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© Borgis - Postępy Nauk Medycznych 12/2015, s. 825-828
*Agnieszka Majos, Maria Stelmachowska-Banaś, Izabella Czajka-Oraniec, Wojciech Zgliczyński
Porównanie skuteczności jednorazowego podania krótkodziałających analogów somatostatyny: oktreotydu i pasireotydu u pacjentów z akromegalią
A comparison of single-dose effects of short acting somatostatin analogs: octreotide vs pasireotide in patients with acromegaly
Department of Endocrinology, Centre of Postgraduate Medical Education, Bielański Hospital, Warszawa
Head of Department: prof. Wojciech Zgliczyński, MD, PhD
Streszczenie
Wstęp. Akromegalia jest rzadką chorobą powodowaną najczęściej przez gruczolak przysadki wydzielający autonomicznie hormon wzrostu. Celem leczenia akromegalii jest normalizacja stężeń GH i IGF-1 prowadząca do zmniejszenia śmiertelności do poziomu opisywanego w populacji ogólnej. Lekami z wyboru w akromegalii są długodziałające analogi somatostatyny pierwszej generacji: oktreotyd LAR oraz lanreotyd autogel. W ostatnim czasie pojawiły się doniesienia mówiące o większej skuteczności pasireotydu w porównaniu z oktreotydem u pacjentów z akromegalią.
Cel pracy. Celem pracy było porównanie skuteczności jednorazowego podania krótkodziałających analogów somatostatyny: oktreotydu i pasireotydu u pacjentów z czynną akromegalią.
Materiał i metody. Do badania włączono 13 pacjentów z czynną akromegalią. U wszystkich pacjentów w dwóch kolejnych dniach podano podskórnie krótkodziałający oktreotyd oraz krótkodziałający pasireotyd. Oznaczono stężenie GH i IGF-1 przed podaniem oraz po podaniu obu leków.
Wyniki. Najniższe stężenia GH osiągnięto w 60. minucie po podaniu oktreotydu oraz w 180. minucie po podaniu pasireotydu. Wynosiły one średnio 3,25 ug/l (1,99-4,11) po podaniu oktreotydu oraz 1,84 ug/l (0,97-2,03) po podaniu pasireotydu. Różnica jest istotna statystycznie (p = 0,002).
Wnioski. Krótkodziałający pasireotyd okazał się skuteczniejszy niż krótkodziałający oktreotyd w obniżaniu stężenia GH u pacjentów z czynną akromegalią.
Summary
Introduction. Acromegaly is a rare endocrine disorder caused in most cases by growth hormone secreting pituitary adenoma. The aim of acromegaly treatment is biochemical normalization of GH and IGF-1 concentrations leading to mortality risk reduction to the level expected in the general population. First-line medical treatment includes first generation long acting somatostatin analogs: octreotide LAR and lanreotide autogel. Recently, pasireotide – a second generation somatostatin analog has been widely investigated in acromegalic patients.
Aim. The aim of this study was to compare the single-dose effects of short acting somatostatin analogs: octreotide and pasireotide in patients with active acromegaly.
Material and methods. 13 patients with active acromegaly were enrolled in the study. All patients had short acting octreotide and pasireotide administered on two following days and GH and IGF-1 concentrations measured before and after drug administration. Nadir GH concentrations were compared.
Results. Nadir GH value in octreotide test was reached 60 minutes after drug administration, while in pasireotide test – 180 minutes after drug administration. Median nadir GH was 3.25 ug/L (1.99-4.11) vs 1.84 ug/L (0.97-2.03) respectively, p = 0.002.
Conclusions. Short acting pasireotide is more effective than short acting octreotide in supression of GH release in patients with active acromegaly.
iNTRODUCTION
Acromegaly is a rare and severe disease. In over 90% of cases it is caused by excessive secretion of growth hormone (GH) by pituitary adenoma resulting in elevated serum insulin-like growth factor-1 (IGF-1) (1). This leads to doubling of the mortality rate and reduction in life expectancy by about 10 years among acromegalic patients compared to general population (1, 2). The main goals of treatment are biochemical normalization, symptoms relief, reduction of tumor volume, maintenance of pituitary function and finally mortality risk reduction.
