Efficacy of a slow-release formulation of lanreotide (Autogel® 120 mg) in patients with acromegaly previously treated with octreotide long acting release (LAR): an open, multicentre longitudinal study
C. L. Ronchi
Department of Medical Sciences, University of Milan, Unit of Endocrinology and Metabolism, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Italy,
Search for more papers by this authorM. Boschetti
Di.S.E.M. Department of Endocrinology and Metabolism, Genova, Italy,
Search for more papers by this authorE. C. Degli Uberti
Department of Biomedical Sciences and Advanced Therapies, University of Ferrara, Unit of Endocrinology, Ferrara, Italy,
Search for more papers by this authorS. Mariotti
Institute of Endocrinology, Department of Medical Sciences, University of Cagliari, Policlinico Monserrato, Cagliari, Italy,
Search for more papers by this authorS. Grottoli
Department of Internal Medicine, Division of Endocrinology and Metabolism, University of Turin, Turin, Italy,
Search for more papers by this authorP. Loli
Division of Endocrinology, Niguarda Cà Granda Hospital, Milan, Italy,
Search for more papers by this authorG. Lombardi
Department of Molecular and Clinical Endocrinology and Oncology, University Federico II, Naples, Italy,
Search for more papers by this authorG. Tamburrano
Department of Endocrinology, University La Sapienza, Policlinico Umberto I, Rome, Italy,
Search for more papers by this authorM. Arvigo
Di.S.E.M. Department of Endocrinology and Metabolism, Genova, Italy,
Search for more papers by this authorG. Angeletti
Department of Internal Medicine and Endocrinological and Metabolic Sciences, University of Perugia, Perugia, Italy,
Search for more papers by this authorP. Beck-Peccoz
Department of Medical Sciences, University of Milan, Unit of Endocrinology and Metabolism, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Italy,
Search for more papers by this authorM. Arosio
Unit of Endocrinology, Ospedale S. Giuseppe Milano-Cuore, AFaR, University of Milan; Milan, Italy
Search for more papers by this authorfor the Italian Multicenter Autogel Study Group in Acromegaly
The Italian Multicenter Autogel Study Group in Acromegaly comprises L. De Marinis (Division of Endocrinology, Catholic University, Rome, Italy), E. De Menis (Service of Endocrinology, Cà Foncello Hospital, Treviso, Italy), M. Giusti (Di.S.E.M. Department of Endocrinology and Metabolism, Genova, Italy), F. Grimaldi (Division of Endocrinology, S. Maria della Misericordia Hospital, Udine, Italy), F. Mantero (Division of Endocrinology, Department of Surgical and Medical Sciences, University of Padua, Padua, Italy), P. Tita (Garibaldi Hospital, Catania, Italy), R. Valcavi (Arcispedale S. Maria Nuova, Reggio Emilia, Italy), F. Minuto (Di.S.E.M. Department of Endocrinology and Metabolism, Genova, Italy), M. R. Ambrosio (Department of Biomedical Sciences and Advanced Therapies, University of Ferrara, Unit of Endocrinology, Ferrara, Italy), F. Pigliaru (Institute of Endocrinology, Department of Medical Sciences, University of Cagliari, Policlinico Monserrato, Cagliari, Italy), R. Baldelli (Policlinico Umberto I, Rome, Italy), A. Colao (Department of Molecular and Clinical Endocrinology and Oncology, University Federico II, Naples, Italy), R. Cozzi (Division of Endocrinology, Niguarda Cà Granda Hospital, Milan, Italy; ), E. Ghigo, V. Gasco (Department of Internal Medicine, University of Turin, Division of Endocrinology and Metabolism, Turin, Italy), P. Ferolla, D. La Torre (University of Perugia, Italy).
