Transcript 20120315PasireotideForCushing (2839574bytes)

Journal Club
Colao A, Petersenn S, Newell-Price J, Findling JW, Gu F,
Maldonado M, Schoenherr U, Dipl-Biol, Mills D, Salgado
LR, Biller BM; Pasireotide B2305 Study Group.
A 12-month phase 3 study of pasireotide in Cushing's
disease.
N Engl J Med. 2012 Mar 8;366(10):914-24.
2012年3月15日 8:30-8:55
８階 医局
埼玉医科大学 総合医療センター 内分泌・糖尿病内科
Department of Endocrinology and Diabetes,
Saitama Medical Center, Saitama Medical University
松田 昌文
Matsuda, Masafumi
１．消化管ホルモン産生腫瘍 通常、成人にはオクトレオチドとして20mgを４週毎に３ヵ 月間、殿部筋肉内に注射する。その後
は症状により10mg、 20mg又は30mgを４週毎に投与する。ただし、初回投与後２ 週間は薬物濃度が十分な濃度に達しな
いことから、本剤投 与前に投与していた同一用量のオクトレオチド酢酸塩注射 液を併用する。
２．消化管神経内分泌腫瘍 通常、成人にはオクトレオチドとして30mgを４週毎に、殿 部筋肉内に注射する。なお、患者の状態
により適宜減量す ること。
３．先端巨大症・下垂体性巨人症 通常、成人にはオクトレオチドとして20mgを４週毎に３ヵ 月間、殿部筋肉内に注射する。その
後は病態に応じて10mg、 20mg又は30mgを４週毎に投与するが、30mg投与で効果が不 十分な場合に限り40mgまで増
量できる。
ソマトスタチンは、血中半減期が2～3分と短いため臨床上での応用
ができませんでした。
そこで、ソマトスタチンの生物学的活性を示すのに重要な部分である
4つのアミノ酸（Phe-Trp-Lys-Thr）をそのままの配列で残し、
disulfide(S-S)結合をはさんでD-PheとThr(ol)を配した8個のアミノ
酸よりなる環状ペプチドとしたものがオクトレオチドです。これによっ
て作用の持続性が得られ、ソマトスタチンに比べ成長ホルモン（GH）
に対する選択性が高く、強力な作用を持つことが可能になりました。
サンドスタチンLARは、長期にわたるオクトレオチド酢酸塩による治
療を可能とするために開発された徐放性製剤です。従来の1日2～3
回の皮下注射を、4週毎に1回の筋肉内注射とすることで、1ヵ月あた
りの注射回数を約1/60～1/90と著しく減らすことができることから、投
与の利便性・コンプライアンス及び治療受容の向上が期待できます。
サンドスタチン注射液５０μｇ
経路：注射薬｜規格：５０μｇ１ｍＬ１管 ｜｜薬価：1930.00
サンドスタチン注射液１００μｇ
経路：注射薬｜規格：１００μｇ１ｍＬ１管 ｜薬価：3449.00
サンドスタチンＬＡＲ筋注用１０ｍｇ
経路：注射薬｜規格：１０ｍｇ１瓶（溶解液付） ｜薬価：121201.00
サンドスタチンＬＡＲ筋注用２０ｍｇ
経路：注射薬｜規格：２０ｍｇ１瓶（溶解液付） ｜薬価：216706.00
サンドスタチンＬＡＲ筋注用３０ｍｇ
経路：注射薬｜規格：３０ｍｇ１瓶（溶解液付） ｜薬価：304843.00
J Clin Endocrinol Metab, June 2010, 95(6):2781–2789
Percentage change in pituitary tumor volume from baseline (before
octreotide treatment) to the end of the study after 3 months of
pasireotide treatment in the 51 assessable patients. The 14 de novo
patients, all of whom had a macroadenoma, are highlighted in gray.
