Self-limited acute hepatotoxicity caused by pegvisomant

We present a case of acute severe hepatitis in a patient with acromegaly receiving combination therapy with somatostatin analogs and pegvisomant. Hepatitis resolved completely 18 weeks after diagnosis of hypertransaminasemia without discontinuation of therapy and with a close clinical and biochemical follow-up. In this case, despite the severity of the hepatitis, therapy could be continued as hypertransaminasemia was gradually decreasing after the maximum peak. We also review the literature on toxic hepatitis associated to pegvisomant therapy analyzing the etiology, clinical predisposing factors and natural evolution.     

Lipodystrophy in patients with acromegaly receiving pegvisomant

Context: Pegvisomant, a GH receptor antagonist, suppresses serum IGF-I levels into the normal range in more than 95% of patients with acromegaly. Documented side effects in the initial registration studies included headache, injection-site reactions, flu-like syndrome, and reversible elevation of hepatic enzymes. Objective: We report seven patients with acromegaly treated with pegvisomant who developed lipodystrophy at the site of injection (anterior abdominal wall, thigh, buttock, and upper arm). This side effect resulted in discontinuation of pegvisomant in four patients, with subsequent regression of lipohypertrophy. Subjects: Six female and one male patient with acromegaly, aged 24-59 yr, are reported. All patients had undergone prior transsphenoidal surgery, and four received subsequent radiotherapy. Four patients had been treated with maximal doses of somatostatin analogs with partial suppression of IGF-I levels before initiation of pegvisomant therapy. Pegvisomant suppressed IGF-I levels into the normal range in five of seven subjects, before discontinuation of the drug. Two of seven patients received pegvisomant as first-line medical therapy, without prior somatostatin analog treatment, and one received combination therapy with a long-acting somatostatin analog and weekly pegvisomant injections. One patient experienced an erythematous superficial injection-site reaction that responded to application of steroid cream before the onset of lipohypertrophy. Conclusions: We report seven patients with acromegaly who developed lipohypertrophy at the pegvisomant injection site. Pegvisomant was discontinued due to dissatisfaction with lipohypertrophy by four patients. Lipohypertrophy regressed in all patients when the medication was discontinued. Lipohypertrophy recurred when two patients were rechallenged with pegvisomant. Patients receiving pegvisomant should undergo frequent examination of injection sites for lipohypertrophy.     

Conversion of daily pegvisomant to weekly pegvisomant combined with long-acting somatostatin analogs,in controlled acromegaly patients

The efficacy of combined treatment in active acromegaly with both long-acting somatostatin analogs (SRIF) and pegvisomant (PEG-V) has been well established. The aim was to describe the PEG-V dose reductions after the conversion from daily PEG-V to combination treatment. To clarify the individual beneficial and adverse effects, in two acromegaly patients, who only normalized their insulin like growth factor (IGF-I) levels with high-dose pegvisomant therapy. We present two cases of a 31 and 44 years old male with gigantism and acromegaly that were controlled subsequently by surgery, radiotherapy, SRIF analogs and daily PEG-V treatment. They were converted to combined treatment of monthly SSA and (twice) weekly PEG-V. High dose SSA treatment was added while the PEG-V dose was decreased during carful monitoring of the IGF-I. After switching from PEG-V monotherapy to SRIF analogs plus pegvisomant combination therapy IGF-I remained normal. However, the necessary PEG-V dose, to normalize IGF-I differed significantly between these two patients. One patient needed twice weekly 100 mg, the second needed 60 mg once weekly on top of their monthly lanreotide Autosolution injections of 120 mg. The weekly dose reduction was 80 and 150 mg. After the introducing of lanreotide, fasting glucose and glycosylated haemoglobin concentrations increased. Diabetic medication had to be introduced or increased. No changes in liver tests or in pituitary adenoma size were observed. In these two patients, PEG-V in combination with long-acting SRIF analogs was as effective as PEG-V monotherapy in normalizing IGF-I levels, although significant dose-reductions in PEG-V could be achieved. However, there seems to be a wide variation in the reduction of PEG-V dose, which can be obtained after conversion to combined treatment.     

Treatment of pituitary tumors: pegvisomant

Pegvisomant is a pegylated analog of growth that functions as a growth hormone receptor antagonist. The drug is capable of normalizing serum IGF-I concentrations (the chief mediator of disease activity in acromegaly) in 97% of patients, and therapy is associated with significant improvements in the symptoms and signs of GH excess. Biochemical control may be achieved with pegvisomant in patients wholly or partially resistant to somatostatin analogs, and there are emerging data to suggest that the drug may be particularly suitable for patients with acromegaly and co-existent diabetes mellitus.     

