Calcitriol: After 0.5 µg Cmax <2× basal level [Bioanalytics]
Hi John,
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.
❝ 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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Complete thread:
- Calcitriol jag009 2017-07-20 22:47 [Bioanalytics]
- Calcitriol: After 0.5 µg Cmax <2× basal levelHelmut 2017-07-21 01:07
- Calcitriol: After 0.5 µg Cmax <2× basal level jag009 2017-07-21 21:19
- Calcitriol: After 0.5 µg Cmax <2× basal levelHelmut 2017-07-21 01:07