Search for more papers by this authorC. L. Ronchi
Department of Medical Sciences, University of Milan, Unit of Endocrinology and Metabolism, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Italy,
Search for more papers by this authorM. Boschetti
Di.S.E.M. Department of Endocrinology and Metabolism, Genova, Italy,
Search for more papers by this authorE. C. Degli Uberti
Department of Biomedical Sciences and Advanced Therapies, University of Ferrara, Unit of Endocrinology, Ferrara, Italy,
Search for more papers by this authorS. Mariotti
Institute of Endocrinology, Department of Medical Sciences, University of Cagliari, Policlinico Monserrato, Cagliari, Italy,
Search for more papers by this authorS. Grottoli
Department of Internal Medicine, Division of Endocrinology and Metabolism, University of Turin, Turin, Italy,
Search for more papers by this authorP. Loli
Division of Endocrinology, Niguarda Cà Granda Hospital, Milan, Italy,
Search for more papers by this authorG. Lombardi
Department of Molecular and Clinical Endocrinology and Oncology, University Federico II, Naples, Italy,
Search for more papers by this authorG. Tamburrano
Department of Endocrinology, University La Sapienza, Policlinico Umberto I, Rome, Italy,
Search for more papers by this authorM. Arvigo
Di.S.E.M. Department of Endocrinology and Metabolism, Genova, Italy,
Search for more papers by this authorG. Angeletti
Department of Internal Medicine and Endocrinological and Metabolic Sciences, University of Perugia, Perugia, Italy,
Search for more papers by this authorP. Beck-Peccoz
Department of Medical Sciences, University of Milan, Unit of Endocrinology and Metabolism, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Italy,
Search for more papers by this authorM. Arosio
Unit of Endocrinology, Ospedale S. Giuseppe Milano-Cuore, AFaR, University of Milan; Milan, Italy
Search for more papers by this authorfor the Italian Multicenter Autogel Study Group in Acromegaly
The Italian Multicenter Autogel Study Group in Acromegaly comprises L. De Marinis (Division of Endocrinology, Catholic University, Rome, Italy), E. De Menis (Service of Endocrinology, Cà Foncello Hospital, Treviso, Italy), M. Giusti (Di.S.E.M. Department of Endocrinology and Metabolism, Genova, Italy), F. Grimaldi (Division of Endocrinology, S. Maria della Misericordia Hospital, Udine, Italy), F. Mantero (Division of Endocrinology, Department of Surgical and Medical Sciences, University of Padua, Padua, Italy), P. Tita (Garibaldi Hospital, Catania, Italy), R. Valcavi (Arcispedale S. Maria Nuova, Reggio Emilia, Italy), F. Minuto (Di.S.E.M. Department of Endocrinology and Metabolism, Genova, Italy), M. R. Ambrosio (Department of Biomedical Sciences and Advanced Therapies, University of Ferrara, Unit of Endocrinology, Ferrara, Italy), F. Pigliaru (Institute of Endocrinology, Department of Medical Sciences, University of Cagliari, Policlinico Monserrato, Cagliari, Italy), R. Baldelli (Policlinico Umberto I, Rome, Italy), A. Colao (Department of Molecular and Clinical Endocrinology and Oncology, University Federico II, Naples, Italy), R. Cozzi (Division of Endocrinology, Niguarda Cà Granda Hospital, Milan, Italy; ), E. Ghigo, V. Gasco (Department of Internal Medicine, University of Turin, Division of Endocrinology and Metabolism, Turin, Italy), P. Ferolla, D. La Torre (University of Perugia, Italy).
Search for more papers by this authorSummary
Objective Lanreotide Autogel® 120 mg (ATG120; Ipsen S.p.A, Milan, Italy) is a high-dose, sustained-release aqueous gel formulation, supplied in a prefilled syringe and given by deep subcutaneous injection. The aim of this study was to compare efficacy and tolerability of ATG120 given every 4–8 weeks with those of octreotide LAR (o-LAR) given every 4 weeks.
Design patients and intervention A phase III multicentre Italian open clinical study of 23 acromegalic patients (15 female, 8 male). All patients had received o-LAR for 6–18 months and, after 3 months wash out, ATG120 was given every 6 weeks for a total of four injections (Period 1). Then the interval between ATG120 injections was adjusted according to three different schemes: every 4, 6 or 8 weeks depending on GH levels (GH > 2·5 µg/l; 1 < GH ≤ 2·5 µg/l; GH ≤ 1 µg/l, respectively). ATG120 was given for a further two to three doses, with a final assessment (Period 2) at Week 34, 36 or 42.
Measurements Hormonal (GH and IGF-I) and clinical efficacy and tolerability.
Results ATG120 induced a significant GH decrease from 9·9 ± 11·3 at baseline (Visit 1) to 3·5 ± 5·7 at the end of Period 1 (P < 0·01) and to 3·8 ± 5·7 µg/l at the final visit (P < 0·01). IGF-I also decreased from 544 ± 312 at baseline (Visit 1) to 318 ± 181 at Period 1 and to 356 ± 187 µg/l at the final visit (both P < 0·05 vs. baseline). The frequency of ATG120 administrations was adjusted to every 4 weeks in 12 patients, every 6 weeks in 4 patients and every 8 weeks in 6 patients; 1 patient withdrew before the dose adjustment. Serum GH and IGF-I achieved at the end of Period 1 and Period 2 were similar to those reached with o-LAR. The number of patients who achieved GH < 2·5 µg/l was comparable between o-LAR (43%) and ATG120 at Period 1 (48%) and at Period 2 (62%). Normal IGF-I levels were recorded in 8 patients during o-LAR (35%), 11 during ATG Period 1 (48%) and 10 at the final visit (43%). Last, 4 patients showed a better response to ATG120 and 2 to o-LAR.
