Gender, Body Weight, Disease Activity, and Previous Radiotherapy ...

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The Journal of Clinical Endocrinology & Metabolism 92(1):190 –195 Copyright © 2007 by The Endocrine Society doi: 10.1210/jc.2006-1412

Gender, Body Weight, Disease Activity, and Previous Radiotherapy Influence the Response to Pegvisomant Craig Parkinson, Pia Burman, Michael Messig, and Peter J. Trainer Department of Diabetes and Endocrinology (C.P.), Ipswich Hospital, Ipswich IP4 5PD, United Kingdom; Department of Endocrinology (P.B.), University Hospital MAS, Malmo¨ S-205 02, Sweden; Pfizer Inc. (M.M.), New York, New York 10017; and Department of Endocrinology (P.J.T.), Christie Hospital, Manchester M20 4BX, United Kindgom Context/Objective: To effectively normalize IGF-I in patients with acromegaly, various covariates may affect dosing and plasma concentrations of pegvisomant. We assessed whether sex, age, weight, and previous radiotherapy influence dosing of pegvisomant in patients with active disease.

with pegvisomant, IGF-I levels were similar in men and women. A significant correlation between baseline GH, IGF-I, body weight, and the dose of pegvisomant required to normalize serum IGF-I was observed (all P ⬍ 0.001). Women required an average of 0.04 mg/kg more pegvisomant than men and a mean weight-corrected dose of 19.2 mg/d to normalize serum IGF-I [14.5 mg/d (men); P ⬍ 0.001]. Patients treated with radiotherapy required less pegvisomant to normalize serum IGF-I despite similar baseline GH/IGF-I levels (15.2 vs. 18.5 mg/d for no previous radiotherapy; P ⫽ 0.002).

Design: Data from 69 men and 49 women participating in multicenter, open-label trials of pegvisomant were retrospectively evaluated using multiple regression techniques. Sixty-nine subjects (39 men, 30 women) had undergone external beam pituitary radiotherapy. Serum IGF-I was at least 30% above age-related upper limit of normal in all patients at study entry. After a loading dose of pegvisomant (80 mg), patients were commenced on 10 mg/d. Pegvisomant dose was adjusted by 5 mg every eighth week until serum IGF-I was normalized.

Conclusions: Sex, body weight, previous radiotherapy, and baseline GH/IGF-I influence the dose of pegvisomant required to normalize serum IGF-I in patients with active acromegaly. (J Clin Endocrinol Metab 92: 190 –195, 2007)

Results: At baseline, men had significantly higher mean serum IGF-I levels than women despite similar GH levels. After treatment

I

N ACROMEGALY, GH hypersecretion results in high circulating levels of GH-dependent peptides, such as IGF-I, IGF binding protein-3, and acid labile subunit. IGF-I mediates most of the known effects of GH. Pegvisomant is a genetically engineered, highly selective GH-receptor antagonist (1) that normalizes serum IGF-I in most patients with acromegaly (2, 3). The dose of pegvisomant required to normalize serum IGF-I is variable, and the determinants of this variability are largely unknown. Whereas plasma concentrations of pegvisomant are crucial to its efficacy and IGF-I is closely correlated to GH levels, multiple factors may influence IGF-I levels in acromegaly. As the dose of pegvisomant is titrated against serum IGF-I levels, these factors may therefore affect the dose of pegvisomant required to normalize serum IGF-I. Sex is an important determinant of GH secretion (4). Healthy women secrete three times more GH over 24 h than age-matched men (5), yet they have IGF-I concentrations that are similar (6, 7). Women with GH deficiency (GHD) have been shown to have lower pretreatment serum IGF-I concentrations than men, despite similar peak GH responses to the provocative tests used to define GHD (8). Furthermore, women with GHD require approximately 50 to 100% more

