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BRIEF REPORT |
Department of Medicine, Columbia College of Physicians and Surgeons, New York, New York 10032
Address all correspondence and requests for reprints to: Pamela U. Freda, M.D., Department of Medicine, Columbia College of Physicians and Surgeons, 630 West 168th Street, New York, New York 10032. E-mail: puf1{at}columbia.edu.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Clinical trials to date have demonstrated that pegvisomant therapy is highly efficacious, normalizing serum IGF-I levels in 89% of patients treated with 20 mg/d for 3 months (3) and in 97% patients treated with 10–40 mg/d for up to 18 months (4). In these trials, pegvisomant was administered as daily sc injections, and thus the drug’s efficacy has been proven to date only with this dosing schedule. However, we hypothesized that because pegvisomant has a long half-life after sc injection (5, 6), it could be administered less frequently and still be as effective in normalizing IGF-I levels and improving the clinical signs and symptoms of acromegaly. The fact that the doses required to normalize serum IGF-I levels varied considerably among patients in clinical studies (4) also suggested that individualized dosing regimens for pegvisomant therapy would be needed. We further hypothesized that, given the potency of pegvisomant, dose titration might be warranted to prevent a fall of serum IGF-I levels into the lower normal range, which could potentially be associated with an increase in risk of functional GH deficiency (7). In this brief report, we present our experience with pegvisomant treatment of at least 6 months duration in 10 consecutive patients with active acromegaly and describe the effect of alternate-day administration of pegvisomant on IGF-I and clinical parameters.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Baseline characteristics and prior therapies of the patients studied are shown in Table 1
. The study included 10 patients (three females, seven males) treated at our center. All patients had active acromegaly at the start of the study as defined by a serum IGF-I above the age-related reference range (Table 2). All had prior transsphenoidal surgery, which pathologically confirmed a GH-secreting tumor, and three had postoperative radiotherapy (RT) in addition. RT was performed in patients 4 and 5 after ineffective medical therapy and directly postoperatively in patient 6. Eight patients had received medical therapy with a dopamine agonist (DA) and/or somatostatin analog (SA) before study entry; in patients 1, 4, 5, 7, 9, and 10, SA followed lack of efficacy of DA and in patients 5 and 9, DA and SA were then combined. These eight patients were switched to pegvisomant because of failure of IGF-I normalization on these therapies. These medications were withdrawn at least 4 wk before the start of pegvisomant therapy except in the case of patient 3, who remained on sc octreotide therapy during the study for therapy of persistent severe headaches. Two patients, 9 and 10, had previously been treated with pegvisomant as part of earlier clinical trials (3, 4) but had not received pegvisomant for 27 and 30 months, respectively, before entry into this study. Patients 9 and 10 were also participating in a multicenter trial during the first 8 months of this study (8). Patients with hypopituitarism were receiving stable doses of replacement therapy during the course of the study. Screening pituitary imaging studies were performed to confirm that all patients’ remnant pituitary tumor, if present, was more than 5 mm from the optic chiasm before initiating pegvisomant therapy.
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Pegvisomant administration and dose titration. Pegvisomant was administered on the first day of therapy as a loading dose of 40 mg, and this was followed by daily self-administered sc injections of 10 mg. Serum IGF-I levels were assessed at monthly intervals, and if the level was above the age-adjusted range, the dose of pegvisomant was increased in 5-mg increments up to a maximum of 40 mg/d. Patients 9 and 10 did not receive the loading dose and were adjusted at bimonthly intervals for the first 8 months of therapy and thereafter as above. The goal of dose titration was to maintain the serum IGF-I level as close as possible to the third quartile (50–75th percentile) of the patient’s age-adjusted normal range. In patients in whom the serum IGF-I fell below the target range, the dosing interval of pegvisomant was lengthened to every other day (qod). If the serum IGF-I remained below the target range, the dosing interval was lengthened another time to twice a week (biw), and if it rose, on qod dosing, pegvisomant was administered on 2 of every 3 d (q2/3). Once the target IGF-I was reached, patients were assessed every 3 months.
Laboratory testing. GH was measured before the start of therapy. At baseline and during dose titration monthly (every 3 months in the dose-stable phase), measurements of fasting IGF-I, glucose, insulin, and liver enzymes (alanine aminotransferase, aspartate transaminase, and alkaline phosphatase) were conducted. Serum IGF-I levels were measured fasting before administration of pegvisomant.
Magnetic resonance imaging of the pituitary was conducted at baseline, after 6 and 12 months, and then yearly thereafter during pegvisomant therapy.
