Pharmacokinetics of doxercalciferol, a new vitamin D analogue that lowers parathyroid hormone.
BACKGROUND
This is the first detailed pharmacokinetic report published on the administration of doxercalciferol [1alpha(OH)D(2)] recently introduced to treat secondary hyperparathyroidism.


METHODS
1alpha(OH)D(2) was administered in a range of single and multiple doses to volunteers with and without normal renal and/or hepatic function. Subsequent serial blood samples were assayed by HPLC/radioimmunoassay for the metabolite 1,25-dihydroxyvitamin D(2) [1,25(OH)(2)D(2)], the major active species.


RESULTS
Bioavailability of 1,25(OH)(2)D(2) from a single 5 micro g 1alpha(OH)D(2) oral-capsule dose was estimated to be normally approximately 42% of that from a 5 micro g intravenous injection. Steady-state serum concentrations of 1,25(OH)(2)D(2) were attainable within 8 day, and fluctuated approximately 2.5-fold from peak to trough when oral 1alpha(OH)D(2) doses were taken every second day, and the terminal half-life was 34+/-14 h. Mean steady-state serum concentrations rose less than proportionally (from 20 to 45 pg/ml) on increasing oral 1alpha(OH)D(2) doses from 5 to 15 micro g every 48 h. Renal patients showed 39+/-37% increase in serum 1,25(OH)(2)D(2) concentration during 3-4 h haemodialysis sessions, but no other difference in steady-state pharmacokinetics was found between these or hepatically impaired patients and normal subjects.


CONCLUSIONS
Given the sensitivity limits of current assays, the pharmacokinetics of this and other vitamin-D compounds is best elucidated from steady-state studies. The pharmacokinetics of 1,25(OH)(2)D(2) from 1alpha(OH)D(2) doses appears to be similar to that of 1,25(OH)(2)D(3) from 1alpha(OH)D(3) doses, albeit D(3) data have to date largely derived from single-dose studies. Deviation of 1,25(OH)(2)D(2) pharmacokinetics from linearity appears to be marginal enough to be clinically manageable with adequate precaution.
Upton
Robert A
RA
Department of Biopharmaceutical Sciences, University of California, San Francisco, CA, USA. cupton@netpro.net.au
Knutson
Joyce C
JC
Bishop
Charles W
CW
LeVan
Leon W
LW
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D001682:Biological Availability; D016022:Case-Control Studies; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004872:Ergocalciferols / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006962:Hyperparathyroidism, Secondary / Q000175:diagnosis / Q000188:drug therapy*; D007262:Infusions, Intravenous; D007676:Kidney Failure, Chronic / Q000150:complications; D008107:Liver Diseases / Q000150:complications; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010280:Parathyroid Glands / Q000187:drug effects* / Q000378:metabolism; D010281:Parathyroid Hormone / Q000378:metabolism; D012016:Reference Values; D012307:Risk Factors; D016896:Treatment Outcome; D014807:Vitamin D / Q000031:analogs & derivatives*
D004872:Ergocalciferols; D010281:Parathyroid Hormone; D014807:Vitamin D; C042533:1 alpha-hydroxyergocalciferol