Discovery and mechanism of action of pegvisomant

Using a structure-function approach to the understanding of the molecular topology of the GH molecule, we discovered that glycine in the third alpha-helix of GH (G119 of bovine GH and G120 of human GH) was an important amino acid required for GH action. Substitution of this glycine residue with a variety of amino acids results in molecules that lack growth-promoting activity. More importantly, these molecules inhibit the actions of GH both in vitro and in vivo. These results, obtained more than a decade ago, were the basis for the discovery of GH antagonists. Since that time, efforts have been focused on establishing the mechanism by which these antagonists inhibit GH action. In this regard, in vivo expression of GH-antagonist genes in transgenic mice results in dwarf animals. The animals are fertile and possess no abnormal 'phenotypes'. Dwarf mice have also been created by disrupting or 'knocking out' the GH receptor gene. Together, these results have laid the foundation for the clinical use of GH antagonists when endogenous GH levels are increased or when GH is known to be a factor in the progression of the disorder.     

Long-term effects of pegvisomant in patients with acromegaly

Despite improved surgical and radiotherapy techniques and the development of long-acting somatostatin analogs, some patients with acromegaly cannot attain biochemical remission. As a consequence they continue to endure debilitating symptoms and mortality remains high. Pegvisomant, a recombinant growth-hormone-receptor antagonist, suppresses production of insulin-like growth factor I. Since the introduction of this drug several years ago, long-term studies involving hundreds of patients have established efficacy of more than 85%. Raised transaminase concentrations have, however, been reported as a side effect of therapy, albeit an infrequent one. In addition, increases in tumor volume have been reported in several cases. In this Review we present the long-term data that have been gathered on pegvisomant therapy, discuss the related risks and benefits, and frame a potential therapeutic approach.     

Drug-induced hepatitis in an acromegalic patient during combined treatment with pegvisomant and octreotide long-acting repeatable attributed to the use of pegvisomant

We report on a patient with acromegaly who developed severe drug-induced hepatitis during combined treatment with the long-acting somatostatin-analog octreotide and the GH receptor antagonist pegvisomant. The hepatic enzyme disturbances normalized after discontinuation of pegvisomant. After rechallenge with monotherapy pegvisomant, however, the hepatic enzyme disturbances reappeared within a few weeks, indicating that most likely pegvisomant alone and not the long-acting somatostatin analog or the combination of these two drugs was responsible for this case of drug-induced hepatitis. Clinicians should be aware of this potential severe adverse drug reaction and therefore frequent control of hepatic enzymes is mandatory during treatment with pegvisomant.     

A randomized, controlled, multicentre trial comparing pegvisomant alone with combination therapy of pegvisomant and long-acting octreotide in patients with acromegaly

Objective For patients with acromegaly who are suboptimally controlled on long‐acting octreotide (LAR), treatment options are to switch to pegvisomant monotherapy (PM) or add pegvisomant to LAR (P‐LAR). Our objective was to evaluate if the safety and efficacy of these regimens differ. Design This was an open‐label, multicentre, randomized, 40‐week outpatient study. The control arm consisted of patients controlled on LAR (n = 28). Patients A total of 27 patients with suboptimally controlled acromegaly [as indicated by a serum IGF‐I level ≥ 1·3 × upper limit of normal (ULN) of the age‐related reference range] were randomized to PM (10 mg once daily initially, then adjusted in 5‐mg increments every 8 weeks based on IGF‐I levels) and 29 to P‐LAR (LAR dosing remained fixed). Measurements The primary end‐point was adverse events (AEs). The secondary end‐point was biochemical IGF‐I‐based efficacy. The RIA for IGF‐I was discontinued by the manufacturer during the study and a chemiluminescent assay was subsequently used. Previously obtained IGF‐I levels were re‐analysed. Results PM and P‐LAR were well tolerated and there were no differences in the number of AEs. Patients receiving P‐LAR tended to be more likely to have clinically significant increases in hepatic transaminase levels, especially those receiving high‐dose LAR. Normalization of IGF‐I was similar with both regimens (56% and 62% of patients for PM and P‐LAR respectively). The change in IGF‐I assay resulted in lower rates of IGF‐I normalization than expected. Reductions in fasting glucose levels were greater with PM than with P‐LAR (−0·8 mmol/l; 95% confidence interval −1·16, −0·53 mmol/l). Conclusions In patients suboptimally controlled on LAR, PM and P‐LAR were equally well tolerated and effective in normalizing IGF‐I, and overall clinical improvement was observed with both regimens. Thus, pegvisomant monotherapy and adjunctive therapy are equally viable options for the treatment of LAR‐resistant acromegaly.     

