Skip to main content
SpringerLink
Log in

Pharmacokinetic Profile of the Somatostatin Analogue Lanreotide in Individuals with Chronic Hepatic Insufficiency

  • Original Research Article
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background and objectives

The somatostatin analogue lanreotide is indicated for the treatment of acromegaly and to relieve the symptoms of neuroendocrine tumours. The objective of the present study was to compare the pharmacokinetic profile and safety of intravenous lanreotide in healthy volunteers and individuals with hepatic impairment.

Methods

Immediate-release lanreotide was administered at 7 μg/kg during a 20-minute intravenous infusion. Blood samples were collected over 24 hours and lanreotide serum levels determined by radioimmunoassay. Pharmacokinetic parameters were estimated by non-compartmental analyses.

Results

Two study centres recruited 53 individuals. Study A comprised 10 individuals with hepatic insufficiency Child-Pugh grade A (mild), 7 with grade B (moderate) and 12 healthy volunteers — all Caucasian. Study B comprised 4 individuals with hepatic insufficiency Child-Pugh grade A, 6 with grade B, 2 with grade C (severe) and 12 healthy volunteers — all Chinese. All participants were included in the safety analysis. The pharmacokinetic analysis included all participants from study B, but only 12 with hepatic impairment and 11 healthy volunteers from study A. Combined analysis of both studies showed an increased serum elimination half-life (57%; p ≤ 0.001), mean residence time (53%; p ≤ 0.001) and volume of distribution (at steady state, 57%; at terminal disposition phase, 64%; both p ≤ 0.001) in individuals with mild hepatic insufficiency compared with healthy volunteers. These differences were more pronounced in individuals with moderate-to-severe hepatic insufficiency compared with healthy volunteers; additionally, the area under the serum concentration-time curve from time zero to infinity (AUC∞) was increased (23%; p ≤ 0.05) and clearance (CL) decreased (19%; p ≤ 0.05) compared with healthy volunteers. The peak serum concentration of lanreotide tended to be lower in individuals with hepatic insufficiency than in healthy volunteers (statistically non-significant). There were no pharmacokinetic differences between the two groups of healthy volunteers. Lanreotide was well tolerated with only two mild adverse events that were considered to be possibly related to treatment (both nausea and headache with either vomiting or dizziness). There were no clinically relevant changes in laboratory parameters or vital signs during the study.

Conclusion

The pharmacokinetic profile of lanreotide depends on the severity of hepatic insufficiency with CL and AUC∞, which are only slightly altered with moderate-to-severe insufficiency. The changes in exposure do not, however, require dosage adjustment. Moreover, lanreotide is usually given as a prolonged-release microparticle or Autogel® formulation, and terminal half-life and serum concentrations depend on the release properties of the formulation. Dosing is also adapted for each patient, based on therapeutic response. Thus, hepatic insufficiency does not require additional dosage adjustments.

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

Table I
Table II
Fig. 1
Table III
Fig. 2

Similar content being viewed by others

References

  1. Lightman S. Somatuline Autogel: an extended release lanreotide formulation. Hosp Med 2002 Mar; 63(3): 162–5

    PubMed  Google Scholar 

  2. Culler MD, Taylor JE, Moreau JP. Somatostatin receptor subtypes: targeting functional and therapeutic specificity. Ann Endocrinol (Paris) 2002 Apr; 63 (2 Pt 3): 2S5–12

    CAS  Google Scholar 

  3. Racine MS, Barkan AL. Somatostatin analogs in medical treatment of acromegaly. Endocrine 2003 Apr; 20(3): 271–8

    Article  PubMed  CAS  Google Scholar 

  4. Caron P, Bex M, Cullen DR, et al. One-year follow-up of subjects with acromegaly treated with fixed or titrated doses of lanreotide Autogel. Clin Endocrinol (Oxf) 2004 Jun; 60(6): 734–40

    Article  CAS  Google Scholar 

  5. Caron P, Beckers A, Cullen DR, et al. Efficacy of the new long-acting formulation of lanreotide (lanreotide Autogel) in the management of acromegaly. J Clin Endocrinol Metab 2002 Jan; 87(1): 99–104

    Article  PubMed  CAS  Google Scholar 

  6. Ashwell SG, Bevan JS, Edwards OM, et al. The efficacy and safety of lanreotide Autogel in subjects with acromegaly previously treated with octreotide LAR. Eur J Endocrinol 2004 Apr; 150(4): 473–80