According to Endocrine Society Clinical Practice Guidelines the first-line therapy is transsphenoidal surgery followed by medical treatment in patients with active disease postoperatively. The medical treatment of choice are somatostatin receptor ligands (3).
Somatostatin receptors are present on the surface of GH-secreting pituitary adenomas, 90% of which are sst2 and sst5 (two from all 5 subtypes of somatostatin receptors). Due to their anti-proliferative effect somatostatin receptor ligands reduce not only the secretion of GH but also tumor volume. There are two equally effective long-acting preparations of first generation available: octreotide LAR and lanreotide autogel (4). They bind selectively to sst2 and to lesser extend to sst5 receptors. Recently, the use of pasireotide – a second generation somatostatin analogue with higher affinity to sst5 receptors has been widely investigated in acromegalic patients.
AIM
The aim of this study was to compare the effects of short acting pasireotide and octreotide on GH release in acromegalic patients.
MATERIAL AND METHODS
Thirteen adult male and female patients with active acromegaly (GH > 1.0 ug/L and/or elevated IGF-1 for age- and sex-matched controls) were enrolled in the study. There were 4 men and 9 women with an average age of 45 years ± 12 in the group. There were 2 de novo patients with acromegaly and 11 acromegalic patients who have already been treated with long acting somatostatin analogs alone or with dopamine agonists. The median time of treatment was 5 years (2.5-12.5). Eight patients underwent a transsphenoidal surgery, 2 patients had inoperable tumors and 1 had been prepared for operation with octreotide LAR. Three patients were treated with long acting somatostatin analogs alone and 8 with long acting somatostatin analogs and dopamine agonists. There were no patients treated with radiotherapy. Table 1 shows the characteristics of the patients.
Table 1. The characteristics of the enrolled patients.
 AgeSexGH [ug/L] baselineIGF-1 [ng/mL] baselineTreatment duration [years]Surgical treatmentPharmacological treatment
130M11.8810.20.50Octreotide LAR
255F3.36477.9141Octreotide LAR
338F4.2167851Lanreotide autogel + cabergoline
458F18.6627.300De novo
547F3.97732.8171Octreotide LAR + bromocriptine
643F59.3882.100De novo
767F4.15681.70InoperableOctreotide LAR + bromocriptine
844F5.05626.431Lanreotide autogel + bromocriptine
928F7.49577.921Octreotide LAR
1034M5.82905.8111Octreotide LAR + cabergoline
1155M0.78306.7151Lanreotide autogel + cabergoline
1256F2.48507.2101Lanreotide autogel + bromocriptine
1335M27.2973.85InoperableOctreotide LAR + bromocriptine
All patients had both short acting octreotide and short acting pasireotide tests performed on two following days. On the first day short acting octreotide 100 μg was administered subcutaneously. On the next day short acting pasireotide 60 mg was administered subcutaneously. On both days blood samples for GH were collected just before and 60, 120 and 180 minutes after drug administration and for IGF-1 at time points 0’ and 180’.
The statistical analysis was performed using STAT software. The assumption of normality of all data was investigated by Shapiro-Wilk test. When the data did not represent a random sample from normal distribution, p-values from Wilcoxon’s signed-rank tests were reported (GH concentrations). By normal distribution p-values from paired t-tests were reported (IGF-1 concentration).
RESULTS
The median baseline serum GH concentration was 5.05 μg/L (IQR: 3.97-11.8) before octreotide administration and 7.89 μg/L (3.75-21.0) before pasireotide administration. The average baseline serum IGF-1 concentration was 675.98 ng/mL ± 187.93 before octreotide administration and 662.28 ng/mL ± 185.34 before pasireotide administration. The differences in baseline GH and IGF-1 concentrations were statistically insignificant (p = 0.34 and p = 0.23). In octreotide test most patients (61.54%) reached the nadir GH value 60 minutes after drug administration, whereas in pasireotide test 84.61% of patients reached the nadir GH 180 minutes after drug administration. We compared nadir GH concentrations after octreotide vs pasireotide administration. Median nadir GH in octreotide test was 3.25 ug/L (1.99-4.11) vs 1.84 ug/L (0.97-2.03) (p = 0.002). Figure 1 presents nadir GH values in both tests. In all patients nadir GH after pasireotide administration was lower than nadir GH after octreotide administration. Nadir GH values after octreotide administration were lower than 2.5 ug/L in 6 patients (46.15%) and lower than 1 ug/L in 2 patients (15.38%) compared to 10 patients (76.92%) and 4 patients (30.77%) after pasireotide administration respectively.