用法／用量 メチラポンとして１回５００～７５０ｍｇを１日６回４時間毎に経口投与する。
小児には、１回１５ｍｇ／ｋｇに相当する量を１日６回４時間毎に経口投与するが、１回の最小
量は、メチラポンとして２５０ｍｇが望ましい。
the Department of Molecular and Clinical Endocrinology and Oncology, Section of Endocrinology, University of Naples Federico II,
Naples, Italy (A.C.); ENDOC Center for Endocrine Tumors, Hamburg, and the Faculty of Medicine, University of Duisburg–Essen,
Essen — both in Germany (S.P.); the Department of Human Metabolism, University of Sheffield, Sheffield, United Kingdom ( J.N.-P.);
the Division of Endocrinology, Metabolism, and Clinical Nutrition, Medical College of Wisconsin, Milwaukee ( J.W.F.); the Department
of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health Peking Union Medical College Hospital, Beijing (F.G.); Clinical
Development, Oncology Business Unit, Novartis Pharma, Basel, Switzerland (M.M., U.S., D.M.); the Division of General Internal
Medicine, Hospital das Clínicas, University of S.o Paulo Medical School, S.o Paulo (L.R.S.); and the Neuroendocrine Clinical Center,
Massachusetts General Hospital, Boston (B.M.K.B.).
N Engl J Med 2012;366:914-24.
BACKGROUND
Cushing’s disease is associated with high
morbidity and mortality. Pasireotide, a
potential therapy, has a unique, broad
somatostatin-receptor–binding profile, with
high binding affinity for somatostatin-receptor
subtype 5.
a 40-fold increased affinity to
somatostatin receptor 5
METHODS In this double-blind, phase 3 study, we
randomly assigned 162 adults with Cushing’s
disease and a urinary free cortisol level of at least
1.5 times the upper limit of the normal range to
receive subcutaneous pasireotide at a dose of 600
μg (82 patients) or 900 μg (80 patients) twice daily.
Patients with urinary free cortisol not exceeding 2
times the upper limit of the normal range and not
exceeding the baseline level at month 3 continued to
receive their randomly assigned dose; all others
received an additional 300 μg twice daily. The
primary end point was a urinary free cortisol level at
or below the upper limit of the normal range at
month 6 without an increased dose. Open-label
treatment continued through month 12.
washout periods for patients on medical treatment
Inhibitors of steroidogenesis (ketoconazole, metyrapone): 1 week
Dopamine agonists (bromocriptine, cabergoline): 4 weeks
Rosiglitazone: 1 week
Octreotide LAR and Lanreotide Autogel: 8 weeks
Lanreotide SR: 4 weeks
Octreotide (immediate release formulation): 1 week
Figure 2. Mean Change in Urinary Free
Cortisol Levels from Baseline to Month 12 and
Proportion of Patients with Normalized Levels
at Month 6.
Panel A shows the mean urinary free cortisol level
at time points up to month 12 according to dose
group; the change from baseline to months 6 and
12 was significant for both the 600-μg group
(P<0.001) and the 900-μg group (P<0.001). The
dashed line represents the upper limit of the
normal range (ULN), which is 145 nmol per 24
hours. The mean percentage change in the
urinary free cortisol level from baseline to month 6
was –27.5% (95% CI, –55.9 to 0.9) in the 600-μg
group and –48.4% (95% CI, –56.6 to –40.2) in the
900-μg group; the corresponding changes from
baseline to month 12 were –41.3% (95% CI, –
66.0 to –16.6) and –54.5% (95% CI, –65.2 to –
43.7). The median percentage change in the
urinary free cortisol level was –47.9% (95% CI, –
74.1 to –40.7) in the 600-μg group and –47.9%
(95% CI, –66.9 to –35.5) in the 900-μg group at
month 6 and –67.6% (95% CI, –72.7 to –42.4)
and –62.4% (95% CI, –78.7 to –38.5),
respectively, at month 12. I bars indicate standard
errors. Panel B shows the percentage of patients
in whom the urinary free cortisol level was at or
below the ULN at month 6, categorized according
to whether hypercortisolism at baseline was mild
(urinary free cortisol level, >1.5 to 2 times the
ULN), moderate (>2 to 5 times the ULN), or
severe or very severe (>5 times the ULN).