    Article  PubMed  CAS  Google Scholar 

  7. Cannavò S, Squadrito S, Curtò L, et al. Results of a two-year treatment with slow release lanreotide in acromegaly. Horm Metab Res 2000 Jun; 32(6): 224–9

    Article  PubMed  Google Scholar 

  8. Cannavò S, Squadrito S, Curtò L, et al. Effectiveness of slow-release lanreotide in previously operated and untreated subjects with GH-secreting pituitary macroadenoma. Horm Metab Res 2001 Oct; 33(10): 618–24

    Article  PubMed  Google Scholar 

  9. Baldelli R, Colao A, Razzore P, et al. Two-year follow-up of acromegalic subjects treated with slow release lanreotide (30mg). J Clin Endocrinol Metab 2000 Nov; 85(11): 4099–103

    Article  PubMed  CAS  Google Scholar 

  10. Ruszniewski P, Ish-Shalom S, Wymenga M, et al. Rapid and sustained relief from the symptoms of carcinoid syndrome: results from an open 6-month study of the 28-day prolonged-release formulation of lanreotide. Neuroendocrinology 2004; 80(4): 244–51

    Article  PubMed  CAS  Google Scholar 

  11. Arnold R, Wied M, Behr TH. Somatostatin analogues in the treatment of endocrine tumors of the gastrointestinal tract. Expert Opin Pharmacother 2002 Jun; 3(6): 643–56

    Article  PubMed  CAS  Google Scholar 

  12. O’Toole D, Ducreux M, Bommelaer G, et al. Treatment of carcinoid syndrome: a prospective crossover evaluation of lanreotide versus octreotide in terms of efficacy, patient acceptability, and tolerance. Cancer 2000 Feb; 88(4): 770–6

    Article  PubMed  Google Scholar 

  13. Wymenga AN, Eriksson B, Salmela PI, et al. Efficacy and safety of prolonged-release lanreotide in subjects with gastrointestinal neuroendocrine tumors and hormone-related symptoms. J Clin Oncol 1999 Apr; 17(4): 1111

    PubMed  CAS  Google Scholar 

  14. Ruszniewski P, Ducreux M, Chayvialle JA, et al. Treatment of the carcinoid syndrome with the longacting somatostatin analogue lanreotide: a prospective study in 39 subjects. Gut 1996 Aug; 39: 279–83

    Article  PubMed  CAS  Google Scholar 

  15. Heron I, Thomas F, Dero M, et al. Pharmacokinetics and efficacy of a long-acting formulation of the new somatostatin analog BIM 23014 in subjects with acromegaly. J Clin Endocrinol Metab 1993 Mar; 76(3): 721–7

    Article  PubMed  CAS  Google Scholar 

  16. Amato G, Mazziotti G, Rotondi M, et al. Long-term effects of lanreotide SR and octreotide LAR on tumour shrinkage and GH hypersecretion in subjects with previously untreated acromegaly. Clin Endocrinol (Oxf) 2002 Jan; 56(1): 65–71

    Article  CAS  Google Scholar 

  17. Antonijoan RM, Barbanoj MJ, Cordero JA, et al. Pharmacokinetics of a new Autogel formulation of the somatostatin analogue lanreotide after a single subcutaneous dose in healthy subjects. J Pharm Pharmacol 2004 Apr; 56(4): 471–6

    Article  PubMed  CAS  Google Scholar 

  18. Kuhn JM, Basin C, Mollard M, et al. Pharmacokinetic study and effects on growth hormone secretion in healthy subjects of the new somatostatin analogue BIM 23014. Eur J Clin Pharmacol 1993; 45(1): 73–7

    Article  PubMed  CAS  Google Scholar 

  19. Kuhn JM, Legrand A, Ruiz JM, et al. Pharmacokinetic and pharmacodynamic properties of a long-acting formulation of the new somatostatin analogue, lanreotide, in normal healthy subjects. Br J Clin Pharmacol 1994 Sep; 38(3): 213–9

    Article  PubMed  CAS  Google Scholar 

  20. Bronstein M, Musolino N, Jallad R, et al. Pharmacokinetic profile of lanreotide Autogel® in subjects with acromegaly after four deep subcutaneous injections of 60, 90 or 120mg every 28 days. Clin Endocrinol (Oxf) 2005; 63: 514–9

