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Peter J Trainer - One of the best experts on this subject based on the ideXlab platform.
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effective combination treatment with cabergoline and low dose Pegvisomant in active acromegaly a prospective clinical trial
The Journal of Clinical Endocrinology and Metabolism, 2012Co-Authors: Claire E Higham, Martin Bidlingmaier, A B Atkinson, Simon Aylwin, W M Drake, Andrew P Lewis, Niamh Martin, V Moyes, John Newellprice, Peter J TrainerAbstract:Context: With adequate dose titration, Pegvisomant normalizes IGF-I in up to 97% of patients with acromegaly. Pegvisomant is indicated for treatment-resistant disease but is expensive, particularly at a high dose. It has been used successfully in combination with somatostatin analogs. However, there are no therapeutic reports of Pegvisomant in combination with dopamine agonists. Cabergoline is orally active, well-tolerated, and relatively inexpensive, and as monotherapy for acromegaly it is reported to normalize IGF-I in up to 30% of patients. Objective: The aim of the study was to investigate the efficacy of cabergoline monotherapy and Pegvisomant in combination with cabergoline to control serum IGF-I in patients with active acromegaly. Twenty-four patients were recruited into a United Kingdom, multicenter, open-label, prospective clinical trial. Main Outcome Measure: We measured the change in serum IGF-I. Results: After 18 wk of dose titration to a maximum dose of 0.5 mg once daily, cabergoline monother...
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long term experience of Pegvisomant therapy as a treatment for acromegaly
Clinical Endocrinology, 2009Co-Authors: Claire E Higham, Tengteng Chung, Jeremy A L Lawrance, William M Drake, Peter J TrainerAbstract:Summary Aims To evaluate the long-term efficacy and safety of Pegvisomant as a treatment for acromegaly. Design Retrospective analysis of clinical and trial data from all patients treated with Pegvisomant since 1997 at two centres with common protocols. Results Fifty-seven patients (age range 27–78 years) have been treated with Pegvisomant since 1997 for up to 91 months (median 18 months). Before commencing Pegvisomant, patients had an IGF-I above the upper limit of normal (ULN) of the age-related reference range (median 1·8 × ULN, range 1·2–4·1). Ninety-five per cent normalized IGF-I using a median dose of 15 mg daily (range 10 mg alternate day to 60 mg daily) with no influence of gender on dose requirement. Five patients had combination therapy with either somatostatin analogues (SSA) or cabergoline. Two patients initially controlled on 10 mg and 20 mg required dose increases (to 20 mg + 40 mg) over 24 months to reduce IGF-I. Twenty-seven patients stopped Pegvisomant. Reasons included side-effects [abnormal liver function tests (LFTs)] and patient choice. Two patients developed elevated liver transaminases, which normalized on stopping Pegvisomant. Patients had 6–12-monthly pituitary magnetic resonance imaging (MRI) scans. One patient had significant tumour size increase. Conclusion This long-term experience in 57 patients indicates Pegvisomant to be effective, safe and well-tolerated. Raised transaminases occurred within the first month of therapy in two patients, and tumour growth was seen in one patient (tumour was growing prior to Pegvisomant). In two patients increasing doses of Pegvisomant were required to keep IGF-I within the target range.
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Pegvisomant improves insulin sensitivity and reduces overnight free fatty acid concentrations in patients with acromegaly
The Journal of Clinical Endocrinology and Metabolism, 2009Co-Authors: Claire E Higham, Susannah Rowles, D L Russelljones, A M Umpleby, Peter J TrainerAbstract:Introduction: Acromegaly is complicated by an increased incidence of diabetes mellitus caused by impaired insulin sensitivity and reduced β-cell function. Pegvisomant blocks activity at GH receptors, normalizing IGF-I in over 90% of patients and improving insulin sensitivity. The mechanisms for this increase in insulin sensitivity are not fully determined. We used stable isotope techniques to investigate the effects of Pegvisomant on glucose and lipid metabolism in acromegaly. Methods: Five patients (age, 43 yr ± sd) with active acromegaly were studied on two occasions: before Pegvisomant and after 4 wk of Pegvisomant (20 mg daily sc). 2H5-glycerol was infused overnight to measure overnight and early morning (basal) glycerol production rate (Ra). The next morning 2H2-glucose was infused for 2 h before and throughout a hyperinsulinemic euglycemic (1.5 mU/kg · min insulin) clamp to measure basal glucose Ra and insulin-stimulated peripheral glucose disposal (Rd). Results: Mean IGF-I was significantly reduced...