Clinical monitoring. Physical examinations including vital signs, confrontation visual fields and ring size measurements were performed at every study visit. Patients completed a Signs and Symptoms of Acromegaly questionnaire at every visit in which they rated headache, perspiration, join pain, fatigue, and soft tissue swelling with scores ranging from 0 (no symptoms) to 8 (severe, incapacitating symptoms).
This protocol was approved by the Western Institutional Review Board, and informed consent was obtained from all patients.
Hormone assays
GH. GH was measured by a two-site immunoradiometric assay obtained from Diagnostic Systems Laboratories (Webster, TX). The standards for this immunoradiometric assay contain 22 K recombinant human GH (hGH) and are calibrated to the World Health Organization International Reference Preparation of human GH (code 88/624). The intraassay coefficient of variation is 3.1% and the interassay coefficient of variation is 5.9%. In our laboratory, the assay sensitivity is 0.05 µg/liter (9, 10).
IGF-I. IGF-I was measured by polyclonal RIA after acid-ethanol extraction (Nichols Institute, San Juan Capistrano, CA). The standard is calibrated against World Health Organization First International Reference Reagent 1988, IGF-I 87/518. The intraassay coefficient of variation is 4% and the interassay coefficient of variation is 11%. Assay sensitivity is 13.5 ng/ml. The normal ranges for this assay are: age 16–24 yr, 182–780 ng/ml; 25–39 yr, 114–492; 40–54 yr, 90–360; older than 55 yr, 71–290 ng/ml. All subjects’ IGF-I levels were compared with their age-appropriate normal ranges.
Serum glucose. Serum glucose was measured by the hexokinase method.
Insulin. Insulin was measured by the Immulite immunoassay (Diagnostics Product Corp., Los Angeles, CA).
Statistical analysis
All data are expressed as a mean ± SD. Insulin sensitivity was estimated by calculating homeostasis model assessment (HOMA) scores [fasting serum insulin (microunits per milliliter) x fasting plasma glucose (millimoles per liter)/22.5] (11). Mean insulin, glucose, and HOMA scores were calculated without patient 3 (because he was also on octreotide) and patient 7 (type 1 diabetes mellitus on insulin). Ring sizes given are the inner diameter (millimeters) of the ring. For analysis of signs and symptoms, a total score for each patient’s visit was calculated by summing the score for each symptom. For the total score the maximum (worst) was 40 and the minimum (best) was 0. The various outcome parameters at baseline and on pegvisomant therapy were compared by two-tailed paired t test. The relationship between the dose of pegvisomant and body mass index (BMI) or baseline GH or IGF-I levels were assessed by simple regression analysis. Results were considered significant if P < 0.05.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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The 10 patients were treated with pegvisomant for a mean period of 15.3 ± 4.6 months.
Patients’ IGF-I level before and during pegvisomant therapy and their most recent pegvisomant dose are shown in Table 2
. Initial IGF-I normalization was achieved with 10 mg/d in five patients, 15 mg/d in four patients, and 40 mg/d in one patient.
In four patients (4, 6, 7, 8), serum IGF-I fell into the lower half of the normal range on 10 mg/d, and the dose of pegvisomant was decreased to 10 mg qod (Fig. 1). After the IGF-I level remained persistently in the lower half of the normal range, second dosing adjustments were made in patients 4 and 6 to 10 mg biw (Fig. 1). On qod dosing, patient 7 had a rise in IGF-I to 288 ng/ml, still within the normal range, but at this IGF-I level, the patient noted a worsening of his blood sugar control, which then improved when his dosing was changed to 10 mg q2/3. In patient 8, a change of pegvisomant to qod led to a rise in IGF-I above normal, and the dose was further adjusted to 10 mg taken on q2/3 with a return of IGF-I level to the normal range (Fig. 1). In an additional patient, patient 5, 15 mg/d was required to normalize his IGF-I level initially, but after 9 months of this therapy, his serum IGF-I was 130 ng/ml (within the lower half of normal), and his dose interval was lengthened to qod, resulting in a serum IGF-I of 224 ng/ml. In patients 4, 5, and 6, who had received RT, pegvisomant was withdrawn for 2–4 wk with a rise in IGF-I above the age-adjusted normal in all three patients (Fig. 1).