Long-term experience of pegvisomant therapy as a treatment for acromegaly

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.     

Growth hormone receptor polymorphism and the effects of pegvisomant in acromegaly

Background    Sensitivity to pegvisomant therapy is highly variable in patients with acromegaly but determinants of this variability are still unknown. Lack of exon 3 (d3-) of the growth hormone (GH) receptor (GHR) has been associated with increased biological activity of GH. Objective    To assess whether the presence of d3-GHR haplotype may have a role in predicting dose regimen and response to pegvisomant in acromegaly. Design    Case series. Setting    Institutional referral center at a tertiary care hospital. Patients    Ninenteen acromegalic patients with active disease after unsuccessful neurosurgery and somatostatin analog therapy. Measurements    before and 1, 3, 6 and 12 months after treatment with pegvisomant, IGF-I; GH receptor genotype, determined from peripheral blood by polymerase chain reaction. All patients started treatment with pegvisomant at 10 mg/daily and then increased the dose, according to a fixed schedule, during a 12-month follow-up until normalization of IGF-I levels. Results    d3-GHR patients required a significant lower dose of pegvisomant and shorter treatment time to normalize IGF-I. Conclusion    the GHR genotype could be useful in predicting dose and individual response to pegvisomant in acromegaly.     

Pituitary tumor enlargement in two patients with acromegaly during pegvisomant therapy

BACKGROUND: Several classes of pharmacological agents are approved for the medical therapy of acromegaly, including dopamine agonists, somatostatin analogs and a growth hormone receptor antagonist. Pegvisomant, a growth hormone receptor antagonist, suppresses IGF-1 levels into the normal range in over ninety percent of patients. However, increased tumor volume was reported in patients receiving pegvisomant who had not received prior radiotherapy. OBJECTIVES: To describe two patients with acromegaly who developed significant tumor enlargement on pegvisomant and discuss the potential mechanisms involved. INTERVENTION: Both patients received long-acting somatostatin analog (octreotide) therapy subsequent to incomplete transsphenoidal tumor resection. Octreotide did not normalize GH/IGF-1 levels in either patient but did control tumor mass size. Pegvisomant therapy was initiated after discontinuing octreotide. RESULTS: Both patients exhibited suppression of IGF-1 into the normal range during pegvisomant therapy. However, significant tumor enlargement occurred in both. Potential mechanisms for tumor enlargement include the natural tendency of the tumor to grow with time, discontinuation of tumor suppressive effects of the somatostatin analog, or a direct effect of pegvisomant. The presumed mechanism of tumor enlargement is by loss of the inhibitory effect on tumor growth when IGF-1 levels are reduced. This could also explain the increase in circulating GH levels in patients with acromegaly receiving pegvisomant; patient 1 demonstrated an 18-fold increase in circulating GH levels while receiving the drug. CONCLUSIONS: The mechanisms of tumor enlargement in patients with acromegaly on pegvisomant are likely multifactorial. Patients, especially those who have not received prior radiotherapy, should be closely monitored for tumor enlargement.     

Endogenous estradiol may influence IGF-I levels in acromegalic women treated with pegvisomant

We present the case of a 46-year-old woman with acromegaly currently being treated with the growth hormone (GH) receptor antagonist pegvisomant showing strongly fluctuating IGF-I levels. We prospectively measured estradiol, IGF-I, IGF-I binding protein, acid labile subunit, basal endogenous GH, binding protein and pegvisomant levels for 6 months every week. Estradiol levels showed a strongly negative correlation with IGF-I (r = −0.733, P < 0.001), and less so with ALS (r = −0.433, P < 0.05) and IGFBP3 (r = −0.590, P < 0.01). Estradiol was not significantly correlated with endogenous GH or pegvisomant levels. Likewise, IGF-I did not correlate with endogenous GH or pegvisomant levels. In our patient, endogenous estradiol levels have a significant influence on IGF-I levels. When female acromegalic patients on permanent pegvisomant treatment show fluctuating IGF-I levels, estradiol levels should be taken into consideration.