Falecalcitriol Research Articles

Efficacy of Falecalcitriol for Post-operative Hypoparathyroidism

進行下咽頭癌や声門下癌の根治手術時に，傍気管リンパ節の郭清とともに甲状腺，副甲状腺の全摘あるいは亜全摘をおこなうことがある。術後性副甲状腺機能低下症に対して，腸管におけるカルシウム吸収促進を期待して，活性型ビタミンD製剤を投与し，血清カルシウム濃度の調整がおこなわれる。カルシウム製剤の投与は血中，尿中カルシウム濃度の大幅な上昇をきたすことがあり，腎機能に対する悪影響が懸念される。われわれは副甲状腺機能低下症例に活性型ビタミンD3製剤であるファレカルシトリオール（フルスタン®）を投与し，その効果を検討した。対象は癌術後の副甲状腺機能低下症13症例である。ビタミンD3製剤をアルファカルシドールからファレカルシトリオールに変更し，投与前，投与中の血清，尿中カルシウムなどを指標に，併用するカルシウム製剤とファレカルシトリオールの投与量を調整した。13例中1例は副甲状腺機能が回復したため中止し，残り12例全例でカルシウム製剤を中止できた。これらの症例の血清カルシウム値は正常で，テタニー症状もない。ファレカルシトリオールの長時間作用と強力な小腸カルシウム吸収促進作用は，術後性副甲状腺機能低下症のカルシウム濃度の調整に有効にはたらき，過剰なカルシウム負荷を防ぐことができ，重篤な有害事象もみられなかった。

Falecalcitriol as a new therapeutic agent for secondary hyperparathyroidism

The 26 and 27 positions of vitamin D molecular structure of calcitriol were fluorinated with 3 atoms of fluorine each and the new compound was named falecalcitriol (F6). This new compound was found to be 10 to 100 times more active compared with calcitriol depending on the target organs. As a mechanism of strong action of F6 it was discovered that F6 is hydroxylated at 23 position which has almost the same activity as the mother compound. It was also demonstrated that the PTH suppressive effect was relatively stronger than the calcium absorption action from the intestine. Thus F6 was authorized to be applied to the treatment of secondary hyperparathyoroidism in hemodialysed patients as well as to the treatment of hypoparathyroidism.

Vitamin D therapy in renal osteodystrophy

In Japan, three oral preparations (calcitriol, alfacalcidol and falecalcitriol) and two intravenous preparations (calcitriol and maxacalcitol) are now available for the vitamin D(3) therapy in renal osteodystrophy. In general, oral therapy is indicated for mild cases of secondary hyperparathyroidism (intact PTH<300 pg/mL) to maintain adequate level of serum PTH except "calcitriol oral pulse therapy" for moderate to severe cases. Recently, intravenous therapy has been introduced to treat more severe cases by using the advantage of rapid clearance of these metabolites. In order to use these preparations safely, adequate level of both serum intact PTH (150-300 pg/mL) and Ca/P product (<55) should be maintained to prevent from adynamic bone and vascular calcification.

Recent medication to renal osteodystrophy

P control according to phosphorus (P) adsorbent by the medication to renalosteodystrophy (ROD) and the medical treatment by active vitamin D are main. Although the present calcium carbonate is used as P adsorbent, sufficient quantity to control P for hypercalcemia may be unable to be prescribed for the patient. The near future use of sevelamer hydrochloride under development which does not cause hypercalcemia will be attained at such a case. Although alphacalcidol and calcitriol are used for some time, the present clinical use of the vitamin derivatives which made calcitriol basic structure and made the action powerful, such as maxacalcitol and falecalcitriol, is developed and carried out. Thus, although the choice of vitamin D medical treatment increased by clinical use of much active vitamin D or its derivative having been attained and the adaptation range also spread, there is no view which now unified how such a medicine would be used properly. The validity to ROD, such as calcitonin, vitamin K, and bisphosphonates, is examined in addition to P adsorbent, or vitamin D and its derivative, and calcimimetics is developed as a new medicine.

Renal failure and vitamin D

Secondary hyperparathyroidism (2HPT), a common disorder in patients with chronic renal failure, develops in response to phosphate retention and low serum 1,25-dihydroxyvitamin D(3) [1,25 (OH) (2)D(3), calcitriol] . Replacement therapy with calcitriol or its precursor 1alpha-hydroxyvitamin D(3) [1alpha (OH) D(3), alfacalcidol] often produces hypercalcemia and hyperphosphatemia in these patients. Several vitamin D analogues have been developed that retain the direct suppressive action of 1,25 (OH) (2)D(3) on the parathyroid glands but have less calcemic activity, therapy offering a safer and more effective means of controlling 2HPT. 1,25-D dihydroxy-19-norvitamin D(2) (19-nor D(2)) and 1alpha-hydroxyvitamin D(2) (1alphaOHD(2)) are available in the United States and 1,25-dihydrox-22-oxavitamin D(3) (22-oxacalcitriol, OCT) and 1,25-dihydroxy-26,26,26,27,27,27-hexafluorovitamin D(3) [1,25 (OH)(2)26,27F(6)D(3), falecalcitriol] have been approved for use in Japan. Animal studies have demonstrated that OCT and 19-nor D(2) have a wider therapeutic window for suppression of parathyroid hormone (PTH) because of their lower calcemic activities of OCT has been attributed to its rapid clearance which prevents sustained effects on intestinal calcium absorption and bone resorption, but still allows a prolonged suppression of PTH gene expression and parathyroid cell growth. The calcemic activity of 19-norD(2) diminishes with the duration of treatment by as yet unknown mechanisms. The lower toxicity of 1alphaOHD(2), compared 1alphaOHD(3). has also been noted with chronic, but not acute administration, perhaps due to differential metabolism. The unique actions of falecalcitriol may also result from altered metabolism. A clear understanding of the molecular basis for the selectivity of vitamin D analogues on parathyroid function may allow the design of even more effective analogues.