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follow up of pituitary tumor volume in patients with acromegaly treated with Pegvisomant in clinical trials
European Journal of Endocrinology, 2008Co-Authors: Camilo Jimenez, Peter J Trainer, Kent R Hutson, Pia Burman, Michael Messig, William M Drake, Roger Abs, David R Clemmons, Michael O Thorner, Robert F GagelAbstract:Objective: We examined pituitary tumor volumes in patients treated with Pegvisomant for 18 months or longer and in whom the tumors were monitored for at least 3 years. We present details on 9 of 304 patients in clinical trials with Pegvisomant who experienced tumor growth within the first year of treatment. Method: Magnetic reonance images prior to start of Pegvisomant and at last follow-up were examined in 43 patients (14% of participating patients). Twenty-nine had received prior radiation therapy (18% of irradiated patients and all but live received somatostatin analogs between periods of Pegvisomant treatment. Results: At follow-up, the received tumor volume was 0.6 cc (range 0.0-19.7 ccl. in comparison with 1.6 cc (0.0-19.7 cc) at baseline (P<0.001). Twenty-five patients, of which 23 received radiation therapy, had tumor volume reduction therapy, had an increase in tumor volume from 1.61 to 1.93 cc. Of the nine patients with tumor growth, six had progressive growth before initiating Pegvisomant. Two patients with stable tumors while on octreotide experienced enlargement after octreotide discontinuation but remained stable on long-term Pegvisomant therapy. Conclusion: The present data indicate that Pegvisomant does not promote tumor growth and suggest that the nine observed cases of tumor progression. which occured within 8 months after commencing Pegvisomant, are likely rebound expansions after discontinuation of somatostatin analogs and/or the natural history of aggressively growing pituitary tumors. Continued long-term surveillance of tumor volume, particularly in non-irradiated patients is recommended. (Less)
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Pegvisomant interference in gh assays results in underestimation of gh levels
European Journal of Endocrinology, 2007Co-Authors: Angela N Paisley, Kathleen M Hayden, Alicia M Ellis, John Anderson, Gilbert E Wieringa, Peter J TrainerAbstract:INTRODUCTION Pegvisomant use in acromegaly negates the use of GH levels to monitor disease activity. To achieve antagonism, plasma concentrations must be approximately 1000-fold greater than GH which with the high homology between the peptides makes GH measurement a challenge when Pegvisomant is present. OBJECTIVE We investigated the effect of Pegvisomant on GH measured using commercially available assays. METHODS Pooled serum samples with GH concentrations <0.38, 3.85 and 7.69 microg/l were spiked with increasing Pegvisomant concentrations (9000-494 000 microg/l). Samples were analysed by the Nichols Advantage, DPC Immulite 2000, Diasorin IRMA, Beckman Access Dxl, Tosoh AIA and Wallac Delfia assays. RESULTS With baseline GH <0.38 microg/l measured levels were <0.38 in all assays except Nichols, Diasorin and Beckman where GH peaked at 1.5, 9.6 and 17.7 micarog/l respectively at low Pegvisomant concentrations, falling thereafter. With the other two samples, measured GH levels progressively fell with increasing Pegvisomant concentrations, except the Beckman assay where an increase (30.8 microg/l) was seen at a Pegvisomant concentration of 9000 microg/l; and Diasorin and Tosoh where smaller increases were seen at lower Pegvisomant concentrations, levels gradually falling thereafter. CONCLUSION The presence of Pegvisomant resulted in artefactually low measured GH in most assays. We speculate this fall is due to assay antibody-binding Pegvisomant, reducing the amount of available antibody to bind actual GH thereby producing less sandwich formation: the 'high-dose hook' effect. In most assays, this effect is modest and results in lower GH, but the level of interference makes them unsuitable for studies on the influence of Pegvisomant on GH neuroregulation.
Christian J Strasburger - One of the best experts on this subject based on the ideXlab platform.
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diabetes in patients with acromegaly treated with Pegvisomant observations from acrostudy
Endocrine, 2019Co-Authors: Thierry Brue, Michael Droste, Aart Jan Van Der Lely, Christian J Strasburger, Roy Gomez, Judith Heyhadavi, Maria Koltowskahaggstrom, Anders Lindberg, Ann Charlotte Akerblad, Cecilia CamachohubnerAbstract:PurposeTo explore the effects of Pegvisomant (PEGV) on glucose metabolism in patients with acromegaly within ACROSTUDY, an international, observational, prospective safety surveillance study.Method ...
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increasing frequency of combination medical therapy in the treatment of acromegaly with the gh receptor antagonist Pegvisomant
European Journal of Endocrinology, 2018Co-Authors: Christian J Strasburger, Judith Heyhadavi, Anders F Mattsson, Patrick Wilton, Ferah Aydin, Beverly M K BillerAbstract:Pegvisomant monotherapy is effective and safe in treatment of acromegaly. However, some clinicians combine Pegvisomant with somatostatin analogues (SSA) or dopamine agonist (DA). In this analysis of ACROSTUDY, a long-term non-interventional study, the use of combination regimens was evaluated. Based on their baseline treatment, 2043 patients were retrospectively categorized as: long-acting SSA combined with Pegvisomant, 'Combo SSA' 768 patients (38%); DA combined with Pegvisomant, 'Combo DA' 123 (6%); Pegvisomant monotherapy, 'Peg mono' 1128 (55%). Treatment patterns changed over the 10-year period, with recent patients more likely to receive any combination (20% in 2003 vs 54% in 2012). Combo SSA use varied widely among countries from 22% to 78%. Exposure periods of the three treatment modalities were defined from Pegvisomant start until the last visit in ACROSTUDY; patients could switch treatment categories. At year 4, IGF-I was normal in 62% of Combo SSA, 63% of Combo DA and 65% of Peg mono groups. Pegvisomant was initiated as daily injections in 94% of patients in the Peg mono group, 66% of Combo SSA and 91% of Combo DA patients. During 6169 years of treatment exposure, 3424 adverse events (AEs) were reported in 946 (51%) patients, of which 617 (18%) were serious and 401 (12%) were considered treatment related. The reported incidence of serious AEs and treatment-related non-serious AEs were similar among the three treatment modalities. This analysis describes real-world clinical care and shows favorable efficacy and safety for Peg mono and combinations. Novel findings include an increased use of combination therapy over time and variability in treatment modalities between countries.
