注射薬pazufloxacin 1回1,000mg 1日2回投与時の細菌性肺炎を対象とした臨床第III相試験

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  • A clinical phase III study of pazufloxacin in patients with bacterial pneumonia

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Pazufloxacin（PZFX）1,000 mg×2回/日投与時のStreptococcus pneumoniaeに対する有効性を評価するため，ヒト血清中蛋白非結合体濃度を再現したin vitro pharmacokinetic（PK）modelを用い，殺菌効果ならびに耐性菌出現の有無について500 mg×2回/日投与時と比較検討し，以下の成績を得た。　1）S. pneumoniae D-979に対し，1,000 mg×2回/日投与時では24時間後に再増殖は認められず，強い殺菌効果を示した。500 mgおよび1,000 mg×2回/日投与時の殺菌曲線上面積（area above the killing curve：AAKC）は76.1および＞104 ΔLog CFU・h/mLであり，1,000 mg×2回/日への増量により殺菌効果は増強した。本菌株に対する1,000 mg×2回/日投与時のfree AUC（fAUC）/MICは35.3で，500 mg×2回/日投与時に比べ2.4倍大きかった。　2）PZFX 500 mg×2回/日投与時の24時間後の菌液では，薬剤非添加時に比べ感受性が1/2に低下したポピュレーションが一部認められたが，GyrA, GyrB, ParCおよびParEのキノロン耐性決定領域（quinolone resistance-determining region：QRDR）にアミノ酸変異はなく，reserpine添加により影響を受ける薬剤排出ポンプの発現亢進は認められなかった。一方，1,000 mg×2回/日投与時では感受性の低下したポピュレーションは認められなかった。　以上，PZFX 1,000 mg×2回/日の用量は，S. pneumoniaeに対し，有効性の確保ならびに耐性菌出現抑制の観点から有用である可能性が示唆された。

The clinical efficacy and safety of pazufloxacin(PZFX), an injectable fluoroquinolone antimicrobial, administered at a dose of 1,000 mg twice daily, were evaluated for 99 subjects with bacterial pneumonia, including severe or intractable pneumonia or that caused by Streptococcus pneumoniae in an open uncontrolled clinical study. The relationship between pharmacokinetics and the clinical efficacy or safety of PZFX was also investigated. Clinical efficacy rate at the end of treatment was 81.8% (81/99 subjects) in all pneumonia, 76.9% (20/26 subjects) in pneumonia caused by S. pneumoniae, and 81.3% (13/16 subjects) in severe or intractable pneumonia including 4 caused by S. pneumoniae. Eradication rate at the end of treatment was 96.8% (60/62 strains) in all pneumonia, 100% (25/25 strains) in pneumonia caused by S. pneumoniae, and 100% (9/9 strains) in severe or intractable pneumonia including 4 caused by S. pneumoniae. Main causative organisms were 26 S. pneumoniae, 17 Haemophilus influenzae, 8 Moraxella(Branhamella)catarrhalis, and 7 Klebsiella pneumoniae. PZFX MICs against S. pneumoniae were 0.78-3.13 μg/mL, and MIC90 was 1.56 μg/mL. PK parameters by 1,000 mg dose were 137.0 μg・hr/mL for AUC and 32.0 μg/mL for Cmax. Clinical efficacy rate were 77.3% (34/44 subjects) and 78.0% (32/41 subjects) in those whose fAUC/MIC and Cmax/MIC exceeded the target. Eradication rate were 98.1% (51/52 strains) and 98.0% (48/49 strains) in those whose fAUC/MIC and Cmax/MIC exceeded the target. Adverse events were observed in 114 of 140 subjects (81.4%), and adverse drug reactions in 93 (66.4%). Severe adverse drug reactions were one each of asthma and interstitial pneumonia. Adverse drug reactions exceeding 5% were injection site in 36.4% (51/140 subjects), increased ALT in 12.1% (17/143 subjects), increased AST in 12.1% (17/140 subjects). Most adverse drug reactions were mild or moderate and similar to those previously known for PZFX. A relationship was seen between the incidence of moderate or severe adverse events and AUC and/or Cmax. To ensure safety, it is vital to adequately observe and consider the interval of drug-administration or dosage adjustment in low Ccr subjects. We concluded that 1,000 mg dose twice daily is useful in those with bacterial pneumonia, including pneumonia severe or intractable or caused by S. pneumoniae.

日本化学療法学会雑誌, 58(6), pp.664-680; 2010

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