recombinant human GH than men to achieve equivalent IGF-I levels (8 –11). This sex difference is particularly marked in women receiving oral estrogen replacement therapy (11– 13). Previously, we have demonstrated that for a given serum GH level women with acromegaly have IGF-I concentrations lower than men with the same serum GH level (14, 15). On average, this difference is 82 ␮g/liter [95% confidence interval (CI): 15, 149; P ⬍ 0.02], but it is further influenced by the use of oral estrogen because serum IGF-I level is on average 130 ␮g/liter lower in women receiving this treatment than it is in men with the same serum GH level (95% CI: 29.8, 230.2; P ⫽ 0.01) (14). Whether age influences the relationship between GH and IGF-I remains a matter of debate. Lieberman et al. (16) observed that the IGF-I response to a single-bolus dose of GH was blunted in healthy older men (60 – 69 yr old) compared with younger men (20 –29 yr old). In contrast, Arvat et al. (17) reported that the percentage increase in serum IGF-I after single doses of GH was greater in healthy elderly subjects than in healthy young adults; the percentage increase after repeated GH administration was similar in both groups. We have reported a small but significant influence of age on IGF-I levels in patients with acromegaly such that, for a given serum GH level, elderly patients have lower serum IGF-I levels than younger subjects (15). Although two previous studies (14, 15) have not demonstrated an influence of radiotherapy on the relationship between serum GH and IGF-I in patients with acromegaly, it has been suggested that the mode of therapy used to achieve

First Published Online October 31, 2006 Abbreviations: CI, Confidence interval; CV, coefficient of variation; GHBP, GH-binding protein; GHD, GH deficiency. JCEM is published monthly by The Endocrine Society (http://www. endo-society.org), the foremost professional society serving the endocrine community.

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disease control may influence the 24-h GH secretion profile (18, 19). Whether radiotherapy influences the efficacy of adjuvant medical therapies, however, is unclear. Because normalization of serum IGF-I is the goal of pegvisomant therapy in acromegaly and pegvisomant dosage is titrated against this parameter, we investigated whether disease activity—as assessed by baseline GH/IGF-I levels—sex, estrogen therapy, age, body weight, and previous pituitary radiotherapy influence the dose of pegvisomant required to normalize IGF-I in patients with active acromegaly. Subjects and Methods Subjects Data from 147 patients with an established diagnosis and clinical features of acromegaly participating in multicenter, open-label trials of pegvisomant were retrospectively evaluated. Insufficient data were available for, or the dose of pegvisomant to normalize serum IGF-I could not be ascribed in, 29 subjects. The median age of the remaining 118 patients was 44 yr (range, 20 –78), and 69 subjects (58%) were men. Sixty-nine subjects (58%) had previously undergone external beam pituitary radiotherapy (30 women, 39 men). A total of 62 (52.5%) patients had hormone deficiencies; of those, 23 had panhypopituitarism and 39 had partial hypopituitarism (defined as one or two documented anterior pituitary hormone deficits). Panhypopituitarism was present in nine of 39 (51.3%) and partial hypopituitarism in 11 of 39 (28.2%) men who had received pituitary irradiation. In women who had received pituitary irradiation, panhypopituitarism was present in four of 30 (13.3%) and partial hypopituitarism in seven of 11 (23.3%). In the nonirradiated group, panhypopituitarism was present in 2 of 30 (6.7%) of men and one of 19 (5.3%) of women, whereas partial hypopituitarism was present in eight of 30 (26.7%) of men and five of 19 (26.3%) of women. In patients receiving medical therapy, appropriate washout periods (5 wk for dopamine agonists, 2 wk for sc octreotide) were used before baseline data were obtained. Patients receiving long-acting octreotide and lanreotide were not permitted to enter the study. All participating patients had baseline serum IGF-I concentrations at least 30% above the age-related upper limit of normal after appropriate washout of medical therapy.

