Bioequivalence and Bioavailability Forum

¡Hola Averroes!

❝ Do you think poor frequency of blood sampling could have influenced CV intra?

Absolutely! Like all bisposphonates alendronate has (very!) low and highly variable absorption, spiced with lag-times. With too few sampling time points we might get a biased estimates of the C_max-ratio in individual subjects. Regularly missing the ‘true’ C_max directly translates into an increased CV_intra. See this example (slides 44–45).
Now your colleague learned the hard way one of the purposes of a pilot study (nicely outlined by the FDA):

[…] a pilot study in a small number of subjects […] can be used to validate analytical metho­do­logy, assess vari­ability, optimize sample collection time intervals, and provide other infor­ma­tion. For example, for conventional immediate-release products, careful timing of initial samples may avoid a subsequent finding in a full-scale study that the first sample collection occurs after the plasma concentration peak. For modified-release products, a pilot study can help determine the sampling schedule to assess lag time and dose dumping.

(my emphasis)

BTW, since alendronate is well known to be a HVD, n=12 is too small by far – if he/she wanted to get reliable estimates of the ratios and CVs for sample size estimation. IMHO, alendronate would be a candi­date for reference-scaling (ABEL). In that case the pilot study should be performed in a replicate design.