25     11.46    51.21
 0.50     21.04    69.24
 0.75     29.01    74.80
 1.0      35.60    75.69
 1.5      45.41    73.39
 2.0      51.75    70.01
 2.5      55.57    66.62
 3.0      57.55    63.38
 3.5      58.22    60.29
 4        57.96    57.35
 6        52.15    46.95
 9        40.21    34.78
12        30.04    25.77
16        20.18    17.27
24         9.07     7.76     T/R
——————————————————————————————————
AUCt     748.96   762.32   101.78%
AUC∞     839.85   839.93   100.01%
AUCext    10.82%    9.24%          ← ≤20% (sufficient sampling)
Kel        0.10     0.10           ← identical elimination (drug specific)
Cmax      58.22    75.69   130.00%
tmax       3.5       1.0           ← shift in t_max due to faster absorption
Lower extent of absorption together with a faster rate of absorption will result in 100% for AUC_∞, but 130% for C_max.

❝ So I am wondering that is it a really the formulation problem or there is problem with the food given as breakfast and all other parameters which can likely effect the formulation release.

Both is possible. We simply don’t know.

❝ If I will reformulate and I will go to control the Release of the drug from the formulation in the fed condition as per the current data then it may likely impact the fasting data also which has a ratio of around 100 and it may come down to 90 also.

Possible. It seems that test and reference are subjected to a different food effect. You have to find a compromise.

❝ So sir please suggests me the best way as you have stated in the previous reply.

You can try to find a dissolution method which is discriminatory. There’s a problem that in vivo you are measuring the metabolite and in vitro the parent. You can only cross fingers that the enzyme system does not get saturated by different initial concentrations. Start with biorelevant media (FaSSIF, FeSSIF). If you have (a lot) of money to spare, try an artificial digestive system (f.i. TNO’s TIM-1).