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Back to the forum  Query: 2017-08-24 06:56 CEST (UTC+2h)
 
jag009
Hero

NJ,
2017-07-20 22:47

Posting: # 17586
Views: 417
 

 Calcitriol [Bioanalytics]

Hi all,
Is calcitriol bioanalytical method a really difficult method?

Thanks
John
Helmut
Hero
Homepage
Vienna, Austria,
2017-07-21 01:07

@ jag009
Posting: # 17587
Views: 337
 

 Calcitriol: After 0.5 µg Cmax <2× basal level

Hi John,

» Is calcitriol bioanalytical method a really difficult method?

Define difficult. ;-)
An LLOQ of 15 pg/mL will do the job. That’s doable with a validated (!) commercial RIA.

IMHO, the design recommended in the FDA’s guidance is problematic. I don’t get the point of the FDA’s 0, –6, –12, and –18 hours sampling. Averaging (as suggested) IMHO, is crap. There is a circadian rhythm of basal levels (24 ♂ x 30–50 pg/mL). See also Rejnmark et al. 2002.*
I recommend full basal profiles in each period. A dose of 0.5 µg will be extremely difficult. Not analytically but you will be very close to basal levels. Our Cmax (unadjusted geometric mean) was 222 pg/mL after a 4 µg dose. CVintra of Cmax,adj was 27% and of AUC0–t,adj 20%. Given that, after a 0.5 µg dose you could expect an unadjusted Cmax of ~62 pg/mL at a time when basal levels are ~39 pg/mL. That’s difficult. I guess you will run into serious troubles estimating λz.
I know of another study with a 2 µg dose, where (with averaging as suggested by the FDA) the CRO only by some acrobatic means could deal with the later part of the profile. The unadjusted Cmax was 134 µg/mL and Cmax,adj 76 µg/mL (25 ♀♂).
Im pretty sure that at least the CV of Cmax will be >30% and and therefore, a candidate for RSABE. I don’t expect that demonstrating BE with a 0.5 µg dose is realistic at all. Talk to the OGD.


  • Rejnmark L, Lauridsen AL, Vestergaard P, Heickendorff L, Andreasen F, Mosekilde L. Diurnal rhythm of plas­ma 1,25-dihydroxyvitamin D and vitamin D-binding protein in postmenopausal women: relationship to plasma parathyroid hormone and calcium and phosphate metabolism. Eur J Endocrin. 2002;146:635-42. doi:10.1530/eje.0.1460635

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jag009
Hero

NJ,
2017-07-21 21:19

@ Helmut
Posting: # 17591
Views: 261
 

 Calcitriol: After 0.5 µg Cmax <2× basal level

Thank you Helmut! :)

Yes it's going to be difficult and such a dose. I am thinking of asking RA to get blessing from the agency about increasing the dose (multiple tablets) :)

Difficult as in difficult BA method which leads to a higher price per sample. I have heard pricing at $30USD from India! I spoke with my friends and some said the extracting method requires a kit which costs like $15USD. I don't see how (Of course it's possible but...) the pricing can be $30/sample.

John
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