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Clinical signs and symptoms of acromegaly
Signs and symptoms scores improved in eight of 10 patients and, overall, showed a trend for improvement (P = 0.06) (Table 3). Of the five patients on qod pegvisomant, these scores continued to improve in two patients and remained stable in the other three. Mean ring size also decreased significantly from 12.3 ± 2.2 to 11.5 ± 2.3 mm (P = 0.04). Blood pressure was lowered within the normal range: systolic pressure decreased from a mean of 130 ± 13 to 117 ± 8 mm Hg (P = 0.0085) and diastolic pressure from 86 ± 10 to 79 ± 8 mm Hg (P = 0.08) during pegvisomant therapy. Blood pressure improvements remained during dose reductions. There were trends for improvements in fasting glucose (P = 0.07) and serum insulin concentrations (P = 0.08) with pegvisomant therapy. Insulin resistance, as assessed by the HOMA score, decreased significantly overall (P = 0.04) (Table 3). Reductions in insulin resistance remained improved in those patients whose dose interval was lengthened. Patient 7, with type 1 diabetes mellitus treated with an insulin pump, had a decrease in daily insulin requirements from 85–90 to 35–40 U and a fall in hemoglobin A1C from 7.3 to 6.8% with pegvisomant therapy. During pegvisomant therapy in the two patients with type 2 diabetes mellitus, hemoglobin A1C fell from 6.8 to 6% in patient 2 and from 6.6 to 5.9% in patient 8, and both had a halving of their metformin dose. The addition of pegvisomant to octreotide therapy in patient 3 resulted in a reduction in fasting glucose (96 to 85 mg/dl), fasting insulin (10.5 to 7.0 µU/ml), and HOMA score (2.4 to 1.5). Patient 7 reported resolution of carpal tunnel syndrome during pegvisomant therapy.
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Before therapy, four patients had residual tumor greater than 1 cm in size (patients 2, 5, 8, 9), two patients had residual tumor less than 1 cm (patients 6, 7), and four patients had no visible tumor remnant (patients 1, 3, 4, 10). Only two patients had a change in pituitary tumor size during the study. Patient 2, who could be imaged only with a computed tomography scan because of a pacemaker, had a 1- to 2-mm increase in the transverse dimension of his tumor at 12 months of therapy. Patient 9 had a 2-mm increase in transverse and 1-mm increase in anterior-posterior tumor dimensions after 8 months of therapy with no subsequent change. In both cases the tumor change was clinically nonsignificant.
Adverse events
Pegvisomant was well tolerated. Two patients complained of mild transient insomnia, three patients complained of transient worsening of headache and one persistent headache (this patient, patient 3, remained on concurrent octreotide therapy as described above), three patients had fatigue, one dry skin, and one a urinary tract infection during therapy. None of these side effects limited therapy.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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To date, the efficacy of pegvisomant has been demonstrated when administered as daily sc injections. However, data both in vitro and in vivo after single dosing in healthy subjects and patients with acromegaly have demonstrated its long half-life after sc administration, up to 100 h (5, 6). Therefore, we sought to investigate whether less frequent dosing of pegvisomant would continue to prove efficacious with regard to biochemical and clinical outcomes of therapy in patients with acromegaly.
In this brief report, we have demonstrated that not all patients require daily pegvisomant to maintain serum IGF-I levels within their age-adjusted normal range. In addition, we have shown that individualized dosing regimens can allow for some tailoring of the extent of reduction in serum IGF-I levels. In all, five of 10 patients did not require daily dosing, and specifically three could be managed on qod pegvisomant, two of these subsequently also on biw dosing, and two others most recently have been on dosing q2/3. We also found persistent reductions in ring size, blood pressure, and insulin resistance in these patients.
In clinical trials to date, considerable intersubject variability in the dose of pegvisomant required to normalize IGF-I levels has been observed, with these varying from 10 to 40 mg daily. Pegvisomant dose has been reported to be correlated positively with baseline GH and IGF-I levels (16), suggesting that larger doses of pegvisomant are required to achieve the plasma drug concentrations necessary for antagonism of native circulating GH for the GHRs (15). We did not observe this relationship, although our study was small. We have also not yet determined whether patients with higher GH levels than ours could be maintained on qod administration of larger doses of pegvisomant. One study also found that pegvisomant dose seems to correlate positively with weight (16). Interestingly, we similarly found that pegvisomant dose correlated positively with BMI. It has also been reported that women may require larger doses of pegvisomant than men, even accounting for weight, serum concentrations of pegvisomant, and baseline GH levels (16). We had too few subjects to properly address gender differences of dosing regimens of pegvisomant in patients with acromegaly. Interestingly, three of the five patients whose pegvisomant dosing interval could be lengthened had prior RT. It is possible that a reduction of disease severity by radiotherapy could be a factor in the success of less frequent pegvisomant dosing. Additional study into these clinical determinants of dosing needs is required.