Treatment Pegvisomant therapy was initiated with an 80-mg loading dose, followed by once-daily sc injections of 10 mg. Every 8 wk, doses were reevaluated and titrated in 5-mg/d increments or decrements to maintain IGF-I concentrations within the normal range. Mean treatment duration was 12 ⫾ 7 (⫾sd) months. In women receiving oral estrogen replacement therapy, doses remained stable throughout the study period. The dose of pegvisomant needed to normalize IGF-I (defined as the lowest dose needed to obtain a serum IGF-I value below the upper limit of normal for the age-specific reference range) in each subject was retrospectively determined by two independent investigators who were blinded to patient age, sex, weight, and previous use of radiotherapy.

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Statistical analysis Determinants of the dose of pegvisomant required to normalize serum IGF-I concentrations were analyzed (SAS version 8.02; SAS Institute, Cary, NC) using multiple regression analyses in which the dose was considered right censored (i.e. the dose was only known to be greater than a particular value) for those patients who had not achieved normal serum IGF-I at the time of their last dose. Model-adjusted means by sex, radiation therapy, and estrogen usage were calculated according to the least squares mean method. Covariates included sex, body weight, age, baseline serum GH concentrations, end point serum pegvisomant concentrations, estrogen usage, and previous radiotherapy. Similar analyses were performed for the dose per kilogram of body weight required to normalize serum IGF-I and pegvisomant concentration levels required to normalize serum IGF-I. Correlations were determined as the square root of Laitila’s pseudo-R2 (21). Analyses of end point IGF-I and change from baseline to end point in IGF-I were analyzed using standard analysis of covariance techniques. Pegvisomant concentrations during treatment were analyzed using repeated measures analysis of covariance. Comparisons of demographic factors were performed using two-sample t tests. P ⬍ 0.05 was considered indicative of a statistically significant finding.

Results Baseline GH and IGF-I concentrations

A correlation between baseline GH levels and pegvisomant serum concentrations required for IGF-I normalization was observed (R ⫽ 0.43; P ⬍ 0.001). Similarly, a relationship was observed between baseline IGF-I levels and the pegvisomant dose required to normalize serum IGF-I (R ⫽ 0.49; P ⬍ 0.001; Fig. 1). Sex

Table 1 shows baseline characteristics of the study subjects according to sex. Mean serum GH levels were similar in men and women [10.7 ng/ml (men) and 12.3 ng/ml (women); P ⫽ 0.65]; however, men had greater serum IGF-I concentrations [803 ng/ml (men) and 685 ng/ml (women); P ⫽ 0.04]. Men and women were similar in age; however, there was a significant difference in body weight between the groups. The mean (⫾se) change in IGF-I from baseline to end point (adjusted for baseline GH) was greater in men than in women (⫺479 ⫾ 32 ng/ml and ⫺375 ⫾ 38 ng/ml, respectively; P ⫽ 0.04). The final mean IGF-I concentrations were not different between men and women (322 ⫾ 18 and 314 ⫾ 21 ng/ml, respectively; P ⫽ 0.76), which was anticipated given that the

IGF-I, GH, and pegvisomant concentrations Serum IGF-I was measured monthly using a competitive binding RIA (Nichols Institute Diagnostics, San Juan Capistrano, CA), and an agerelated, non-sex-related reference range was used. The intraassay coefficient of variation (CV) was 2.4 –3.0%, and the interassay CV was 5.2– 8.4%. Serum GH was measured at baseline using RIA (Endocrine Sciences, Inc., Calabasas Hills, CA); interassay CV was 12% at 3.4 ng/ml, and sensitivity was 0.03 ng/ml. Serum concentrations of pegvisomant (␮g/ml) were measured monthly using a specific RIA (Phoenix International Life Sciences, Saint-Laurent, Quebec, Canada), which has been previously described (20). The interassay CVs were 1.6% at 87 ␮g/liter and 4.5% at 199 ␮g/liter. The intraassay CVs were 2.8% at 87 ␮g/liter and 3.2% at 199 ␮g/liter. All serum samples were obtained after an overnight fast.

