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Analgesic effect of long-acting somatostatin receptor agonist pasireotide in a patient with acromegaly and intractable headaches.

ABSTRACT: A 22-year-old woman presented with worsening vision loss and headaches. A diagnosis of acromegaly was confirmed after detection of an invasive pituitary macroadenoma and biochemical testing. Despite two attempts of surgical debulking of the tumour and administration of long-acting octreotide and cabergoline, growth hormone (GH) and insulin-like growth factor 1 (IGF-1) levels were uncontrolled. The patient experienced persistent headaches despite surgery, gamma knife radiation and ventriculoperitoneal shunt placement; she was then enrolled in the ACCESS trial (ClinicalTrials.gov identifier, NCT01995734). Pasireotide (Signifor; Signifor LAR) was initiated, which led to reduced GH and IGF-1 levels and resolution of her intractable headaches. This highlights the use of monthly pasireotide in resolving headaches and improved biochemical control in a patient with acromegaly. We postulate that the headaches improved due to an analgesic and/or anti-inflammatory effect mediated by somatostatin receptors targeted by pasireotide. This may represent an additional benefit of pasireotide and requires further investigation.

SUBMITTER: Lovato CM

PROVIDER: S-EPMC6011455 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Analgesic effect of long-acting somatostatin receptor agonist pasireotide in a patient with acromegaly and intractable headaches.

Lovato Christina M CM Kapsner Patricia L PL

BMJ case reports 20180619

A 22-year-old woman presented with worsening vision loss and headaches. A diagnosis of acromegaly was confirmed after detection of an invasive pituitary macroadenoma and biochemical testing. Despite two attempts of surgical debulking of the tumour and administration of long-acting octreotide and cabergoline, growth hormone (GH) and insulin-like growth factor 1 (IGF-1) levels were uncontrolled. The patient experienced persistent headaches despite surgery, gamma knife radiation and ventriculoperit ...[more]

PMID: 29925553

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Project description:Abstract Background: In a 24-week, Phase 3 study (PAOLA), long-acting pasireotide demonstrated superior efficacy (GH <2.5 µg/L and IGF-1 <ULN) over continued treatment with long-acting octreotide/lanreotide in pts with uncontrolled acromegaly (Gadelha MR, et al. Lancet Diabetes Endocrinol. 2014;2:875-884). An earlier (3 months) switch to long-acting pasireotide and the current criteria for biochemical control, i.e. GH <1 μg/L and IGF-1 <ULN, are considered in the present phase 3b study. This study (clinicaltrials.gov: NCT02354508) evaluated the efficacy (GH <1 μg/L and IGF-1 <ULN) and safety of long‑acting pasireotide in pts with uncontrolled acromegaly despite ≥3 months of treatment with maximal approved doses of first-generation SSAs. Methods: Adults with uncontrolled acromegaly (mean GH [mGH] ≥1 µg/L and IGF-1 >1.3xULN) despite ≥3 months of treatment with maximal approved doses of long-acting octreotide/lanreotide received open-label long-acting pasireotide 40 mg/28 days. Pasireotide dose could be up titrated to 60 mg/28 days after week 12 if the biochemical control was not achieved or down titrated to 20 mg/28 days or 10 mg/28 days for tolerability. Primary endpoint: proportion of pts with mGH <1 μg/L and IGF-1 <ULN at week 36 overall and by screening mGH (1.0-2.5 μg/L and >2.5 μg/L). Results: 123 pts received long-acting pasireotide: median age, 43.0 years (range, 22-76); female, 50.4%; baseline median (range) mGH, 5.4 µg/L (1.2-195.5) and IGF-1, 2.3xULN (1.4-7.9); prediabetic/diabetic at baseline, n=112 (91.1%). The median duration of exposure to pasireotide was 36.0 weeks (median dose intensity, 53.3 mg/month). Overall, 18 pts (14.6% [95%CI, 8.9-22.1]) achieved biochemical control at week 36 (primary endpoint); 12 (42.9% [95%CI, 24.5-62.8]) and 6 pts (6.4% [95%CI, 2.4-13.4]) by screening mGH levels of 1.0 to 2.5 µg/L (n=28) and >2.5 µg/L (n=94), respectively. At week 36, 23 (18.7%), 16 (57.1%) and 7 pts (7.4%) had GH <1 µg/L; and 38 (30.9%), 14 (50.0%) and 24 pts (25.5%) had IGF-1 <ULN overall and by screening mGH levels of 1.0 to 2.5 µg/L and >2.5 µg/L, respectively. The median percentage decreases in mGH and standardized IGF-1 from baseline to week 36 were 56.8% and 42.8%. The most common AEs (>15%) regardless of study drug relationship were hyperglycemia (43.1%), diabetes mellitus (22.0%), and diarrhea (15.4%). Hyperglycemia-related AEs suspected to be drug related occurred in 81 pts (66%) overall and 4 of 11 pts (36.4%) who were nondiabetic at baseline. A total of 10 pts (8.1%) discontinued treatment either because of AEs (n=4; 3.3%) or unsatisfactory therapeutic effect (n=3; 2.4%), or consent withdrawal (n=3; 2.4%). Conclusions: In pts with uncontrolled acromegaly, switching to long-acting pasireotide after ≥3 months of treatment with first-generation SSAs provided biochemical control (mGH <1.0 μg/L and IGF-1 <ULN) in 15% of all pts and 43% of pts with lower screening mGH (1.0-2.5 µg/L).