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therapy of acromegalic patients exacerbated by concomitant type 2 diabetes requires higher Pegvisomant doses to normalise igf1 levels
European Journal of Endocrinology, 2014Co-Authors: Michael Droste, Michael Buchfelder, Klaus Mann, Julia Domberg, Anja Schwanke, Gunter K Stalla, Christian J StrasburgerAbstract:Objective: Acromegaly is associated with an increased prevalence of glucose metabolism disorders. Clinically confirmed diabetes mellitus is observed in approximately one quarter of all patients with acromegaly and is known to have a worse prognosis in these patients. Design: Of 514 acromegalic patients treated with Pegvisomant and recorded in the German Cohort of ACROSTUDY, 147 had concomitant diabetes mellitus. We analysed these patients in an observational study and compared patients with and without concomitant diabetes. Results: Under treatment with Pegvisomant, patients with diabetes mellitus rarely achieved normalisation (64% in the diabetic cohort vs 75% in the non-diabetic cohort, PZ0.04) for IGF1. Diabetic patients normalised for IGF1 required higher Pegvisomant doses (18.9 vs 15.5 mg Pegvisomant/day, P!0.01). Furthermore, those diabetic patients requiring insulin therapy showed a tendency towards requiring even higher Pegvisomant doses to normalise IGF1 values than diabetic patients receiving only oral treatment (22.8 vs 17.2 mg Pegvisomant/day, PZ0.11). Conclusions: Hence, notable interdependences between the acromegaly, the glucose metabolism of predisposed patients and their treatment with Pegvisomant were observed. Our data support recent findings suggesting that intra-portal insulin levels determine the GH receptor expression in the liver underlined by the fact that patients with concomitant diabetes mellitus, in particular those receiving insulin therapy, require higher Pegvisomant doses to normalise IGF1. It is therefore important to analyse various therapy modalities to find out whether they influence the associated diabetes mellitus and/or whether the presence of diabetes mellitus influences the treatment results of an acromegaly therapy.
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automated 22 kd growth hormone specific assay without interference from Pegvisomant
Clinical Chemistry, 2012Co-Authors: Jenny Manolopoulou, Christian J Strasburger, Jochen Schopohl, Stephan Petersenn, Younes Alami, Martin BidlingmaierAbstract:BACKGROUND: Large variability exists among different growth hormone (GH) assays owing to differences in calibration, antibody specificity, isoform recognition, and interference from GH binding protein (GHBP). The GH receptor antagonist Pegvisomant presents a new challenge because Pegvisomant interferes with many GH assays. A recent consensus conference established criteria for standardization and evaluation of GH assays. Following consensus recommendations, we developed a new GH assay on an automated analyzer (IDS-iSYS, Immunodiagnostic Systems). METHODS: A monoclonal antibody not cross-reacting with Pegvisomant was combined with a monoclonal antibody specific for 22-kD GH. Isoform specificity and interference from GHBP was tested and compared to that seen in 2 existing automated GH assays (Siemens Immulite, Diasorin Liaison). We also compared GH concentrations measured by the 3 assays for healthy volunteers and patients with acromegaly receiving different treatments. Using the iSYS assay, we also established nadir GH values during oral glucose load and analyzed changes in endogenous GH during Pegvisomant treatment. RESULTS: Analytical and functional sensitivities were 0.01 μg/L and 0.04 μg/L, with a dynamic range from 0.04 to 100 μg/L. Intraassay CVs were 2%–4%, whereas interassay CVs were 5%–7% at GH concentrations between 1.7 and 27.5 μg/L. The assay was specific for 22-kD GH and not affected by GHBP. The presence of Pegvisomant, which leads to a negative bias on the Immulite and dramatic overestimation of GH on the Liaison, had no impact on the iSYS GH assay. CONCLUSIONS: The new assay fulfils recent consensus recommendations and presents a useful new tool for reliable measurement of GH.