    Article  CAS  Google Scholar 

  21. Cendros JM, Peraire C, Troconiz IF, et al. Pharmacokinetics and population pharmacodynamic analysis of lanreotide Autogel. Metabolism 2005 Oct; 54(10): 1276–81

    Article  PubMed  CAS  Google Scholar 

  22. Barbanoj M, Antonijoan R, Morte A, et al. Pharmacokinetics of the somatostatin analog lanreotide in subjects with severe chronic renal insufficiency. Clin Pharmacol Ther 1999 Nov; 66(5): 485–91

    Article  PubMed  CAS  Google Scholar 

  23. Adedoyin A, Arns PA, Richards WO, et al. Selective effect of liver disease on the activities of specific metabolizing enzymes: investigation of cytochromes P450 2C19 and 2D6. Clin Pharmacol Ther 1998 Jul; 64(1): 8–17

    Article  PubMed  CAS  Google Scholar 

  24. McLean AJ, Morgan DJ. Clinical pharmacokinetics in subjects with liver disease. Clin Pharmacokinet 1991 Jul; 21: 42–69

    Article  PubMed  CAS  Google Scholar 

  25. Polonsky KS, Jaspan JB, Berelowith M, et al. Hepatic and renal metabolism of somatostatin-like immunoreactivity. J Clin Invest 1981 Nov; 68(5): 1149–57

    Article  PubMed  CAS  Google Scholar 

  26. Sheppard M, Shapiro B, Pimstone B, et al. Metabolic clearance and plasma half-disappearance time of exogenous somatostatin in man. J Clin Endocrinol Metab 1979 Jan; 48(1): 50–3

    Article  PubMed  CAS  Google Scholar 

  27. Ottesen LH, Flyvbjerg A, Jakobsen P, et al. The pharmacokinetics of octreotide in cirrhosis and in healthy man. J Hepatol 1997 May; 26(5): 1018–25

    Article  PubMed  CAS  Google Scholar 

  28. Demotes-Mainard F, Vincon G, Amouretti M, et al. Pharmacokinetics and protein binding of cefpiramide in patients with alcoholic cirrhosis. Clin Pharmacol Ther 1991 Mar; 49(3): 263–9

    Article  PubMed  CAS  Google Scholar 

  29. US Food and Drug Administration. Pharmacokinetics in patients with impaired hepatic function: study design, data analysis, and impact on dosing labeling. Guidance for industry. Rockville (MD): Center for Drug Evaluation and Research (CDER), 2003

    Google Scholar 

Download references

Acknowledgements

This study was sponsored by Ipsen (Paris, France). The authors wish to thank JM Cendrós for reviewing the pharmacokinetic results. The authors have no conflicts of interest that are directly relevant to the content of this study.

Author information

Authors and Affiliations

  1. Department of Medicine and Therapeutics, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China

    Brian Tomlinson, Neil G. Thomas & Irene W. Lan

  2. Research Drug Centre, Institute of Research, Clinical Pharmacology Service, Hospital of Santa Creu and Sant Pau, Barcelona, Spain

    Manuel Barbanoj & Rosa M. Antonijoan

  3. Department of Gastroenterology, Charles University, Prague, Czech Republic

    Eva Drazna

  4. Pharmacokinetics and Metabolism Service, Ipsen Pharma S.A., Crta, Laurea Miro 395, Sant Feliu de Llobregat, 08980, Barcelona, Spain

    Joaquim Ramis, Rosendo Obach &  Concepción Peraire

Authors
  1. Brian Tomlinson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Neil G. Thomas
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Irene W. Lan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Manuel Barbanoj
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rosa M. Antonijoan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Eva Drazna
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Joaquim Ramis
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Rosendo Obach
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Concepción Peraire
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Concepción Peraire.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tomlinson, B., Thomas, N.G., Lan, I.W. et al. Pharmacokinetic Profile of the Somatostatin Analogue Lanreotide in Individuals with Chronic Hepatic Insufficiency. Clin Pharmacokinet 45, 1003–1011 (2006). https://doi.org/10.2165/00003088-200645100-00004

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003088-200645100-00004

Keywords

Search

Navigation