Fig. 1. Nadir GH values octreotide vs pasireotide.
In our study short acting octreotide was well tolerated, while in pasireotide test 5 patients (38.46%) reported nausea and weakness lasting up to 2 hours after drug administration. Serious adverse events were not reported.
DISCUSSION
We have observed better response to short acting pasireotide vs short acting octreotide expressed as lower values of nadir GH concentration in all enrolled patients (in both de novo patients and previously treated and uncontrolled patients). The suppression of GH release is stronger after pasireotide administration.
Not much has been published regarding short acting somatostatin analogs use in acromegaly. Van der Hoek et al. have already compared acute effects of octreotide and pasireotide (5). They have presented three different patterns of response to pasireotide, related to sst receptors distribution on tumor cells: equal effectiveness in lowering GH concentration of both analogs, better effectiveness of pasireotide than octreotide or better effectiveness of octreotide. It shows the pivotal meaning of molecular mechanisms responsible for pasireotide effects.
It is already known that there are five somatostatin receptors expressed in the adult human pituitary gland (sst1, sst2, sst3, sst4, sst5). Sst2 receptors are found in 95% of GH-secreting pituitary adenomas whereas sst5 receptors are expressed in 85% (6). Other receptors are less common. First generation somatostatin analogs bind mainly to sst2 receptors, while a second generation analog – pasireotide has the ability to bind to four of the five types of sst receptors (sst1, sst2, sst3 and sst5). Pasireotide’s affinity for sst5 is 39-fold higher than octreotide’s and for sst2 is 2,6-fold lower than octreotide’s, but 2-fold higher in comparison to endogenous somatostatin (7-9). Due to its specific receptors affinity pasireotide seems to be promising in patients resistant to first generation somatostatin analogs. In our study we had no data on the receptors’ pattern on the tumor cells, so the efficacy of the analogs administered cannot be assessed regarding its receptors affinity. However, due to the fact that the majority of enrolled patients were previously treated with first generation long acting somatostatin analogs without reaching the biochemical control of disease, we may presume the high expression of sst5 on their tumor cells.
The fact that nadir GH levels were reached in our study in various time points after octreotide and pasireotide administration is the evidence of different pharmacokinetics of the investigated analogs. As already indicated short acting octreotide reaches its peak concentration 40 minutes after the injection and has a mean t1/2 of 1.7 hours (1, 8). That is why we observed the lowest GH levels 60 minutes after octreotide administration and no statistic significance between GH level before and 180 minutes after octreotide injection was reported. Pasireotide has much longer half-life (t1/2 = 7-11 hours), more stable biochemical structure and reaches its peak concentration after 0.25-0.5 hours after the injection, which causes more sustained working profile (8, 9).
There are much more data published regarding long acting somatostatin analogs. As already known both first generation analogs seem to be equally effective in acromegaly (10). Although there was no head to head well-designed trial comparing the efficacy of octreotide LAR and lanreotide autogel, it has been shown that 20 to 70% (depending on population and study protocol) of patients treated with octreotide long acting release or lanreotide depot do not achieve biochemical control of acromegaly (10-12). Colao et al. have shown several possible reasons for octreotide and/or lanreotide resistance pointing the expression of sst2 and sst5 receptors on tumor surface, somatostatin receptor genes mutations and clinical predictors such as age, gender, initial GH and IGF-1 serum concentration and tumor mass (7).