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long term safety of Pegvisomant in patients with acromegaly comprehensive review of 1288 subjects in acrostudy
The Journal of Clinical Endocrinology and Metabolism, 2012Co-Authors: A J Van Der Lely, Michael Buchfelder, Ezio Ghigo, Beverly M K Biller, Natasa Rajicic, Thierry Brue, Roy Gomez, Judith Heyhadavi, Frida Lundgren, Christian J StrasburgerAbstract:Context: Pegvisomant is a GH receptor antagonist. The ACROSTUDY is a global safety surveillance study of long-term treatment of acromegaly with Pegvisomant. Objective: The objective of the study was to monitor long-term safety and treatment outcomes. Design: ACROSTUDY is open to all patients with acromegaly who are treated with Pegvisomant. We report an interim analysis of data captured from 1288 subjects enrolled before a database freeze of December 31, 2009. Setting: This was a global noninterventional surveillance study. Main Outcome Measure(s): Long-term monitoring of safety, including central magnetic resonance imaging (MRI) reading and treatment outcomes, was measured. Results: Subjects (n = 1288) were treated with Pegvisomant for a mean of 3.7 yr and followed up in ACROSTUDY for a mean of 2.1 yr. A total of 1147 adverse events (AE) were recorded in 477 subjects (37%), among which 192 AE in 124 subjects (9.6%) were considered to be related to Pegvisomant. Serious AE were recorded in 159 subjects (12...
Aart Jan Van Der Lely - One of the best experts on this subject based on the ideXlab platform.
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diabetes in patients with acromegaly treated with Pegvisomant observations from acrostudy
Endocrine, 2019Co-Authors: Thierry Brue, Michael Droste, Aart Jan Van Der Lely, Christian J Strasburger, Roy Gomez, Judith Heyhadavi, Maria Koltowskahaggstrom, Anders Lindberg, Ann Charlotte Akerblad, Cecilia CamachohubnerAbstract:PurposeTo explore the effects of Pegvisomant (PEGV) on glucose metabolism in patients with acromegaly within ACROSTUDY, an international, observational, prospective safety surveillance study.Method ...
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efficacy and safety of switching to pasireotide in acromegaly patients controlled with Pegvisomant and somatostatin analogues pape extension study
European Journal of Endocrinology, 2018Co-Authors: Ammar Muhammad, Aart Jan Van Der Lely, Patric J D Delhanty, Alof H G Dallenga, Iain Haitsma, J A M J L Janssen, Eva C Coopmans, Sebastian J C M M NeggersAbstract:OBJECTIVE: to assess the efficacy and safety after 48 weeks of treatment with pasireotide long-acting-release (PAS-LAR) alone or in combination with Pegvisomant in patients with acromegaly. In addition, we assessed the relation between insulin secretion and pasireotide-induced hyperglycemia.DESIGN: The PAPE extension study is a prospective follow-up study until 48 weeks after the core study of 24 weeks.METHODS: 59 out of 61 patients entered the extension study. Efficacy was defined as the percentage of patients achieving IGF-I normalization (≤ 1.2 x the Upper Limit of Normal (ULN)) at 48-weeks through protocol-based adjustment of Pegvisomant and PAS-LAR doses. At baseline, insulin secretion was assessed by an oral glucose tolerance test (OGTT).RESULTS: At the end of the study median IGF-I was 0.98 x ULN, and 77% of patients achieved normal IGF-I levels with a mean Pegvisomant dose of 64 mg/week, and an overall cumulative Pegvisomant dose reduction of 52%. Frequency of diabetes mellitus increased from 68% at 24 weeks to 77% at 48 weeks, and 9 patients discontinued PAS-LAR treatment, mainly because of severe hyperglycemia. Pasireotide-induced hyperglycemia was inversely correlated with baseline insulin secretion (r = -0.37, P < 0.005).CONCLUSIONS: PAS-LAR normalizes IGF-I levels in most acromegaly patients, with a fifty percent Pegvisomant-sparing effect. However, PAS-LAR treatment coincided with a high incidence of diabetes mellitus. The risk for developing diabetes during PAS-LAR treatment seems inversely related to insulin secretion at baseline.
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efficacy and safety of switching to pasireotide in patients with acromegaly controlled with Pegvisomant and first generation somatostatin analogues pape study
The Journal of Clinical Endocrinology and Metabolism, 2017Co-Authors: Ammar Muhammad, Aart Jan Van Der Lely, Patric J D Delhanty, Alof H G Dallenga, Iain Haitsma, J A M J L Janssen, Sebastian J C M M NeggersAbstract:markdownabstractAim: To assess the efficacy and safety of pasireotide long-Acting release (PAS-LAR) alone or in combination with Pegvisomant by switching patients with acromegaly who were well controlled with long-Acting somatostatin analogues (LA-SSAs) and Pegvisomant to PAS-LAR with or without Pegvisomant. Methods: Sixty-one patients with acromegaly were enrolled in a prospective open-label study. We included patients with an insulin-like growth factor I (IGF-I) #1.2 3 upper limit of normal (ULN) during treatment with LA-SSAs and Pegvisomant. At baseline, the Pegvisomant dose was reduced by 50% up to 12 weeks. When IGF-I remained#1.23ULN after 12 weeks, patients were switched to PAS-LAR 60 mg monotherapy. When IGF-I was .1.2 3 ULN, patients were switched to PAS-LAR 60 mg, and they continued with the 50% reduced Pegvisomant dose. Results: At baseline, mean IGF-I was 0.97 3 ULN, and the median Pegvisomant dose was 80 mg/wk. At 12 weeks, mean IGF-I increased to 1.59 3 ULN, and IGF-I levels #1.2 ULN were observed in 24.6% of participants. At 24 weeks, IGF-I levels were reduced into the reference range in 73.8% of patients. Between baseline and 24 weeks, the Pegvisomant dose was reduced by 66.1%. PAS-LAR was well tolerated, but hyperglycemia was the most frequent adverse event. The frequency of diabetes increased from 32.8% at baseline to 68.9% at 24 weeks. Conclusions: Switching to PAS-LAR, either as monotherapy or combination with Pegvisomant, can control IGF-I levels in most patients. PAS-LAR demonstrated a Pegvisomant-sparing effect of 66% compared with the combination with LA-SSAs. Hyperglycemia was the most important safety issue.