FIG. 1. Correlation between baseline IGF-I and pegvisomant concentration required to normalize IGF-I levels.

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Parkinson et al. • Factors Influencing Response to Pegvisomant

TABLE 1. Baseline characteristics by sex Characteristic

Women (n ⫽ 49)

Men (n ⫽ 69)

P

Age, yr Body weight, kg IGF-I, ng/ml GH, ng/ml

46 (14.4) 81 (18.4) 685 (221) 12.3 (21.0)

43 (12.7) 101 (18.7) 803 (349) 10.7 (17.8)

0.26 ⬍0.01 0.04 0.65

Values shown are mean (SD). P values are based on t test.

aim of therapy was the restoration of normal, age-matched, serum IGF-I levels. Despite the greater decrease in serum IGF-I in men, overall mean (⫾se) serum pegvisomant concentrations were similar in men and women (13,330 ⫾ 812 and 13,336 ⫾ 958 ng/ml, respectively; P ⫽ 0.99), indicating a greater sensitivity to pegvisomant in men. The mean dose of pegvisomant required to achieve serum IGF-I normalization was similar in men and women (16.6 ⫾ 1.0 and 15.9 ⫾ 1.2 mg/d, respectively; P ⫽ 0.66). We identified two influences of sex on the dose of pegvisomant required to achieve serum IGF-I normalization. First, to achieve comparable mean plasma concentrations of pegvisomant, the dose per kilogram was significantly greater in women, who required on average 0.04 mg/kg more pegvisomant than men (0.20 and 0.16 mg/kg䡠d, respectively; 95% CI: 0.01, 0.06; P ⫽ 0.002) (Fig. 2). Expressed another way, when pegvisomant serum concentrations were adjusted for dose per kilogram of body weight, they were found to be lower in women than in men (10,684 ⫾ 842 vs. 15,600 ⫾ 724 ng/ml; 95% CI: ⫺7108, ⫺2723; P ⬍ 0.001). Second, for equivalent mean plasma concentrations of pegvisomant, a smaller reduction in serum IGF-I was observed in women. Thus, after correcting for the influence of weight in multivariate analysis, women required a mean weight-corrected pegvisomant dose that was 4.7 mg/d higher than for men (19.2 and 14.5 mg/d, respectively; 95% CI: 2.3, 7.2; P ⬍ 0.001) (Fig. 2). A total of 21 women were receiving oral estrogen therapy. When considering the mean (⫾se) weight-corrected dose of pegvisomant required to nor-

malize serum IGF-I concentrations, there was no significant difference between women receiving oral estrogen (19.4 ⫾ 1.0 mg) and those not receiving it (19.1 ⫾ 0.9 mg) (95% CI: ⫺3.09, 3.59; P ⫽ 0.88). Age and body weight

In a multiple regression analysis controlling for sex, pegvisomant concentration and baseline values of IGF-I, GH, weight, and age, no significant linear relationship was found between age and the dose needed to normalize IGF-I (P ⫽ 0.69). However, a linear association was found between body weight and the dose needed to normalize IGF-I. In the present data set (weight range, 55–158 kg), for identical covariates in men and women, the pegvisomant dose required to normalize IGF-I was estimated to increase by 0.24 mg for each kilogram increase in body weight (95% CI: 0.18, 0.30; P ⬍ 0.01). Radiotherapy

With the exception of the presence of hypopituitarism, there were no differences in baseline characteristics between patients treated with pituitary irradiation and those not treated with radiotherapy (Table 2) (see Subjects and Methods). However, previous pituitary radiotherapy influenced the dose of pegvisomant required to normalize serum IGF-I. In multiple regression analysis, the corrected pegvisomant dose (mean ⫾ se mg/kg) adjusted for sex, baseline GH, pegvisomant concentration, and age was lower in patients who had previously received external beam pituitary radiotherapy compared with those who had not (0.17 ⫾ 0.1 vs. 0.19 ⫾ 0.1 mg/kg; 95% CI: 0.01, 0.05; P ⫽ 0.02). Patients receiving previous radiation therapy required a mean of 3.3 mg (95% CI: 1.2, 5.4; P ⫽ 0.002) less pegvisomant per day than those not receiving radiotherapy to achieve IGF-I normalization (15.2 ⫾ 0.6 vs. 18.5 ⫾ 0.7 mg/d) (Fig. 3). Discussion

