Skip to main content

Advertisement

SpringerLink
Log in

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

  • Clinical Trial
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Aims

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).

Methods

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.

Results

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).

Conclusion

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Reference

  1. Tanko LB, Bagger YZ, Alexandersen P, Devogelaer JP, Reginster JY, Chick R, Olson M, Benmammar H, Mindeholm L, Azria M et al (2004) Safety and efficacy of a novel salmon calcitonin (sCT) technology-based oral formulation in healthy postmenopausal women: acute and 3-month effects on biomarkers of bone turnover. J Bone Miner Res 19:1531–1538

    Article  CAS  PubMed  Google Scholar 

  2. Bagger YZ, Tanko LB, Alexandersen P, Karsdal MA, Olson M, Mindeholm L, Azria M, Christiansen C (2005) Oral salmon calcitonin induced suppression of urinary collagen type II degradation in postmenopausal women: a new potential treatment of osteoarthritis. Bone 37:425–430

    Article  CAS  PubMed  Google Scholar 

  3. Manicourt DH, Altman RD, Williams JM, Devogelaer JP, Druetz-Van Egeren A, Lenz ME, Pietryla D, Thonar EJ (1999) Treatment with calcitonin suppresses the responses of bone, cartilage, and synovium in the early stages of canine experimental osteoarthritis and significantly reduces the severity of the cartilage lesions. Arthritis Rheum 42:1159–1167

    Article  CAS  PubMed  Google Scholar 

  4. Sexton PM, Findlay DM, Martin TJ (1999) Calcitonin. Curr Med Chem 6:1067–1093

    CAS  PubMed  Google Scholar 

  5. Karsdal MA, Henriksen K, Arnold M, Christiansen C (2008) Calcitonin: a drug of the past or for the future? Physiologic inhibition of bone resorption while sustaining osteoclast numbers improves bone quality. BioDrugs 22:137–144

    Article  CAS  PubMed  Google Scholar 

  6. Bernkop-Schnurch A, Hoffer MH, Kafedjiiski K (2004) Thiomers for oral delivery of hydrophilic macromolecular drugs. Expert Opin Drug Deliv 1:87–98

    Article  CAS  PubMed  Google Scholar 

  7. Guggi D, Kast CE, Bernkop-Schnurch A (2003) In vivo evaluation of an oral salmon calcitonin-delivery system based on a thiolated chitosan carrier matrix. Pharm Res 20:1989–1994

    Article  CAS  PubMed  Google Scholar 

  8. Karsdal MA, Byrjalsen I, Leeming DJ, Delmas PD, Christiansen C (2008) The effects of oral calcitonin on bone collagen maturation: implications for bone turnover and quality. Osteoporos Int 19:1355–1361

    Article  CAS  PubMed  Google Scholar 

  9. Lamprecht A, Yamamoto H, Takeuchi H, Kawashima Y (2004) pH-sensitive microsphere delivery increases oral bioavailability of calcitonin. J Controlled Release 98:1–9

    Article  CAS  Google Scholar 

  10. Lee YH, Sinko PJ (2000) Oral delivery of salmon calcitonin. Adv Drug Deliv Rev 42:225–238

    Article  CAS  PubMed  Google Scholar 

  11. Torres-Lugo M, Peppas NA (2000) Transmucosal delivery systems for calcitonin: a review. Biomaterials 21:1191–1196

    Article  CAS  PubMed  Google Scholar 

  12. Wang J, Chow D, Heiati H, Shen WC (2003) Reversible lipidization for the oral delivery of salmon calcitonin. J Controlled Release 88:369–380

    Article  CAS  Google Scholar 

  13. Van den MG (2006) Colon drug delivery. Expert Opin Drug Deliv 3:111–125

    Article  Google Scholar 

  14. Streubel A, Siepmann J, Bodmeier R (2006) Gastroretentive drug delivery systems. Expert Opin Drug Deliv 3:217–233

    Article  CAS  PubMed  Google Scholar 

  15. Karsdal MA, Byrjalsen I, Riis BJ, Christiansen C (2008) 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. BMC Clin Pharmacol 8:5