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Pegvisomant treatment in acromegaly
Neuroendocrinology, 2016Co-Authors: Sebastian J C M M Neggers, Ammar Muhammad, Aart Jan Van Der LelyAbstract:Historically, medical treatment of acromegaly has mainly been used as an adjuvant therapy after surgery. In the last decades, an increased range of medical therapy options has been available. Somatostatin analogues have become the cornerstones of medical treatment in acromegaly and are even seen as a primary treatment in a selected group of acromegaly patients. The most recent medical treatment available for acromegaly patients is Pegvisomant, a growth hormone receptor antagonist. To date, it is the most effective medical treatment, but it is costly. Pegvisomant is used as monotherapy and combined with somatostatin analogues. In this article, we review clinical studies and cohorts that have documented the efficacy of Pegvisomant monotherapy and combined therapy and give a concise overview of associated side effects.
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somatostatin analog and Pegvisomant combination therapy for acromegaly
Nature Reviews Endocrinology, 2009Co-Authors: Sebastian J C M M Neggers, Aart Jan Van Der LelyAbstract:Optimal biochemical control cannot be attained by long-acting somatostatin analog monotherapy in a large proportion of patients with acromegaly. Such therapy might result in increased mortality, poor control of signs and symptoms of disease and decreased quality of life. Combination treatment with somatostatin analogs and Pegvisomant (a growth-hormone-receptor antagonist) is, however, highly effective at normalizing the level of insulin-like growth factor I in over 90% of patients and might also have a favorable effect on quality of life in those with biochemically controlled acromegaly. Moreover, whereas Pegvisomant monotherapy does not lead to a decrease in the size of the pituitary tumor, combination therapy with somatostatin analogs results in a clinically relevant decrease in tumor size in about 20% of patients. The main adverse effects of combination treatment are transient elevations in the levels of transaminases, which occur in about 15% of patients, especially in those with diabetes mellitus. In this Review, we discuss the available data on the long-term efficacy and safety of somatostatin analog-Pegvisomant combination treatment and its potential use in patients with acromegaly.
Martin Bidlingmaier - One of the best experts on this subject based on the ideXlab platform.
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automated 22 kd growth hormone specific assay without interference from Pegvisomant
Clinical Chemistry, 2012Co-Authors: Jenny Manolopoulou, Christian J Strasburger, Jochen Schopohl, Stephan Petersenn, Younes Alami, Martin BidlingmaierAbstract:BACKGROUND: Large variability exists among different growth hormone (GH) assays owing to differences in calibration, antibody specificity, isoform recognition, and interference from GH binding protein (GHBP). The GH receptor antagonist Pegvisomant presents a new challenge because Pegvisomant interferes with many GH assays. A recent consensus conference established criteria for standardization and evaluation of GH assays. Following consensus recommendations, we developed a new GH assay on an automated analyzer (IDS-iSYS, Immunodiagnostic Systems). METHODS: A monoclonal antibody not cross-reacting with Pegvisomant was combined with a monoclonal antibody specific for 22-kD GH. Isoform specificity and interference from GHBP was tested and compared to that seen in 2 existing automated GH assays (Siemens Immulite, Diasorin Liaison). We also compared GH concentrations measured by the 3 assays for healthy volunteers and patients with acromegaly receiving different treatments. Using the iSYS assay, we also established nadir GH values during oral glucose load and analyzed changes in endogenous GH during Pegvisomant treatment. RESULTS: Analytical and functional sensitivities were 0.01 μg/L and 0.04 μg/L, with a dynamic range from 0.04 to 100 μg/L. Intraassay CVs were 2%–4%, whereas interassay CVs were 5%–7% at GH concentrations between 1.7 and 27.5 μg/L. The assay was specific for 22-kD GH and not affected by GHBP. The presence of Pegvisomant, which leads to a negative bias on the Immulite and dramatic overestimation of GH on the Liaison, had no impact on the iSYS GH assay. CONCLUSIONS: The new assay fulfils recent consensus recommendations and presents a useful new tool for reliable measurement of GH.
