Investigations of inter- and intraindividual relationships between exposure to oral salmon calcitonin and a surrogate marker of pharmacodynamic efficacy

The aims of the study were to investigate interindividual variations in the bioavailability of salmon calcitonin (sCT) following single oral 0.8 mg doses at three different times of the day, and intraindividual variation in sCT bioavailability at each end of a 14-day treatment period. We also investigated correlations between exposure to sCT and levels of the bone resorption biomarker serum C-terminal telopeptide of collagen type I (CTX-I). Participants were from two randomized, double-blind, placebo-controlled studies. In study I, healthy postmenopausal women received a single dose of 0.8 mg of oral sCT or placebo at 08:00 (n = 42), 17:00 (n = 20), or at 22:00 (n = 19). In study II, age-matched men or postmenopausal women with osteoarthritis received 0.8 mg oral sCT (n = 26) or placebo (n = 23) twice daily for 14 days, with dosing at 08:00 and 17:00. In both studies, drug exposure was assessed by plasma sCT concentrations, and bone resorption by CTX-I levels. The variability in exposure between patients, measured as coefficient of variation (CV), was as follows: 22% for the morning dose, 30% for the predinner dose, and 34% for the evening dose. In study 1, a high degree of correlation was seen between the level of exposure following a single 0.8 mg dose of sCT and suppression of serum CTX-I, with Pearson correlation coefficients of r = −0.74, −0.96, and −0.78, following doses at 08:00, 17:00, and 22:00, respectively. In study II, exposure to sCT varied widely within the same individuals between dosing days 1 and 14, with weak correlations of r = 0.40 and 0.38 at the dose times 08:00 and 17:00, respectively. As expected from this finding, the intraindividual response in serum CTX-I levels was non-significantly associated on dosing days 1 and 14 (r = 0.34 and r = 0.27 at dose times 08:00 and 17:00, respectively). Increased bioavailability of orally administered 0.8 mg sCT was highly correlated with increased suppression of the bone resorption marker serum CTX-I irrespective of the time of day. However, the high inter- and intraindividual variability in sCT exposure demonstrates the importance of determining the optimum conditions for ensuring the most beneficial sCT uptake.