    Article  PubMed  Google Scholar 

  16. Sondergaard BC, Ostergaard S, Christiansen C, Karsdal MA (2007) The effect of oral calcitonin on cartilage turnover and surface erosion in the ovariectomized rat model. Arthritis Rheum 56:2674–2678

    Google Scholar 

  17. Karsdal MA, Byrjalsen I, Azria M, Arnold M, Choi L, Riis BJ, Christiansen C (2009) Influence of food intake on the bioavailability and efficacy of oral calcitonin. Br J Clin Pharmacol 67:413–420

    Article  CAS  PubMed  Google Scholar 

  18. Malkov D, Angelo R, Wang HZ, Flanders E, Tang H, Gomez-Orellana I (2005) Oral delivery of insulin with the Eligen technology: mechanistic studies. Curr Drug Deliv 2:191–197

    Article  CAS  PubMed  Google Scholar 

  19. Mustata G, Dinh SM (2006) Approaches to oral drug delivery for challenging molecules. Crit Rev Ther Drug Carrier Syst 23:111–135

    CAS  PubMed  Google Scholar 

  20. Alexandersen P, Karsdal MA, Qvist P, Reginster JY, Christiansen C (2007) Strontium ranelate reduces the urinary level of cartilage degradation biomarker CTX-II in postmenopausal women. Bone 40:218–222

    Article  CAS  PubMed  Google Scholar 

  21. Karsdal MA, Byrjalsen I, Riis BJ, Christiansen C (2008) Investigation of the diurnal variation in bone resorption for optimal drug delivery and efficacy in osteoporosis with oral calcitonin. BMC Clin Pharmacol 8:12

    Article  CAS  PubMed  Google Scholar 

  22. Karsdal MA, Byrjalsen I, Henriksen K, Riis BJ, Christiansen C (2009) A pharmacokinetic and pharmacodynamic comparison of synthetic and recombinant oral salmon calcitonin. J Clin Pharmacol 49:229–234

    Article  CAS  PubMed  Google Scholar 

  23. Jusko WJ, Ko HC (1994) Physiologic indirect response models characterize diverse types of pharmacodynamic effects. Clin Pharmacol Ther 56:406–419

    CAS  PubMed  Google Scholar 

  24. Karsdal MA, Henriksen K, Leeming DJ, Mitchell P, Duffin K, Barascuk N, Klickstein L, Aggarwal P, Nemirovskiy O, Byrjalsen I et al (2009) Biochemical markers and the FDA Critical Path: how biomarkers may contribute to the understanding of pathophysiology and provide unique and necessary tools for drug development. Biomarkers 14:181–202

    Article  CAS  PubMed  Google Scholar 

  25. Schaller S, Henriksen K, Hoegh-Andersen P, Sondergaard BC, Sumer EU, Tanko LB, Qvist P, Karsdal MA (2005) In vitro, ex vivo, and in vivo methodological approaches for studying therapeutic targets of osteoporosis and degenerative joint diseases: how biomarkers can assist? Assay Drug Dev Technol 3:553–580

    Article  CAS  PubMed  Google Scholar 

  26. Saftig P, Hunziker E, Wehmeyer O, Jones S, Boyde A, Rommerskirch W, Moritz JD, Schu P, von Figura K (1998) Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin-K-deficient mice. Proc Natl Acad Sci USA 95:13453–13458

    Article  CAS  PubMed  Google Scholar 

  27. Schaller S, Henriksen K, Sveigaard C, Heegaard AM, Helix N, Stahlhut M, Ovejero MC, Johansen JV, Solberg H, Andersen TL et al (2004) The chloride channel inhibitor n53736 prevents bone resorption in ovariectomized rats without changing bone formation. J Bone Miner Res 19:1144–1153