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failure of temozolomide and conventional doses of Pegvisomant to attain biochemical control in a severe case of acromegaly
Pituitary, 2012Co-Authors: Emilie Morin, Martin Bidlingmaier, John Weisnagel, Omar SerriAbstract:It has been suggested that treatment with adequate dose titration of Pegvisomant, a GH antagonist, up to a maximum of 40 mg daily, can achieve IGF-1 normalisation in virtually all patients with acromegaly. On the other hand, temozolomide (TMZ), an alkylating cytostatic agent, has been reported to reduce pituitary tumour size and hormone hypersecretion in a small number of aggressive pituitary macroadenomas. In this paper we report the case of a patient resistant to very high doses of Pegvisomant used in combination with somatostatin analogs (SSA) and to TMZ therapy. The patient, initially a 22 year-old man with an invasive GH-secreting pituitary macroadenoma (IGF-1, 371% upper limit of normal), had active acromegaly despite a repeat transsphenoidal surgery followed by radiotherapy and SSA (octreotide 800 μg sc daily) (IGF-1, 262% ULN). In combination with SSA, Pegvisomant was started at 20 mg daily and doses were titrated up to 60 mg daily. IGF-1 was moderately reduced and stabilized at 200% ULN after 1 year of treatment. Serum Pegvisomant level was 30,500 ng/l, the denaturalized GHBP concentration 1,120 pM and the endogenous GH level was 220 μg/l. Pegvisomant was stopped and TMZ therapy was given for 5 cycles. However, the patient reported an increase of acromegaly symptoms and the serum IGF-1 was raised to the same level prior to Pegvisomant therapy. Consequently, Pegvisomant was tried again with doses up to 100 mg daily finally resulting in normalisation of serum IGF-1 level and improvement of acromegaly symptoms and patient well-being. We conclude that in some patients with severe acromegaly refractory to multimodal therapy, biochemical control may be difficult to attain with conventional doses of Pegvisomant or TMZ therapy.
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effective combination treatment with cabergoline and low dose Pegvisomant in active acromegaly a prospective clinical trial
The Journal of Clinical Endocrinology and Metabolism, 2012Co-Authors: Claire E Higham, Martin Bidlingmaier, A B Atkinson, Simon Aylwin, W M Drake, Andrew P Lewis, Niamh Martin, V Moyes, John Newellprice, Peter J TrainerAbstract:Context: With adequate dose titration, Pegvisomant normalizes IGF-I in up to 97% of patients with acromegaly. Pegvisomant is indicated for treatment-resistant disease but is expensive, particularly at a high dose. It has been used successfully in combination with somatostatin analogs. However, there are no therapeutic reports of Pegvisomant in combination with dopamine agonists. Cabergoline is orally active, well-tolerated, and relatively inexpensive, and as monotherapy for acromegaly it is reported to normalize IGF-I in up to 30% of patients. Objective: The aim of the study was to investigate the efficacy of cabergoline monotherapy and Pegvisomant in combination with cabergoline to control serum IGF-I in patients with active acromegaly. Twenty-four patients were recruited into a United Kingdom, multicenter, open-label, prospective clinical trial. Main Outcome Measure: We measured the change in serum IGF-I. Results: After 18 wk of dose titration to a maximum dose of 0.5 mg once daily, cabergoline monother...
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the acute effect of a single application of cabergoline on endogenous gh levels in patients with acromegaly on Pegvisomant treatment
Growth Hormone & Igf Research, 2010Co-Authors: J Roemmler, Martin Bidlingmaier, B Steffin, B Gutt, C Sievers, H J Schneider, Jochen SchopohlAbstract:Abstract Objective Treatment with Pegvisomant, an antagonist of growth hormone (GH) receptors, increases GH levels in a dose dependent manner. Cabergoline can suppress GH secretion in approximately 40% of acromegalic patients. However, the acute effects of cabergoline have not been studied in patients treated with Pegvisomant. We performed this cross-sectional study to evaluate endogenous GH after an additional single cabergoline administration. Design 9 acromegalic patients on Pegvisomant therapy were included. A 6 h GH profile after Pegvisomant alone (P) and a 9 h profile in combination with oral cabergoline 0.5 mg (PC) were performed. After 3 or 6 h, all patients received a standardized light mixed meal. Endogenous serum GH and Pegvisomant levels were measured by special in-house assays. The GH assay showed no interference with Pegvisomant. Results Endogenous GH levels at baseline did not differ significantly between the profiles (P: 16.5 μg/l (range 3.2–36.6 μg/l), PC: 8.0 μg/l (1.6–48 μg/l), p > 0.05). In both profiles, GH fluctuated before meal. GH decreased more pronounced in PC but this decrease was not statistically significant. After meal, a significant decline in endogenous GH levels from 16.4 μg/l (0.4–27.1 μg/l, 100%) to 8.1 μg/l (0.2–24.7 μg/l, 66%) appeared in P at 300 min (p Conclusion Endogenous GH is not significantly decreased after a single oral cabergoline application during Pegvisomant treatment in acromegaly.