Conclusions Lanreotide Autogel 120 mg is an effective and well-tolerated therapy for acromegaly. In approximately half of patients ATG120 may be administered every 6–8 weeks, instead of every 4 weeks, without lost of efficacy.
References
- 1 Lamberts, S.W., Van Der Lely, A.J., De Herder, W.W. & Hofland, L.J. (1996) Octreotide. New England Journal of Medicine, 334, 246–254.
- 2 Colao, A., Ferone, D., Marzullo, P., Cappabianca, P., Cirillo, S., Boerlin, V., Lancranjan, I. & Lombardi, G. (2001) Long-term effects of depot long-acting somatostatin analog octreotide on hormone levels and tumor mass in acromegaly. Journal of Clinical Endocrinology and Metabolism, 86, 2779–2786.
- 3 Bevan, J.S., Atkin, S.L., Atkinson, A.B., Bouloux, P.M., Hanna, F., Harris, P.E. et al . (2002) Primary medical therapy for acromegaly: an open, prospective, multicenter study of the effects of subcutaneous and intramuscular slow-release octreotide on growth hormone, insulin-like growth factor-I, and tumor size. Journal of Clinical Endocrinology and Metabolism, 87, 4554–4563.
- 4 Sheppard, M.C. (2003) Primary medical therapy for acromegaly. Clinical Endocrinology, 58, 387–399.
- 5 Freda, P.U., Katznelson, L., Van Der Lely, A.J., Reyes, C.M., Zhao, S. & Rabinowitz, D. (2005) Long-acting somatostatin analog therapy of acromegaly: a meta-analysis. Journal of Clinical Endocrinology and Metabolism, 90, 4465–4473.
- 6 Cozzi, R., Montini, M., Attanasio, R., Albizzi, M., Lasio, G., Lodrini, S., Doneda, P., Cortesi, L. & Pagani, G. (2006) Primary treatment of acromegaly with octreotide LAR: a long-term (up to nine years) prospective study of its efficacy in the control of disease activity and tumor shrinkage. Journal of Clinical Endocrinology and Metabolism, 91, 1397–1403.
- 7 Giusti, M., Gussoni, G., Cuttica, C.M., Giordano, G. & the Italian Multicenter Slow Release Lanreotide Study Group. (1999) Effectiveness and tolerability of slow release lanreotide treatment in active acromegaly: six-month report of an Italian multicenter study. Journal of Clinical Endocrinology and Metabolism, 81, 2089–2097.
- 8 Baldelli, R., Colao, A., Razzore, P., Jaffrain-Rea, M.L., Marzullo, P., Ciccarelli, E., Ferretti, E., Ferone, D., Gaia, D., Camanni, F., Lombardi, G. & Tamburrano, G. (2000) Two-year follow-up of acromegalic patients treated with slow release lanreotide (30 mg). Journal of Clinical Endocrinology and Metabolism, 85, 4099–4103.
- 9 Verhelst, J.A., Pedroncelli, A.M., Abstract, R., Montini, M., Vandeweghe, M.V., Albani, G., Maiter, D., Pagani, M.D., Legros, J.J., Gianola, D., Bex, M., Poppe, K., Mockel, J. & Pagani, G. (2000) Slow-release lanreotide in the treatment of acromegaly: a study in 66 patients. European Journal of Endocrinology, 143, 577–584.
- 10 Chanson, P., Leselbaum, A., Blumberg, J. & Schaison, G. (2000) Efficacy and tolerability of the long-acting somatostatin analog lanreotide in acromegaly: a 12-month multicenter study of 58 acromegalic patients. French Multicenter Study Group on lanreotide in acromegaly. Pituitary, 2, 269–276.
- 11 Ambrosio, M.R., Franceschetti, P., Bondanelli, M., Doga, M., Maffei, P., Baldelli, R., Tamburrano, G., Sicolo, N., Giustina, A. & Degli Uberti, E.C. (2002) Efficacy and safety of the new 60-mg formulation of the long-acting somatostatin analog lanreotide in the treatment of acromegaly. Metabolism, 51, 387–393.
