Bioequivalence and Bioavailability Forum

Hi Astea,

❝ […] we deal with the standard BE study: mycophenolic acid orally.

Difficult drug to show BE.

❝ The achieved curves have multi-peak form: there is a second small peak, that could be reffered as enterohepatic recycling (known in literature for MPA).

Correct.

❝ So the question is how to determine the half life of such drug? Do we need to use the second terminal part of the curve?

Yes. It might well be possible that you see in some patients no second peak, the second one smaller than the first one or vice versa. This behavior may even change within the same patient. For a nice PK model see Prémaud et al. (2005).*

❝ […] three samples in the log/linear decline can include Cmax-sample…

Not a good idea. Absorption is not (practically) completed at t_max.

❝ … there should be three samples after Tmax?

Yes. If you have a second peak, after this “t_max”.

❝ And if the latest of them is zero is the regression line correct?

There is no zero concentration post dose (well, there is but after a very long, long time). I guess you mean below the limit of quantification (BQL)? Even if you believe in zero, you can’t use it. ln(0) is not defined.

For MFA it is possible that you fail to get a reliable estimate of \(\small{\lambda_\textrm{z}}\) in a substantial number of pro­files. Therefore, you have no formal proof that AUC_t-∞ < 20% of AUC_∞. Discuss it in the study report (according to the GLs don’t exclude subjects). Since the variability of C_max is generally higher than the one of AUC_t, you can try a sensitivity analysis: BE of C_max (all subjects) and BE of AUC_t (only ones with a reliable estimate).

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• Prémaud A, Debord J, Rousseau A, Le Meur Y, Toupance O, Lebranchu Y, Hoizey G, Le Guellec C, Marquet P. A Double Absorption-Phase Model Adequately Describes Mycophenolic Acid Plasma Profiles in De Novo Renal Transplant Recipients Given Oral Mycophenolate Mofetil. Clin Pharmacokinet. 2005;44(8):837–47. doi 10.2165/00003088-200544080-00005.