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a pegylated growth hormone receptor antagonist Pegvisomant does not enter the brain in humans
The Journal of Clinical Endocrinology and Metabolism, 2010Co-Authors: Johannes D Veldhuis, Martin Bidlingmaier, Joy N Bailey, Dana Erickson, Paola SandroniAbstract:Background: GH receptors exist in the hippocampus, cerebral cortex, and hypothalamus, possibly influencing mood, cortical blood flow, and neuronal growth and mediating negative feedback. Rationale: Pegvisomant is a recombinant mutated GH molecule with high affinity, but little or no activating capability, for the GH receptor. It is used clinically as a GH antagonist. Hypothesis: Systemic Pegvisomant enters brain interstitial fluid via putative choroid-plexus GH receptors, thereby allowing for antagonism of central actions of GH. Subjects and Location: Six adults requiring a cerebrospinal fluid (CSF) examination for nonneoplastic and noninflammatory syndromes participated at a tertiary medical center. Methods: Direct assays were conducted of serum and CSF Pegvisomant concentrations 18–24 h after sc injection of Pegvisomant (20 mg). Outcomes: Median (range) concentrations of Pegvisomant in serum were 215 (74–539) μg/liter and in CSF 0.035 (0.010–0.28) μg/liter (P = 0.016). CSF drug levels were indistinguishable from assay threshold. Corresponding GH values were 0.29 (0.010–1.3) in serum and 0.075 μg/liter (0.01–0.13) in CSF. The geometric mean ratios of serum/CSF Pegvisomant and GH concentrations were 5116:1 and 3.5:1, respectively, thus defining a more than 1400-fold difference between mutated and natural GH. Conclusions: Based upon CSF measurements, a pegylated GH-receptor antagonist does not cross the human blood-brain barrier, thereby sparing inhibition of central nervous system GH actions. Thus, the capability of this antagonist to stimulate GH secretion predominantly reflects its actions outside the blood-brain barrier, such as via the median eminence and/or via suppression of IGF-I concentrations.
Sebastian J C M M Neggers - One of the best experts on this subject based on the ideXlab platform.
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efficacy and safety of switching to pasireotide in acromegaly patients controlled with Pegvisomant and somatostatin analogues pape extension study
European Journal of Endocrinology, 2018Co-Authors: Ammar Muhammad, Aart Jan Van Der Lely, Patric J D Delhanty, Alof H G Dallenga, Iain Haitsma, J A M J L Janssen, Eva C Coopmans, Sebastian J C M M NeggersAbstract:OBJECTIVE: to assess the efficacy and safety after 48 weeks of treatment with pasireotide long-acting-release (PAS-LAR) alone or in combination with Pegvisomant in patients with acromegaly. In addition, we assessed the relation between insulin secretion and pasireotide-induced hyperglycemia.DESIGN: The PAPE extension study is a prospective follow-up study until 48 weeks after the core study of 24 weeks.METHODS: 59 out of 61 patients entered the extension study. Efficacy was defined as the percentage of patients achieving IGF-I normalization (≤ 1.2 x the Upper Limit of Normal (ULN)) at 48-weeks through protocol-based adjustment of Pegvisomant and PAS-LAR doses. At baseline, insulin secretion was assessed by an oral glucose tolerance test (OGTT).RESULTS: At the end of the study median IGF-I was 0.98 x ULN, and 77% of patients achieved normal IGF-I levels with a mean Pegvisomant dose of 64 mg/week, and an overall cumulative Pegvisomant dose reduction of 52%. Frequency of diabetes mellitus increased from 68% at 24 weeks to 77% at 48 weeks, and 9 patients discontinued PAS-LAR treatment, mainly because of severe hyperglycemia. Pasireotide-induced hyperglycemia was inversely correlated with baseline insulin secretion (r = -0.37, P < 0.005).CONCLUSIONS: PAS-LAR normalizes IGF-I levels in most acromegaly patients, with a fifty percent Pegvisomant-sparing effect. However, PAS-LAR treatment coincided with a high incidence of diabetes mellitus. The risk for developing diabetes during PAS-LAR treatment seems inversely related to insulin secretion at baseline.
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efficacy and safety of switching to pasireotide in patients with acromegaly controlled with Pegvisomant and first generation somatostatin analogues pape study
The Journal of Clinical Endocrinology and Metabolism, 2017Co-Authors: Ammar Muhammad, Aart Jan Van Der Lely, Patric J D Delhanty, Alof H G Dallenga, Iain Haitsma, J A M J L Janssen, Sebastian J C M M NeggersAbstract:markdownabstractAim: To assess the efficacy and safety of pasireotide long-Acting release (PAS-LAR) alone or in combination with Pegvisomant by switching patients with acromegaly who were well controlled with long-Acting somatostatin analogues (LA-SSAs) and Pegvisomant to PAS-LAR with or without Pegvisomant. Methods: Sixty-one patients with acromegaly were enrolled in a prospective open-label study. We included patients with an insulin-like growth factor I (IGF-I) #1.2 3 upper limit of normal (ULN) during treatment with LA-SSAs and Pegvisomant. At baseline, the Pegvisomant dose was reduced by 50% up to 12 weeks. When IGF-I remained#1.23ULN after 12 weeks, patients were switched to PAS-LAR 60 mg monotherapy. When IGF-I was .1.2 3 ULN, patients were switched to PAS-LAR 60 mg, and they continued with the 50% reduced Pegvisomant dose. Results: At baseline, mean IGF-I was 0.97 3 ULN, and the median Pegvisomant dose was 80 mg/wk. At 12 weeks, mean IGF-I increased to 1.59 3 ULN, and IGF-I levels #1.2 ULN were observed in 24.6% of participants. At 24 weeks, IGF-I levels were reduced into the reference range in 73.8% of patients. Between baseline and 24 weeks, the Pegvisomant dose was reduced by 66.1%. PAS-LAR was well tolerated, but hyperglycemia was the most frequent adverse event. The frequency of diabetes increased from 32.8% at baseline to 68.9% at 24 weeks. Conclusions: Switching to PAS-LAR, either as monotherapy or combination with Pegvisomant, can control IGF-I levels in most patients. PAS-LAR demonstrated a Pegvisomant-sparing effect of 66% compared with the combination with LA-SSAs. Hyperglycemia was the most important safety issue.