Items included in the CushingQoL questionnaire.
1. I have trouble sleeping (I wake up during the night; it takes me a long
time to get to sleep, etc.)
2. I have pain that keeps me from leading a normal life
3. My wounds take a long time to heal
4. I bruise easily
5. I am more irritable, I have sudden mood swings and angry outbursts
6. I have less self-confidence, I feel more insecure
7. I’m worried about the changes in my physical appearance due to my
illness
8. I feel less like going out or seeing relatives or friends
9. I have had to give up my social or leisure activities due to my illness
10. My illness affects my everyday activities such as working or
studying
11. It’s difficult for me to remember things
12. I’m worried about my health in the future
The instructions read: the following sentences refer to what you may think or feel about your Cushing’s syndrome.
Your answers will help us to know how you feel and how much your illness has interfered in your usual activities in
the past 4 weeks. Below each sentence you will find several response choices. Please read each sentence
carefully. After reading each sentence, check the box next to the answer that best describes what you think is
happening to you. There are no rights or wrong answers. We are simply interested in what is happening to you
because of your Cushing’s syndrome.
Eur J Endocrinol 2008;158:623-30.
Figure 3 (previous slide). Changes in Signs and Symptoms of Cushing’s Disease
and Urinary Free Cortisol (UFC) Levels over Time in the Overall Study Population.
Panel A shows systolic blood pressure,
Panel B diastolic blood pressure,
Panel C triglycerides,
Panel D low-density lipoprotein (LDL) cholesterol,
Panel E body weight, and
Panel F health-related quality-of-life (HRQoL) score. HRQoL was measured with
the use of the CushingQoL questionnaire (in which scores range from 0 to 100,
with higher scores indicating better quality of life).
The numbers of patients included in analyses of mean UFC levels at various time
points were as follows: 153 at baseline, 144 at 1 month, 132 at 2 months, 131 at 3
months, 123 at 4 months, 116 at 5 months, 111 at 6 months, 93 at 9 months, and 77
at 12 months. The corresponding numbers of patients included in analyses of the
mean values for signs, symptoms, and quality-of-life scores are shown beneath
each graph. I bars indicate standard errors for both UFC level and clinical signs
and symptoms. To convert the values for triglycerides to mg per deciliter, divide
by 0.01129. To convert the values for LDL cholesterol to mg per deciliter, divide by
0.02586.
RESULTS Twelve of the 82 patients in the 600-μg group and
21 of the 80 patients in the 900-μg group met the primary end
point. The median urinary free cortisol level decreased by
approximately 50% by month 2 and remained stable in both
groups. A normal urinary free cortisol level was achieved
more frequently in patients with baseline levels not
exceeding 5 times the upper limit of the normal range than in
patients with higher baseline levels. Serum and salivary
cortisol and plasma corticotropin levels decreased, and
clinical signs and symptoms of Cushing’s disease
diminished. Pasireotide was associated with hyperglycemiarelated adverse events in 118 of 162 patients; other adverse
events were similar to those associated with other
somatostatin analogues. Despite declines in cortisol levels,
blood glucose and glycated hemoglobin levels increased
soon after treatment initiation and then stabilized; treatment
with a glucose- lowering medication was initiated in 74 of 162
patients.
CONCLUSIONS The significant decrease
in cortisol levels in patients with
Cushing’s disease who received
pasireotide supports its potential use as
a targeted treatment for corticotropin
secreting pituitary adenomas.
(Funded by Novartis Pharma;
ClinicalTrials.gov number, NCT00434148.)
Message
尿中遊離コルチゾール値が正常上限値の1.5倍
以上あるクッシング病の成人患者162人を対象
に、ソマトスタチンアナログpasireotideの効
果を二重盲検第3相試験で検証。600μg投与群、
900μg投与群（各群とも2回/日）の両群で2カ
月目までに尿中遊離コルチゾールの中央値が約
50％と有意に減少し、その後も安定した。
で、LAR製剤とかも出るかもしれないが、お値
段は？．．．