Phase I study of flutamide, a nonsteroidal antiandrogen, in patients with prostatic cancer

1)125, 250, 375および500mgの用量の単回経口投与を受けた計11名の患者では副作用を認めなかった。2)375, 750, 1, 125および1, 500mg/日の用量の1日3分割経口投与を連日28日間行ったところ, 1, 500mg/日の投与を受けた4例中1例に胃部不快感, 悪心・嘔吐, 食欲不振の副作用症状を認めた。他の用量を投与された9例では副作用の訴えはなかった。3)臨床検査値の異常は375mg/日群の3例では認められなかったが, 他の用量群で9例中5例にトラスアミナーゼの上昇を認めた。特に, 1, 500mg/日群では評価可能な3例の全例に異常値を見た。4)LHの濃度の有意な上昇を認めた。5)客観的効果が各群において3例中2例に観察された。また, 疼痛, 排尿障害, PSの改善が認められた。6)投与後速やかに吸収され, 大部分が水酸化を受けたOH-フルタミドとして血液中に存在していた。また, 単回投与と比べ, 連日投与後のOH-フルタミドの半減期には大差を認めなかったがCmaxおよびAUCは増加していた。7)第2相臨床試験の試験用量としては, 375mg/日から1, 125mg/日の範囲が望ましいと結論された
A phase I study of orally administered flutamide (a pure anti-androgen) was performed in 26 patients with prostatic cancer. No side effects were observed in 11 patients receiving single doses of either 125, 250, 375 or 500 mg. However, in the daily dosing schedule of 375, 750, 1125 and 1, 500 mg/day doses, where medication was taken in three divided doses, discomfort in the stomach, nausea, vomiting and anorexia were experienced in one of the four patients receiving the highest dose of 1, 500 mg. Nine patients receiving the other doses did not complain of toxic symptoms. Laboratory values did not change in the three patients receiving the lowest 375 mg/day dose, but elevation of transaminase was observed in five of the nine patients given higher doses. This elevation was observed in all the three patients receiving 1, 500 mg/day dose. Among the serum hormone levels, significant increases of luteinizing hormone were observed. As for efficacy, objective responses were observed in two of the three patients in each of the four daily dosing groups. Improvement of pain, voiding obstruction symptoms, and performance status were also observed. Flutamide was found to be absorbed rapidly and to exist as a hydroxylated form (hydroxy-flutamide) in the plasma. The half-life of hydroxy-flutamide was similar in the single and daily administration, but the peak concentration and area under the concentration versus time curve in the daily administration became greater than those in the single administration. In conclusion, flutamide should be examined for efficacy and safety using doses of 375 to 1, 125 mg/day in the phase II study.