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Pegvisomant treatment in acromegaly
Neuroendocrinology, 2016Co-Authors: Sebastian J C M M Neggers, Ammar Muhammad, Aart Jan Van Der LelyAbstract:Historically, medical treatment of acromegaly has mainly been used as an adjuvant therapy after surgery. In the last decades, an increased range of medical therapy options has been available. Somatostatin analogues have become the cornerstones of medical treatment in acromegaly and are even seen as a primary treatment in a selected group of acromegaly patients. The most recent medical treatment available for acromegaly patients is Pegvisomant, a growth hormone receptor antagonist. To date, it is the most effective medical treatment, but it is costly. Pegvisomant is used as monotherapy and combined with somatostatin analogues. In this article, we review clinical studies and cohorts that have documented the efficacy of Pegvisomant monotherapy and combined therapy and give a concise overview of associated side effects.
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Coadministration of lanreotide Autogel and Pegvisomant normalizes IGF1 levels and is well tolerated in patients with acromegaly partially controlled by somatostatin analogs alone.
European Journal of Endocrinology, 2010Co-Authors: Aart-jan Van Der Lely, Ignacio Bernabeu, Annamaria Colao, Josef Marek, Sebastian J C M M Neggers, Philippe Caron, Pascal BirmanAbstract:Objective: To evaluate the efficacy and safety of coadministered lanreotide Autogel (LA; 120 mg/month) and Pegvisomant (40‐120 mg/week) in acromegaly. Design: This is a 28-week, multicenter, open-label, single-arm sequential study. Methods: Patients (nZ92) biochemically uncontrolled, on somatostatin analogs (SSAs) or using Pegvisomant monotherapy entered a 4-month run-in taking LA (120 mg/month). Patients uncontrolled after the run-in period (nZ57) entered a 28-week coadministration period, receiving LA 120 mg/month plus Pegvisomant (60 mg once weekly, adapted every 8 weeks based on IGF1 levels to 40‐80 mg once weekly or 40 or 60 mg twice weekly). Results: In total, 33 (57.9%) patients had normalized IGF1 following coadministration (P!0.0001 versus 30% minimum clinically relevant); median Pegvisomant dose in normalized patients was 60 mg/week. IGF1 normalized at any time during coadministration in 45 (78.9%) patients (P!0.0001) with median Pegvisomant dose at 60 mg/week. Being nondiabetic (odds ratio (OR): 4.65) and older (OR, upper versus lower quartile: 3.40) showed increased likelihood of normalization. Symptom reduction was greatest for arthralgia (K0.6G1.6) and soft tissue swelling (K0.6G1.8). Five patients reported treatment-emergent adverse events causing treatment withdrawal: three serious (treatment related ‐ thrombocytopenia, urticaria; not treatment related ‐ abdominal pain/vomiting) and two nonserious (hepatotoxicity and cytolytic hepatitis, both elevating alanine aminotransferase to O5!upper limit of normal with normalization after withdrawal). Conclusions: In patients partially controlled by SSAs, LA (120 mg/month) plus Pegvisomant normalized IGF1 in 57.9% of patients after 7 months, at a median effective Pegvisomant dose of 60 mg/week, and 78.9% at any time. In these patients, results suggest a Pegvisomant-sparing effect versus daily Pegvisomant monotherapy.
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somatostatin analog and Pegvisomant combination therapy for acromegaly
Nature Reviews Endocrinology, 2009Co-Authors: Sebastian J C M M Neggers, Aart Jan Van Der LelyAbstract:Optimal biochemical control cannot be attained by long-acting somatostatin analog monotherapy in a large proportion of patients with acromegaly. Such therapy might result in increased mortality, poor control of signs and symptoms of disease and decreased quality of life. Combination treatment with somatostatin analogs and Pegvisomant (a growth-hormone-receptor antagonist) is, however, highly effective at normalizing the level of insulin-like growth factor I in over 90% of patients and might also have a favorable effect on quality of life in those with biochemically controlled acromegaly. Moreover, whereas Pegvisomant monotherapy does not lead to a decrease in the size of the pituitary tumor, combination therapy with somatostatin analogs results in a clinically relevant decrease in tumor size in about 20% of patients. The main adverse effects of combination treatment are transient elevations in the levels of transaminases, which occur in about 15% of patients, especially in those with diabetes mellitus. In this Review, we discuss the available data on the long-term efficacy and safety of somatostatin analog-Pegvisomant combination treatment and its potential use in patients with acromegaly.