Although it is clearly essential that normalization of IGF-I be achieved in the therapy of acromegaly and much data support the validity of monitoring disease activity based on serum IGF-I levels (3, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30), less is known about how to gauge at what point within the normal range the serum IGF-I levels should be in a patient during therapy. In adults, experience with use of serum IGF-I levels to diagnose adult GH deficiency illustrates a potential pitfall of reliance on the serum IGF-I level to estimate GH sufficiency or insufficiency because up to 50% of patients with GHD have normal IGF-I levels (31, 32). In the analysis of a large database of serum IGF-I levels in patients with GH deficiency, IGF-I levels within the upper half of the age-adjusted normal range carried a low risk of GH deficiency (7). Extrapolating from these data, it would seem prudent to suppress serum IGF-I levels with pegvisomant therapy to within the normal range but not to within the lower half of this range. In a large long-term clinical trial, some patients treated with daily pegvisomant had suppression of IGF-I level into the low end of their age-adjusted normal range (4). We too have found that daily doses of the lowest available dose of pegvisomant, 10 mg, can lower serum IGF-I levels into the lower half of the normal range in some patients. Thus, as we have shown here, it may be necessary to administer qod or biw pegvisomant to prevent oversuppression of serum IGF-I levels into a range that may increase the patient’s risk of functional GH deficiency. We also need to consider that because the range of normal IGF-I values appears to be wide and because some data in the general population suggest that IGF-I level (within the spectrum of normal) may correlate with the incidence of certain malignancies (33, 34, 35), clinical outcomes may guide drug titration differently. For example, as in patient 7 in this series, a serum IGF-I within the lower half of normal seemed to be better for his blood sugar control, an important clinical end point of therapy.
Less frequent pegvisomant dosing has other potential advantages with regard to the practicality of this therapy. Less frequent dosing will likely improve patient acceptance of injection therapy as well as compliance with the injections. Less frequent dosing will also significantly reduce the cost of this therapy.
Another important goal of therapy of acromegaly is to remove or reduce the size of the pituitary tumor to relieve symptoms of mass effect on areas surrounding the pituitary and preserve normal pituitary function. Although pegvisomant therapy is not expected to reduce tumor size as somatostatin analogs might, evidence to date suggests that pegvisomant therapy does not accelerate the underlying rate of a particular tumor’s growth. Although most GH-secreting tumors appear to be very slow growing, some are not, and in this latter group, as already reported, a minority of these patients may have continued tumor growth and eventually symptomatic tumor enlargement while on pegvisomant therapy (4). This study was not designed to examine tumor size changes, although we did monitor these and found only a slight change in tumor size in two patients. Interestingly, both these patients had not received prior RT, and neither did two previously reported patients with tumor increase (4). Further larger studies are needed to examine tumor size in patients with pegvisomant therapy.
In conclusion, pegvisomant is very potent and in sufficient doses should normalize serum IGF-I levels in all patients with acromegaly. Although it is not yet clear what the target IGF-I range for this therapy should be, with the prospect of long-term use of this therapy in patients who may begin their therapy in their 40s, its seems prudent to individually tailor therapy. Most data would suggest to do this to an IGF-I level within the mid- to upper half of normal in conjunction with clinical signs and symptoms monitoring. In this brief report, we have shown that serum IGF-I levels can be maintained within the normal range with less frequent than daily dosing of pegvisomant. Although a larger number of subjects should be studied, possibly with additional dosing regimens, these data do provide a proof of concept that pegvisomant at alternate-day dosing can maintain its efficacy with regard to normalizing IGF-I levels as well as persistently improving clinical signs and symptoms.
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Footnotes |
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First Published Online December 7, 2004
Abbreviations: biw, Twice a week; BMI, body mass index; DA, dopamine agonist; GHR, GH receptor; HOMA, homeostasis model assessment; q2/3, 2 of every 3 d; qod, every other day; RT, radiotherapy; SA, somatostatin analog.
Received October 7, 2004.
Accepted December 1, 2004.
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References |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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This article has been cited by other articles:
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  M Rix, P Laurberg, A S Hoejberg, and B Brock-Jacobsen Pegvisomant therapy in pituitary gigantism: successful treatment in a 12-year-old girl Eur. J. Endocrinol., August 1, 2005; 153(2): 195 - 201. [Abstract] [Full Text] [PDF]
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