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.
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.


CONCLUSIONS
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.
Karsdal
Morten A
MA
Nordic Bioscience A/S, CCBR, Herlev/Ballerup, DK-2730 Herlev, Denmark. mk@nordicbioscience.com
Byrjalsen
Inger
I
Riis
Bente J
BJ
Christiansen
Claus
C
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001682:Biological Availability; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism; D002116:Calcitonin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D018592:Cross-Over Studies; D004326:Drinking; D004435:Eating; D005260:Female; D006801:Humans; D007408:Intestinal Absorption; D008875:Middle Aged; D013997:Time Factors
D050071:Bone Density Conservation Agents; C028815:salmon calcitonin; D002116:Calcitonin
J Clin Pharmacol. 1999 Feb;39(2):172-9
11563410
AAPS PharmSci. 2003;5(2):E17
12866944
Int J Pharm. 2002 Jun 4;239(1-2):185-95
12052704
Adv Drug Deliv Rev. 2000 Aug 31;42(3):225-38
10963837
Osteoarthritis Cartilage. 2006 Jul;14(7):617-24
16698291
Bioconjug Chem. 2006 Jul-Aug;17(4):1000-7
16848408
Endocrinology. 1962 May;70:638-49
13881211
Am J Med. 2000 Sep;109(4):267-76
10996576
Clin Pharmacol Ther. 2005 Mar;77(3):170-7
15735611
Lancet. 1963 Sep 7;2(7306):480-2
14065416
Bone. 2005 Sep;37(3):425-30
16005273
Int J Pharm. 2005 May 30;296(1-2):122-32
15885464
Arthritis Rheum. 2006 Oct;54(10):3205-11
17009253
Arthritis Rheum. 2007 Aug;56(8):2674-8
17665432
J Clin Pharmacol. 2005 Dec;45(12):1400-6
16291715
J Control Release. 2004 Jul 23;98(1):1-9
15245884
Curr Med Chem. 1999 Nov;6(11):1067-93
10519914
J Bone Miner Res. 2004 Sep;19(9):1531-8
15312255
Calcif Tissue Int. 1998 Aug;63(2):102-6
9685512
J Pharm Sci. 2007 Feb;96(2):459-72
17075867
Curr Drug Deliv. 2005 Apr;2(2):191-7
16305420
Clin Chem. 1998 Nov;44(11):2281-9
9799755
Expert Opin Drug Deliv. 2006 Jan;3(1):111-25
16370944
Assay Drug Dev Technol. 2005 Oct;3(5):553-80
16305312
Expert Opin Drug Deliv. 2004 Nov;1(1):87-98
16296722
Br J Clin Pharmacol. 2007 Sep;64(3):386-90
17425628
Pharm Res. 2003 Dec;20(12):1989-94
14725364
J Control Release. 2003 Mar 26;88(3):369-80
12644363
J Bone Miner Res. 2002 Aug;17(8):1478-85
12162502
Pharmacology. 1982;24(6):337-45
7111374
Am J Pathol. 2005 Feb;166(2):467-76
15681830
Exp Hematol. 1991 Nov;19(10):1049-54
1915705
Clin Pharmacokinet. 2003;42(4):361-72
12648026
J Clin Endocrinol Metab. 1992 Mar;74(3):476-80
1740479
Biochim Biophys Acta. 2005 Jun 30;1750(2):134-45
15964788
Bone. 2002 Jul;31(1):57-61
12110413
Bone. 2000 Aug;27(2):283-6
10913923
Expert Opin Drug Deliv. 2006 Mar;3(2):217-33
16506949
Biomaterials. 2000 Jun;21(12):1191-6
10811300