Long acting pasireotide has already been investigated in acromegaly. Gadelha et al. have compared the effectiveness of pasireotide LAR to octreotide LAR in acromegalic patients (13). They have shown that after 24 weeks of treatment pasireotide LAR had led to normalization of serum IGF-1 and GH levels in 15 to 20% of patients uncontrolled during octreotide treatment.
The status of pasireotide in acromegaly treatment still remains unclear. It seems to be more effective than octreotide. However, further investigation is required to define the groups of patients who would benefit the most from pasireotide therapy.
CONCLUSIONS
1. Pasireotide was more effective in supressing GH release than octreotide in patients with active acromegaly.
2. Molecular mechanism is probably responsible for differences in effectiveness of pasireotide and octreotide. The analogs have different receptors affinity. Octreotide binds mainly to sst2 receptors, while pasireotide binds to multiple somatostatin receptors, predominant sst5.
3. Pasireotide may be a good alternative in acromegalic patients resistant to octreotide.
Piśmiennictwo
1. Melmed S: Acromegaly pathogenesis and treatment. J Clin Invest 2009 Nov 2; 119(11): 3189-3202.
2. Dekkers O, Biermasz N, Pereira A et al.: Mortality in acromegaly: a metaanalysis. J Clin Endocrinol Metab 2008 Jan; 93(1): 61-67.
3. American guidelines: Acromegaly: An Endocrine Society Clinical Practice Guidelines. J Clin Endocrinol Metab 2014 Nov; 99(11): 3933-3951.
4. Melmed S: A critical analysis of clinically available somatostatin analog formulations for therapy of acromegaly. J Clin Endocrinol Metab 2008 Aug; 93(8): 2957-2968.
5. Van der Hoek J, de Herderer W, Feelders A et al.: A Single-Dose Comparison of the Acute Effects between the New Somatostatin Analog SOM230 and Octreotide in Acromegalic Patients. J Clin Endocrinol Metab 2004; 89(2): 638-645.
6. Cuevas-Ramos D, Fleseriu M: Somatostatin receptor ligands and resistance to treatment in pituitary adenomas. J Mol Endocrinol 2014 Jun; 52(3): R223-240.
7. Colao A, Auriemma R, Lombardi G, Pivonello R: Resistance to somatostatin analogs in acromegaly. Endocr Rev 2011 Apr; 32(2): 247-271.
8. Golor G, Hu K, Ruffin M et al.: A first-in-man study to evaluate the safety, tolerability, and pharmacokinetics of pasireotide (SOM230), a multireceptor-targeted somatostatin analog, in healthy volunteers. Drug Des Devel Ther 2012; 6: 71-79.
9. McKeage K: Pasireotide in Acromegaly: A Review. Drugs 2015; 75: 1039-1048.
10. Carmichael J, Bonert V, Nuno M et al.: Acromegaly clinical trial methodology impact on reported biochemical efficacy rates of somatostatin receptor ligand treatments: a meta-analysis. J Clin Endocrinol Metab 2014; 99: 1825-1833.
11. Mercado M, Borges F, Bouterfa H et al.: A prospective multicentre study to investigate the efficacy, safety and tolerability of octreotide LAR in the primary therapy of patients with acromegaly. Clin Endocrinol (Oxf) 2007; 66: 859-868.
12. Toledano Y, Rot I, Greenman Y et al.: Efficacy of long-term lanreotide treatment in patients with acromegaly. Pituitary 2009; 12: 285-293.
13. Gadelha MR, Bronstein MD, Brue T et al.: Pasireotide versus continued treatment with octreotide or lanreotide in patients with inadequately controlled acromegaly (PAOLA): a randomised, phase 3 trial. Lancet Diabetes Endocrinol 2014 Nov; 2(11): 875-884.
otrzymano: 2015-10-30
zaakceptowano do druku: 2015-11-23

Adres do korespondencji:
*Agnieszka Majos
Department of Endocrinology Centre of Postgraduate Medical Education Bielański Hospital
ul. Cegłowska 80, 01-809 Warszawa
tel. +48 (22) 834-31-31
a.majos.endo@gmail.com

Postępy Nauk Medycznych 12/2015
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