- 12 Attanasio, R., Baldelli, R., Pivonello, R., Grottoli, S., Bocca, L., Gasco, V., Giusti, M., Tamburrano, G., Colao, A. & Cozzi, R. (2003) Lanreotide 60 mg, a new long-acting formulation: effectiveness in the chronic treatment of acromegaly. Journal of Clinical Endocrinology and Metabolism, 88, 5258–5265.
- 13 Colao, A., Ferone, D., Marzullo, P. & Lombardi, G. (2004) Systemic complications of acromegaly: epidemiology, pathogenesis, and management. Endocrine Reviews, 25, 102–152.
- 14 Antonijoan, R.M., Barbanoj, M.J., Cordero, J.A., Peraire, C., Obach, R., Valles, J., Cherif-Cheikh, R., Torres, M.L., Bismuth, F. & Montes, M. (2004) Pharmacokinetics of a new Autogel formulation of the somatostatin analogue lanreotide after a single subcutaneous dose in healthy volunteers. Journal of Pharmacy and Pharmacology, 56, 471–476.
- 15 Bronstein, M., Musolino, N., Jallad, R., Cendros, J.M., Ramis, J., Obach, R., Leselbaum, A. & Catus, F. (2005) Pharmacokinetic profile of lanreotide Autogel in patients with acromegaly after four deep subcutaneous injections of 60, 90 or 120 mg every 28 days. Clinical Endocrinology, 63, 514–519.
- 16 Ciccarelli, A., Daly, A. & Beckers, A. (2004) Lanreotide Autogel for acromegaly: a new addition to the treatment armamentarium. Treatments in Endocrinology, 3, 77–81.
- 17 Caron, P., Beckers, A., Cullen, D.R., Goth, M.I., Gutt, B., Laurberg, P., Pico, A.M., Valimaki, M. & Zgliczynski, W. (2002) Efficacy of the new long-acting formulation of lanreotide (lanreotide Autogel) in the management of acromegaly. Journal of Clinical Endocrinology and Metabolism, 87, 99–104.
- 18 Van Thiel, S.W., Romijn, J.A., Biermasz, N.R., Ballieux, B.E., Frolich, M., Smit, J.W., Corssmit, E.P., Roelfsema, F. & Pereira, A.M. (2004) Octreotide long-acting repeatable and lanreotide Autogel are equally effective in controlling growth hormone secretion in acromegalic patients. European Journal of Endocrinology, 150, 489–495.
- 19 Ashwell, S.G., Bevan, J.S., Edwards, O.M., Harris, M.M., Holmes, C., Middleton, M.A. & James, R.A. (2004) The efficacy and safety of lanreotide Autogel in patients with acromegaly previously treated with octreotide LAR. European Journal of Endocrinology, 150, 473–480.
- 20 Alexopoulou, O., Abrams, P., Verhelst, J., Poppe, K., Velkeniers, B., Abstract, R. & Maiter, D. (2004) Efficacy and tolerability of lanreotide Autogel therapy in acromegalic patients previously treated with octreotide LAR. European Journal of Endocrinology, 151, 317–324.
- 21 Gutt, B., Bidlingmaier, M., Kretschmar, K., Dieterle, C., Steffin, B. & Schopohl, J. (2005) Four-year follow-up of acromegalic patients treated with the new long-acting formulation of Lanreotide (Lanreotide Autogel). Experimental and Clinical Endocrinology and Diabetes, 113, 139–144.
- 22 Caron, P., Cogne, M., Raingeard, I., Bex-Bachellerie, V. & Kuhn, J.M. (2006) Effectiveness and tolerability of 3-year lanreotide Autogel treatment in patients with acromegaly. Clinical Endocrinology, 64, 209–214.
- 23 Matthews, D.R., Hosker, J.P., Rudenski, A.S., Naylor, B.A., Treacher, D.F. & Turner, R.C. (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia, 28, 412–419.
- 24 Matsuda, M. & DeFronzo, R.A. (1999) Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care, 22, 1462–1470.
- 25 Daughaday, W.H., Kapadia, M. & Mariz, I.K. (1986) Serum somatomedin binding proteins: physiologic significance and interference in radioligand assay. Journal of Laboratory and Clinical Medicine, 109, 335–363.
- 26 Barreca, A., Ponzani, P., Arvigo, M., Giordano, G. & Minuto, F. (1995) Effect of the acid-labile subunit on the binding of insulin-like growth factor (IGF)-binding protein-3 to [125I]IGF-I. Journal of Clinical Endocrinology and Metabolism, 80, 1318–1324.
- 27 Reubi, J.C. & Landolt, A.M. (1989) The growth hormone responses to octreotide in acromegaly correlate with adenoma sandostatin receptor status. Journal of Clinical Endocrinology and Metabolism, 68, 844–850.
