Investigation of the diurnal variation in bone resorption for optimal drug delivery and efficacy in osteoporosis with oral calcitonin

M A Karsdal, I Byrjalsen, B J Riis, C Christiansen, M A Karsdal, I Byrjalsen, B J Riis, C Christiansen

Abstract

Background: Bone resorption displays marked diurnal variation. Reversible inhibition of bone resorption may result in best possible efficacy when bone resorption peaks. The aim of the study was to assess the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of 0.8 mg of oral salmon calcitonin (sCT) and the effect of timing of drug intake.

Methods: The study was a randomized, double-blind, double-dummy, placebo-controlled, phase I study to assess the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of 0.8 mg of oral sCT in healthy postmenopausal women. Totally 81 subjects were included, aimed at investigation of a morning dose given at 8:00 (n = 42), a pre-dinner dose given at 17:00 (n = 20), and an evening dose given at 22:00 (n = 19). Plasma sCT concentrations and bone resorption (C-terminal-telopeptide of collagen type I (CTX-I)) was assessed.

Results: Morning and pre-dinner dosing led to comparable concentration of sCT of 45 pg/ml, whereas there was a tendency towards lower Cmax for the evening dosing having a mean of 24 pg/ml. The maximum difference from placebo was observed 1 to 3 hours post-dose with a 40 to 50% suppression consequent to morning dose, and about 75% suppression after pre-dinner and evening dose, due to the increase bone resorption as a result of circadian variation.

Conclusion: The study suggests that orally administered 0.8 mg of salmon calcitonin was effective in suppression of serum CTX irrespective of time of dosing. The pre-dinner dosing resulted in optimum efficacy response corresponding to an overall suppression of bone resorption by 25%.

Trial registration: ClinicalTrials.gov NCT00411125.

Figures

Figure 1
Figure 1
Time course of plasma sCT in each time dose group. Full line shows the results of 0.8 mg of oral sCT and the dotted line that of placebo. Morning dose (n = 42); pre-dinner dose (n = 20); and evening dose (n = 19). Values given are geometric mean ± 1 SEM.
Figure 2
Figure 2
Cmax and AUC0–4 hrs of plasma sCT in the 4 hours following one single dose of 0.8 mg of oral sCT in each time dose group corrected for AUC of the placebo groups. Morning dose (n = 42); pre-dinner dose (n = 20); and evening dose (n = 19). Values given are geometric mean ± 1 SEM.
Figure 3
Figure 3
Time course of absolute levels of serum CTX in each time dose group. Closed circles show the results of 0.8 mg of oral sCT and the open circles that of placebo. The figures show results of the full follow-up period of 24 hours. Morning dose (n = 42); pre-dinner dose (n = 20); and evening dose (n = 19). Values given are geometric mean ± 1 SEM.
Figure 4
Figure 4
AUC of absolute (A) and relative (B) change in serum CTX in the 24 hours following one single dose of 0.8 mg of oral sCT in each time dose group corrected for placebo AUC of the individual subject. Morning dose (n = 42); pre-dinner dose (n = 20); and evening dose (n = 19). Values given are geometric mean ± 1 SEM. The level of significance denotes difference from placebo: **p < 0.01; *** p < 0.001.

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