    Article  CAS  PubMed  Google Scholar 

  28. Ravn P, Hosking D, Thompson D, Cizza G, Wasnich RD, McClung M, Yates AJ, Bjarnason NH, Christiansen C (1999) Monitoring of alendronate treatment and prediction of effect on bone mass by biochemical markers in the early postmenopausal intervention cohort study. J Clin Endocrinol Metab 84:2363–2368

    Article  CAS  PubMed  Google Scholar 

  29. Karsdal MA, Byrjalsen I, Henriksen K, Riis BJ, Lau EM, Arnold M, Christiansen C (2009) The effect of oral salmon calcitonin delivered with 5-CNAC on bone and cartilage degradation in osteoarthritic patients: a 14-day randomized study. Osteoarthritis Cartilage (in press). doi:10.1016/j.joca.2009.08.004

  30. Rosenquist C, Fledelius C, Christgau S, Pedersen BJ, Bonde M, Qvist P, Christiansen C (1998) Serum CrossLaps One Step ELISA. First application of monoclonal antibodies for measurement in serum of bone-related degradation products from C-terminal telopeptides of type I collagen. Clin Chem 44:2281–2289

    CAS  PubMed  Google Scholar 

  31. Abramson SB, Attur M, Yazici Y (2006) Prospects for disease modification in osteoarthritis. Nat Clin Pract Rheumatol 2:304–312

    Article  CAS  PubMed  Google Scholar 

  32. Karsdal MA, Leeming DJ, Dam EB, Henriksen K, Alexandersen P, Pastoureau P, Altman RD, Christiansen C (2008) Should subchondral bone turnover be targeted when treating osteoarthritis? Osteoarthritis Cartilage 16:638–646

    Article  CAS  PubMed  Google Scholar 

  33. Manicourt DH, Devogelaer JP, Azria M, Silverman S (2005) Rationale for the potential use of calcitonin in osteoarthritis. J Musculoskelet Neuronal Interact 5:285–293

    CAS  PubMed  Google Scholar 

  34. Sondergaard BC, Wulf H, Henriksen K, Schaller S, Oestergaard S, Qvist P, Tanko LB, Bagger YZ, Christiansen C, Karsdal MA (2006) Calcitonin directly attenuates collagen type II degradation by inhibition of matrix metalloproteinase expression and activity in articular chondrocytes. Osteoarthritis Cartilage 14:759–768

    Article  CAS  PubMed  Google Scholar 

  35. Manicourt DH, Azria M, Mindeholm L, Devogelaer JP (2005) Efficacy of calcitonin therapy in patients with knee osteoarthritis: a clinical and biochemical preliminary study. Osteoarthritis Cartilage 13:s88

    Google Scholar 

  36. Garnero P, Sornay-Rendu E, Claustrat B, Delmas PD (2000) Biochemical markers of bone turnover, endogenous hormones and the risk of fractures in postmenopausal women: the OFELY study. J Bone Miner Res 15:1526–1536

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors are very grateful to Bonnie Malloy for editorial assistance. The study was supported by Den Danske Forskningsfond, The Danish Research Foundation.

Author information

Authors and Affiliations

  1. Nordic Bioscience A/S, CCBR, Herlev/Ballerup Hovedgade 207, DK-2730, Herlev, Denmark

    Morten A. Karsdal, Inger Byrjalsen, Kim Henriksen, Bente J. Riis & Claus Christiansen

Authors
  1. Morten A. Karsdal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Inger Byrjalsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kim Henriksen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bente J. Riis
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Claus Christiansen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Morten A. Karsdal.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Karsdal, M.A., Byrjalsen, I., Henriksen, K. et al. Investigations of inter- and intraindividual relationships between exposure to oral salmon calcitonin and a surrogate marker of pharmacodynamic efficacy. Eur J Clin Pharmacol 66, 29–37 (2010). https://doi.org/10.1007/s00228-009-0735-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-009-0735-3

Keywords

Search

Navigation