In acromegaly, GH hypersecretion leads to elevated IGF-I concentrations. A close correlation exists between serum IGF-I and markers of disease activity (22) as well as mortality (23). The short half-life and pulsatile secretion of GH limit the clinical usefulness of single measurements as biochemical TABLE 2. Baseline characteristics by prior external beam pituitary radiotherapy

FIG. 2. Dose per kilogram body weight needed to normalize serum IGF-I against baseline GH by sex. The solid line represents women; the broken line represents men.

Characteristic

Radiotherapy

No radiotherapy

Female patients, n Age, yr Body weight, kg Baseline GH, ng/ml Baseline IGF-I, ng/ml Male patients, n Age, yr Body weight, kg Baseline GH, ng/ml Baseline IGF-I, ng/ml

30 46 (46) 84 (77) 16.4 (7.0) 728 (702) 39 44 (42) 105 (107) 11.8 (4.9) 799 (776)

19 47 (46) 78 (76) 5.9 (4.6) 617 (610) 30 43 (42) 96 (90) 9.2 (3.7) 808 (796)

Values shown are mean (median). a P values for mean were based on t test. b P values for median were based on Wilcoxon test.

P

0.86a (0.92)b 0.31a (0.41)b 0.10a (0.14)b 0.09a (0.13)b 0.77a (0.88)b 0.05a (0.01)b 0.55a (0.65)b 0.92a (0.91)b

Parkinson et al. • Factors Influencing Response to Pegvisomant

FIG. 3. Dose per kilogram body weight needed to normalize serum IGF-I against baseline GH by exposure to previous radiotherapy. The solid line represents patients treated with radiotherapy; the broken line represents those who did not receive radiotherapy.

marker in patients with acromegaly. Serum IGF-I has a long half-life and is thus increasingly used as the sole marker of disease activity. In patients treated with pegvisomant, serum IGF-I is the only marker of disease activity available because of an interference with standard GH assays (1). There is increasing evidence that sex influences the relationship between GH and IGF-I across a broad spectrum of GH levels. Relative resistance to the effects of GH with regard to IGF-I generation is well recognized in healthy women and in women with GHD compared with men (7–9, 11, 13, 24). This difference is further increased by concomitant use of oral estrogen therapy (11–13). A similar sex effect has been reported in acromegaly across a broad spectrum of disease control irrespective of the treatment modality (14, 15, 25, 26). Given the influence of sex and oral estrogen on the relationship between GH and IGF-I, these parameters may modulate response to drug treatment in patients with acromegaly. An influence of gender on the response to octreotide in patients with acromegaly has previously been reported (26). The present study used a nonsex-specific end point and observed different dose requirements of pegvisomant to restore age-matched serum IGF-I levels in men and women. We identified two influences of sex on the dose of pegvisomant required. First, women required approximately 20% more pegvisomant than men on a dose-per-kilogram basis to achieve the same mean plasma pegvisomant concentrations. This indicates a sex difference in pharmacokinetics and may involve factors such as absorption, distribution, and/or clearance of the drug. One possibility is that the pharmacokinetics of pegvisomant are influenced by GH-binding protein (GHBP), to which pegvisomant is known to bind with 30-fold greater affinity than the GH receptor (27). GHBP was not measured in the present study, but levels have been observed to increase during treatment with pegvisomant and after successful pituitary surgery (27, 28). There are conflicting data on the possibility of a sex difference in GHBP levels in healthy subjects (29, 30), and, although speculative, there may be qualitative and quantitative sex-based differences in

