Bioequivalence and Bioavailability Forum

Dear Joy!

❝ USFDA BE recommendation for Alendronate is to measure the drug in urine.

Exactly. Alendronate Sodium 70mg (Draft, Jan 2008), Alendronate Sodium and Cholecalciferol (Draft, Apr 2009; reference-scaled average bioequivalence!).

❝ How about EMEA, what is the recommended biological matrix, urine or

❝ plasma

Although products were approved through decentralised procedures (MRP) based on urinary data only in the past, studies probably were performed before EMEA's Q&A-document (2006) was published. For examples see here: Kendarin (2006-10-27), Alendronic Acid 70mg Tablets (2007-10-31), Alendratol tablets 70 mg (2007-12-20), Randronate tablets 70 mg (2007-12-20), Alendronat Hexal (2008-02-25), Alendronic Acid Once weekly 70 mg Tablets (2008-08-28).

EMEA's Q&A-document states:

10. What are the conditions for using urinary pharmacokinetic data for bioequivalence assessment?
The extent of drug input may be determined by the use of urinary excretion data provided elimination is dose-linear and is predominantly renal as intact drug. However, the use of urinary data has to be carefully justified when used to estimate the rate of absorption. If a reliable plasma C_max can be determined, this should be combined with urinary data on the extent of absorption for assessing bioequivalence.

This point of view for bisphosphonates (Ae for extent, C_max for rate of absorption) was univocally expressed by members of EMEA's PK-group at numerous conferences in the last years.

Another reference from members of the Dutch Medicines Evaluation Board:
C Versantvoort, M Maliepaard, and F Lekkerkerker
Generics: what is the role of registration authorities
The Netherlands Journal of Medicine 66/2, 62-66 (2008)
online resource

Low absolute bioavailability
In some cases the systemic absorption of the active substance is so low that plasma levels cannot be measured reliably. This has been reported for e.g. alendronate (Fosamax). Due to its low absolute bioavailability of only 0.6%, the plasma concentrations hardly exceed the detection limit. Since alendronate is almost exclusively excreted unchanged in the urine, the amount excreted in the urine is directly related to the plasma AUC. Thus, the amount excreted in the urine can be used as a measure for the extent of absorption, instead of the plasma AUC value. Analogously, the rate of absorption can be determined using the rate of excretion. It is acknowledged that this rate of excretion can be determined somewhat less accurately in urine than in plasma because of the less frequent sampling of urine. Therefore, to ensure that the rate of absorption does not differ essentially, additional comparable in vitro dissolution under various conditions is required for these alendronate applications. With recent improvements in the sensitivity of alendronate analytical assays, the generic application for the 70 mg, high-dosage form of alendronate can be based on the urine measurement for the amount absorbed, combined with the plasma C_max as an accurate measure for the rate of absorption. With this procedure efficacious and safe generic products for alendronate can be registered.