Project description:Introduction: Acromegaly is a rare, serious endocrine disorder characterized by excess growth hormone (GH) secretion by a pituitary adenoma and overproduction of insulin-like growth factor I (IGF-I). Transsphenoidal surgery is the treatment of choice, although many patients require additional interventions. First-generation somatostatin analogs (SSAs) are the current standard of medical therapy; however, not all patients achieve control of GH and IGF-I. Outcomes from a Phase IIIb open-label study of patients with uncontrolled acromegaly on first-generation SSAs switching to pasireotide are reported. Methods: Adults with uncontrolled acromegaly (mean GH [mGH] ≥1 μg/L from a five-point profile over 2 h, and IGF-I >1.3× upper limit of normal [ULN]) despite ≥3 months' treatment with maximal approved doses of long-acting octreotide/lanreotide received open-label long-acting pasireotide 40 mg/28 days. Pasireotide dose could be increased (maximum: 60 mg/28 days) after week 12 if biochemical control was not achieved, or decreased (minimum: 10 mg/28 days) for tolerability. Patients who completed 36 weeks' treatment could continue receiving pasireotide during an extension (weeks 36-72) when concomitant medication for acromegaly was permitted. Primary endpoint was proportion of patients with mGH <1 μg/L and IGF-I <ULN at week 36. Biochemical control was also assessed during the extension. Safety was assessed throughout. Results: One hundred and twenty-three patients were enrolled and received pasireotide; 88 patients continued into the extension. Overall, 18 [14.6% (95% CI: 8.9-22.1)] patients achieved mGH <1 μg/L and IGF-I <ULN at week 36; biochemical control was achieved in 42.9% with screening mGH 1.0-2.5 μg/L and 6.4% with screening mGH >2.5 μg/L. For patients who entered the extension, 14.8% (95% CI: 8.1-23.9), 12.5% (95% CI: 6.4-21.3), 14.8% (95% CI: 8.1-23.9) and 11.4% (95% CI: 5.6-19.9) had mGH <1 μg/L and IGF-I <ULN at weeks 36, 48, 60, and 72, respectively. During the overall study period, most frequent investigator-reported drug-related adverse events were hyperglycemia (41.5%), diabetes mellitus (23.6%), and diarrhea (11.4%). Conclusions: Switching to long-acting pasireotide provided biochemical control in some patients, which was sustained with continued treatment. Long-term safety and tolerability of long-acting pasireotide was consistent with the known safety profile. These data support long-acting pasireotide for some patients with acromegaly who are uncontrolled on first generation SSAs. Clinical Trial Registration: clinicaltrials.gov, identifier: NCT02354508.