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the turnover of the pegvisomant receptor complex and the GHBP-pegvisomant complex, but to our knowledge this topic has not been addressed. More studies will be necessary to clarify whether sex influences the pharmacokinetics of pegvisomant. Second, for equivalent plasma levels of pegvisomant, the decline in IGF-I was lower in women; hence, to achieve IGF-I normalization, women required an average of 4.7 mg more pegvisomant than men. This difference is in keeping with a reported influence of sex on the relationship between GH and IGF-I in patients with acromegaly, which supports relative GH resistance to IGF-I generation in women. Twentyone of the 49 women in the present analysis were receiving oral estrogen therapy. No significant influence of oral estrogen was observed on the dose of pegvisomant required to normalize IGF-I. In the present study no significant influence of age on the dose of pegvisomant required to normalize serum IGF-I was found. Patients treated with pituitary irradiation therapy required an average of 3.3 mg/d less pegvisomant than those who had not—a finding that may have several explanations. During treatment with pegvisomant, in parallel with the decline in serum IGF-I, mean serum GH increases significantly within the first weeks of therapy, after which levels plateau (2, 3). One may postulate that radiotherapy may attenuate this expected increase in GH levels such that a lower dose of pegvisomant is then required to antagonize GH at the receptor level. In the present study, the relative increase in GH levels, expressed as the ratio of the GH level measured at the time of IGF-I normalization compared with baseline, was 2.6 in the nonirradiated subjects and 2.0 in the irradiated subjects, a difference that did not reach statistical significance. However, the present study relied on a single fasting measurement of GH, and it is conceivable that the area under the curve, as determined by repeated measurements of GH over 24 h, would have detected a significantly larger GH increase in the nonirradiated group. Another contributing factor might have been the influence of radiotherapy on GH secretory dynamics (31). There are many studies in children and adults indicating that radiotherapy acts on the hypothalamus resulting in disturbed GH secretory dynamics (32). Patients with acromegaly treated by radiotherapy have an abnormal pattern of GH secretion with a greater proportion of nonpulsatile GH release (19, 31, 33– 35). It can be speculated that different modes of secretory patterns may affect dose requirements although this hypothesis remains to be proven. Additionally, suboptimal hormone replacement could contribute to the influence of radiotherapy on the dose of pegvisomant required. In the present study, as anticipated, hypopituitarism was observed more often in patients who had received pituitary radiotherapy. Studies have suggested that thyroid hormones play a role in the regulation of IGF-I (36) and that hypothyroidism is associated with significant reductions in IGF-I (37). Glucocorticoid therapy in hypopituitary patients produces a dose-related increase in serum IGF-I (38), and, among healthy young and middle-aged men, there is an association between free testosterone and IGF-I levels (39). However, when the presence of hypopituitarism was incorporated into the model, the different dose requirements between irradi-

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ated and nonirradiated patients remained (data not shown). Further studies are required to determine the mechanism(s) by which pituitary irradiation therapy influences the dose of pegvisomant required to normalize serum IGF-I levels in patients with acromegaly. In conclusion, the results of the present analysis indicate that the response to pegvisomant in patients with active acromegaly is influenced by baseline serum GH and IGF-I, previous radiotherapy, and body weight. Men are more responsive to the drug than women, seemingly reflecting a sex difference in pegvisomant pharmacokinetics as well as in GH sensitivity. Acknowledgments Received July 3, 2006. Accepted October 20, 2006. Address all correspondence and requests for reprints to: Dr. Craig Parkinson, Department of Diabetes and Endocrinology, The Ipswich Hospital National Health Service Trust, Heath Road, Ipswich, Suffolk IP4 5PD, United Kingdom. E-mail: Craig.Parkinson@ipswichhospital. nhs.uk. Disclosure Summary: C.P. has nothing to declare. P.B. has previously received consulting and lecture fees from Pfizer. M.M. is employed by Pfizer Inc. P.J.T. has received grant support from Pfizer.

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