Optimizing bioavailability of oral administration of small peptides through pharmacokinetic and pharmacodynamic parameters: the effect of water and timing of meal intake on oral delivery of Salmon Calcitonin

Abstract

Background: To investigate the influence of water intake and dose timing on the pharmacokinetic and pharmacodynamic parameters of an oral formulation of salmon calcitonin (sCT).

Methods: The study was a randomized, partially-blind, placebo-controlled, single dose, exploratory crossover phase I study. 56 healthy postmenopausal women were randomly assigned to receive five treatments. The treatments comprised a combination of study medication (SMC021 (0.8 mg sCT + 200 mg 5-CNAC), SMC021 placebo, or 200 IU Miacalcic NS nasal spray), water volume given with the tablet (50 or 200 ml water), and time between dosing and meal (10, 30, or 60 minutes pre-meal). Plasma sCT levels and changes in the bone resorption (C-terminal telopeptide of collagen type I) was investigated. Trial regristration.

Results: Oral delivery of 0.8 mg of sCT with 50 ml of water compared to that with 200 ml water resulted in a two-fold increase in maximum concentration (Cmax and AUC0-4) of plasma sCT but comparable time to reach maximum concentration (Tmax). The sCT AUC0-4 with 50 ml of water was 4-fold higher than that obtained with nasal calcitonin. The increased absorption of sCT resulted in increased efficacy demonstrated by AUC of the relative change of serum CTX-I measured in the 6 hours post dosing.

Conclusion: 0.8 mg sCT with 50 ml of water taken 30 and 60 minutes prior to meal time resulted in optimal pharmacodynamic and pharmacokinetic parameters. The data suggest that this novel oral formulation may have improved absorption and reduction of bone resorption compared to that of the nasal form.

Figure 1

Time course of plasma sCT 2 hours following one single dose of 0.8 mg with either 50 or 200 ml of water compared of that of Nasal sCT, as indicated in the legend. Values given are geometric mean ± 1 SEM.

Figure 2

AUC of plasma sCT in the 2 hours following one single dose of 0.8 mg with either 50 or 200 ml of water compared of that of Nasal sCT, as indicated in the legend. Values given are geometric mean ± 1 SEM.

Figure 3

Time course of absolute level of serum CTX-I in the 6 hours following one single dose of 0.8 mg with either 50 or 200 ml of water compared of that of Nasal sCT, as indicated in the legend. Values given are geometric mean ± 1 SEM.

Figure 4

AUC of relative change in serum CTX-I in the 6 hours following one single dose of 0.8 mg with either 50 or 200 ml of water compared of that of Nasal sCT. Values given are geometric mean ± 1 SEM.