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Department of Internal Medicine (A.J.v.d.L., A.F.M., J.A.J., S.W.L.), Erasmus University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands; and Sensus Drug Development Corporation (R.J.D., K.A.Z., J.A.S.), Austin, Texas 78701
Address correspondence and requests for reprints to: A. J. van der Lely, M.D., Department of Internal Medicine, 40 Dr Molewaterplein, 3015 GD Rotterdam, The Netherlands. E-mail: vanderlely{at}inw3.azr.nl
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Introduction |
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In April 1997, he received for the first time pegvisomant, as he participated as the first patient in a dose-finding study in our center. The pegvisomant dose administered was 0.3 mg/kg body weight (27.6 mg). A single sc administration of the GH receptor (GHR) antagonist resulted in a decline in the total serum IGF-I level on day 3 after the injection without reaching normal levels (from 233 nmol/L to 211 nmol/L).
In July 1997, he was enrolled in a Phase 2b study on the efficacy and safety of pegvisomant in the treatment of acromegaly. In this 6-week placebo-controlled study, he was randomized to receive 80 mg pegvisomant sc once weekly. A significant decrease in serum total IGF-I levels was observed (from 305 mmol/L to 190 nmol/L), although the result was still three times the upper age-adjusted normal level (<50 nmol/L).
Because temporarily no study drug was available, he was treated again
with octreotide sc (200 µg sc t.i.d) between October 1997 and
February 1998. In this period, the nadir in total serum IGF-I
concentrations in the pegvisomant-free period remained the same as
before the first period of treatment with the GHR antagonist (around
150 nmol/L; see Table 1
), indicating that
he still was only partially sensitive to octreotide treatment.
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), although the final serum
IGF-I concentration was still slightly above the upper limit of normal.
This resulted in high pegvisomant concentrations (concentrations around
50,000 ng/mL). Also, a very significant increase in serum GH levels was
observed (maximal serum GH concentration during pegvisomant therapy,
260 ng/mL).
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). These observations were accompanied by an unexplained
decrease in serum pegvisomant concentrations, without a change in dose.
The patient’s compliance was considered to be optimal throughout the
whole period of observation, however (e.g. by the
interpretation of drug-accountability forms).
In November 1999, it was decided to start treatment with octreotide,
together with 40 mg sc pegvisomant once daily. Therefore, 30 mg
Sandostatin LAR therapy was initiated. This resulted in a
rapid normalization of serum total IGF-I concentrations within 2 months
(see Fig. 1), whereas the abnormalities in the visual field completely
resolved. Also, no further increase in tumor size on magnetic resonance
imaging (MRI) was observed between July 1999 and March 2000. At the
same time, a striking decrease in serum GH concentrations was observed
as well, down to levels comparable with concentrations before the start
of pegvisomant treatment. As least up to April 2000, serum IGF-I levels
remained well controlled with levels around 35 nmol/L. Signs and
symptoms of acromegaly were considerably improved as well.
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Discussion |
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TopAbstractIntroductionDiscussionReferences |
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The reported efficacy data of the available long-acting somatostatin analogs in reducing serum IGF-I levels in acromegalic patients indicate that effective control of disease activity can be achieved in two thirds of patients who are sensitive to somatostatin analogs (7, 8, 9, 10, 11, 12). This leaves at least one third of the patients without an effective control of disease activity by medical intervention. To our knowledge, there are no reports available that describe an increase in size of a somatotropinoma during long-term treatment with somatostatin analogs.
The present case illustrates several important issues regarding the future use of GHR antagonists on a large scale in the (near) future.
Pegvisomant
Pegvisomant is a genetically manipulated GH molecule that disables functional dimerization of the two GHR molecules involved in signal transduction, due to a single mutation at the site II of the GH molecule. Pegvisomant is pegylated to increase serum half-life time and to reduce the likelihood of antibody formation. Currently, the compound is under investigation in the treatment of acromegaly (13, 14, 15). Pegvisomant blocks GH action, instead of inhibiting GH secretion as somatostatin analogs. This implies that during pegvisomant therapy GH levels are not indicative for GH-mediated action on IGF-I production. Although the unpegylated GHR antagonist does have a higher affinity at site I of the GH, compared with endogenous GH, one must conclude that the pegylation process has major influences on this affinity, because in this particular patient pegvisomant concentrations of as high as 50,000 ng/mL were not able to block GH action of GH concentrations more than 200-fold lower (250 ng/mL), although serum IGF-I concentrations in our patient nearly normalized when pegvisomant levels were around 50,000 ng/mL. Strikingly, in the Phase II and III studies, no clear-cut correlation between pegvisomant concentrations, GH levels, and efficacy data were observed (13, 14, 15). In this particular patient, pegvisomant concentrations seem to be roughly correlated to the serum IGF-I response throughout the course of therapy. An unexpected finding was the 2-fold increase in serum pegvisomant concentrations, which was observed within 1 month after the initiation of octreotide treatment, while pegvisomant dosages were unchanged (40 mg daily). The reasons for this are unclear.
GH concentrations
As has been reported before, pegvisomant induces an increase in endogenous serum GH concentrations in acromegalic patients. Whether this dose-dependant increase in serum GH concentrations reflects a reduction in receptor-mediated GH clearance, an increase in production, or modification of some other pathway remains unclear yet. Studies on the effect of GHR blockade on the pharmacodynamics of serum GH levels are currently being performed. The important observation in the present case, however, is that lowering serum GH concentrations by octreotide coadministration results in a synergistic decrease in serum IGF-I concentrations not achieved with octreotide or pegvisomant administrated alone. This synergistic effect might be predicted, based on the mechanism of action of pegvisomant as a competitive GHR antagonist. Lowering GH levels would, therefore, make a given concentration of pegvisomant more effective.
Tumor size
The present case describes the first patient in whom progression in tumor size was encountered during treatment with pegvisomant. No data are yet available that indicate whether or not the size of a GH-producing tumor is modified by pegvisomant. It is, therefore, possible that some patients with aggressive tumors will show an increase in tumor size during long-term treatment with pegvisomant alone. Therefore, patients treated with pegvisomant should receive routine MRI monitoring of tumor size at least until more data become available. The aggressiveness of the tumor in this particular patient might reflect a subgroup of patients in whom a close follow-up of tumor size is mandatory with any treatment. It is still unclear, however, whether the observed increase in size of the tumor in this patient has been part of the natural history of growth of this tumor, in addition to growth secondary to the use of a GH antagonist. In this patient, cotreatment with octreotide and pegvisomant did result in an improvement in the visual field defects, whereas no further increase in tumor size was observed in between the last two MRI examinations 8 months apart. In this period, cotreatment was applied in the last 4 months.
Conclusion
We describe a 34-yr-old male acromegalic patient in whom a high dose of 40 mg pegvisomant (by sc daily injections) did not completely normalized serum IGF-I concentrations. Furthermore, he is the first patient in whom progression in tumor size was encountered during treatment with pegvisomant, and finally he was the first patient who was successfully treated with long-acting octreotide together with pegvisomant. This cotreatment resulted in an adequate control of biochemical disease activity, as well as an improvement of visual field defects and a further improvement in signs and symptoms.
Received June 23, 2000.
Revised August 15, 2000.
Revised October 9, 2000.
Accepted October 19, 2000.
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This article has been cited by other articles:
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