Project description:Background and objectivesWe assessed safety and efficacy of another somatostatin receptor analog, pasireotide long-acting release, in severe polycystic liver disease and autosomal dominant polycystic kidney disease. Pasireotide long-acting release, with its broader binding profile and higher affinity to known somatostatin receptors, has potential for greater efficacy.Design, setting, participants, & measurementsIndividuals with severe polycystic liver disease were assigned in a 2:1 ratio in a 1-year, double-blind, randomized trial to receive pasireotide long-acting release or placebo. Primary outcome was change in total liver volume; secondary outcomes were change in total kidney volume, eGFR, and quality of life.ResultsOf 48 subjects randomized, 41 completed total liver volume measurements (n=29 pasireotide long-acting release and n=12 placebo). From baseline, there were -99±189 ml/m absolute and -3%±7% change in annualized change in height-adjusted total liver volume (from 2582±1381 to 2479±1317 ml/m) in the pasireotide long-acting release group compared with 136±117 ml/m absolute and 6%±7% increase (from 2387±759 to 2533±770 ml/m) in placebo (P<0.001 for both). Total kidney volumes decreased by -12±34 ml/m and -1%±4% in pasireotide long-acting release compared with 21±21 ml/m and 4%±5% increase in the placebo group (P=0.05 for both). Changes in eGFR were similar between groups. Among the n=48 randomized, adverse events included hyperglycemia (26 of 33 [79%] in pasireotide long-acting release versus four of 15 [27%] in the placebo group; P<0.001), and among the 47 without diabetes at baseline, 19 of 32 (59%) in the pasireotide long-acting release group versus one of 15 (7%) in the placebo group developed diabetes (P=0.001).ConclusionsAnother somatostatin analog, pasireotide long-acting release, slowed progressive increase in both total liver volume/total kidney volume growth rates without affecting GFR decline. Participants experienced higher frequency of adverse events (hyperglycemia and diabetes).Clinical trial registry name and registration numberPasireotide LAR in Severe Polycystic Liver Disease, NCT01670110 PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_08_28_CJN13661119.mp3.

Project description:PurposeCushing's disease (CD) and acromegaly are characterized by excessive hormone secretion resulting in comorbidities such as impaired glucose metabolism, diabetes and hypertension. Pasireotide is a new-generation, multireceptor-targeted somatostatin receptor ligand approved for CD (subcutaneous [SC] injection formulation) and acromegaly (long-acting release [LAR] formulation). In clinical studies of pasireotide, hyperglycemia-related adverse events (AEs) were frequently observed. This review highlights differences in reported rates of hyperglycemia in pasireotide trials and discusses risk factors for and management of pasireotide-associated hyperglycemia.MethodsClinical trials evaluating pasireotide in patients with CD or acromegaly were reviewed.ResultsThe frequency of hyperglycemia-related AEs was lower in patients with acromegaly treated with pasireotide LAR (57.3-67.0 %) than in patients with CD treated with pasireotide SC (68.4-73.0 %). Fewer patients with acromegaly treated with pasireotide LAR discontinued therapy because of hyperglycemia-related AEs (Colao et al. in J Clin Endocrinol Metab 99(3):791-799, 2014, 3.4 %; Gadelha et al. in Lancet Diabetes Endocrinol 2(11):875-884, 2014, 4.0 %) than did patients with CD treated with pasireotide SC (Boscaro et al. in Pituitary 17(4):320-326, 2014, 5.3 %; Colao et al. in N Engl J Med 366(10):914-924, 2012, 6.0 %). Hyperglycemia-related AEs occurred in 40.0 % of patients with acromegaly treated with pasireotide SC, and 10.0 % discontinued treatment because of hyperglycemia. Ongoing studies evaluating pasireotide LAR in patients with CD and management of pasireotide-induced hyperglycemia in patients with CD or acromegaly (ClinicalTrials.gov identifiers NCT01374906 and NCT02060383, respectively) will address these key safety issues.ConclusionsDisease pathophysiology, drug formulation, and physician experience potentially influence the differences in reported rates of pasireotide-induced hyperglycemia in CD and acromegaly. Hyperglycemic effects associated with pasireotide have a predictable pattern, can be managed with antidiabetic agents, and are reversible upon discontinuation.

Dataset Information

Analgesic effect of long-acting somatostatin receptor agonist pasireotide in a patient with acromegaly and intractable headaches.

Publications

Analgesic effect of long-acting somatostatin receptor agonist pasireotide in a patient with acromegaly and intractable headaches.

Similar Datasets

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