- 28 Filopanti, M., Ronchi, C., Ballaré, E., Bondioni, S., Lania, A.G., Losa, M., Gelmini, S., Peri, A., Orlando, C., Beck-Peccoz, P. & Spada, A. (2005) Analysis of somatostatin receptors 2 and 5 polymorphisms in patients with acromegaly. Journal of Clinical Endocrinology and Metabolism, 90, 4824–4828.
- 29 Arosio, M., Garrone, S., Bruzzi, P., Faglia, G. & Barreca, A. (2001) Diagnostic value of the acid-labile subunit in acromegaly: evaluation in comparison with insulin-like growth factor (IGF) I, and IGF-binding protein-1-2, and -3. Journal of Clinical Endocrinology and Metabolism, 86, 1091–1098.
- 30 Epaminonda, P., Porretti, S., Cappiello, V., Beck-Peccoz, P., Faglia, G. & Arosio, M. (2001) Efficacy of radiotherapy in normalizing serum IGF-I, acid-labile subunit (ALS) and IGFBP-3 levels in acromegaly. Clinical Endocrinology, 55, 183–191.
- 31 Feelders, R.A., Bidlingmaier, M., Strasburger, C.J., Janssen, J.A., Uitterlinden, P., Hofland, L.J., Lamberts, S.W., Van Der Lely, A.J. & De Herder, W.W. (2005) Postoperative evaluation of patients with acromegaly: clinical significance and timing of oral glucose tolerance testing and measurement of (free) insulin-like growth factor I, acid-labile subunit, and growth hormone-binding protein levels. Journal of Clinical Endocrinology and Metabolism, 90, 6480–6489.
- 32 Barreca, A.M., Voci, A., Lee, P.D., Arvigo, M., Ghigliotti, V., Fugassa, E., Giordano, G. & Minuto, F. (1997) Effect of the somatostatin analog, octreotide, and of other hormones on the release of the acid-labile subunit of the 150 kDa complex by rat hepatocyte in primary culture. European Journal of Endocrinology, 137, 193–199.
- 33 Jenkins, P.J., Akker, S., Chew, S.L., Besser, G.M., Monson, J.P. & Grossman, A.B. (2000) Optimal dosage interval for depot somatostatin analogue therapy in acromegaly requires individual titration. Clinical Endocrinology, 53, 719–724.
- 34 Turner, H.E., Thornton-Jones, V.A. & Wass, J.A. (2004) Systematic dose-extension of octreotide LAR: the importance of individual tailoring of treatment in patients with acromegaly. Clinical Endocrinology, 61, 224–231.
- 35 Arosio, M., Macchelli, S., Rossi, C.M., Casati, G., Biella, O., Faglia, G. & the Italian Multicenter Study Group. (1995) Effects of treatment with octreotide in acromegalic patients – a multicenter Italian study. European Journal of Endocrinology, 133, 430–439.
- 36 Clemmons, D.R., Chihara, K., Freda, P.U., Ho, K.K., Klibanski, A., Melmed, S., Shalet, S.M., Strasburger, C.J., Trainer, P.J. & Thorner, M.O. (2003) Optimizing control of acromegaly: integrating a growth hormone receptor antagonist into the treatment algorithm. Journal of Clinical Endocrinology and Metabolism, 88, 4759–4767.
- 37 Baldelli, R., Battista, C., Leonetti, F., Ghiggi, M.R., Ribaudo, M.C., Paoloni, A., D’Amico, E., Ferretti, E., Baratta, R., Liuzzi, A., Trischitta, V. & Tamburrano, G. (2003) Glucose homeostasis in acromegaly: effects of long-acting somatostatin analogues treatment. Clinical Endocrinology, 59, 492–499.
- 38 Ronchi, C.L., Orsi, E., Giavoli, C., Cappiello, V., Epaminonda, P., Beck-Peccoz, P. & Arosio, M. (2003) Evaluation of insulin resistance in acromegalic patients before and after treatment with somatostatin analogues. Journal of Endocrinological Investigation, 26, 533–538.
- 39 Ronchi, C.L., Varca, V., Beck-Peccoz, P., Orsi, E., Donadio, F., Baccarelli, A., Giavoli, C., Ferrante, E., Lania, A., Spada, A. & Arosio, M. (2006) Comparison between six-year therapy with long-acting somatostatin analogs and successful surgery in acromegaly: effects on cardiovascular risk factors. Journal of Clinical Endocrinology and Metabolism, 91, 121–128.