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Table 5 Therapeutic effect of RBT and RFP on M. tuberculosis H37Rv infection of mice
(Reference 31)
Interval between infection and treatment Antibiotics ED50 (mg /kg)
3 daysRBTRFP
0.943.57
10 daysRBTRFP
0.765.35
Duration after infection (weeks)
SpleenLo
g 10 C
FU/m
L6
4
2
02 4 6 8
Control
Control
Rifabutin(Pre-treated)
Duration after infection (weeks)
Lung
Log 1
0 CFU
/mL
6
4
2
02 4 6 8
Rifabutin(Pre-treated)
Fig. 3 Prophylactic effect of RBT on M.intracellulare infection of micePre-treated: prophylactic administration (RBT was administered before infection.) (Reference 32, Fig. 5)
Fig. 4 Mean plasma concentration profiles of RBT and 25-O-desacetylrifabutin in healthy western volunteers after administration of a single oral dose of RBT 300, 450 and 600 mg under fasted condition(n=9, mean+SEM)
New Anti-Mycobacterial Agent, Rifabutin /A.Kurashima et al. 747
Table 6 The dosing recommendations on the concomitant use of RBT and common drugs for the treatment of mycobacterial diseases including tuberculosis
Table 7 Antibacterial efficacy of RBT in the treatment of newly diagnosed tuberculosis
NNRTI:non-nucleoside reverse transcriptase inhibitors, *: Not approved in Japan
Note1) : Dosing recommendation of RBT was decided based on the recommended dose in DHHS guidelines50)
2) : In DHHS guidelines50)
3) : HIV infection and its complicating disease, diagnosis and treatment handbook 51)
4) : Although DHHS guidelines defined the reference dose as 1/4, RTV increase the AUC of RBT to 430%. Consequently, it defined that“do not coadminister with RTV 600 mg BID”. Except for RTV-boosted treatment (concomitant treatment with ATV, f-APV, DRV, IDV, LPV, SQV, TPV).
5) : Although DHHS guidelines did not recommend it, it defined caution for combination use by drug interaction data based on the pharmacokinetics and management in package insert.
6) : The concomitant use of RBT and voriconazole was contraindication, because voriconazole is increase more than 300% (331%) AUC of RBT.
7) : Trough concentration of RBT
RBTRFP 600 mg
150 mg 300 mgW12 W24 LVO W12 W24 LVO W12 W24 LVO
Successrate*
87%(150/173)
72%(124/173)
94%(162/173)
83%(140/169)
70%(119/169)
92%(155/169)
86%(147/171)
70%(119/171)
89%(153/171)
W12: Week 12, W24: Week 24 (End of Treatment), LVO: Last Valid Observation, RBT: Rifabutin, RFP: Rifampicin *Success rate (Bacteriological conversion) among all patients (patients with positive baseline culture) enrolled.Success was defined as two consecutive negative cultures including W24 and last valid observation. Companion drugs: Isoniazid (24 weeks), Ethambutol+Pyrazinamide (8 weeks)
New Anti-Mycobacterial Agent, Rifabutin /A.Kurashima et al. 749
Table 8 Frequency of drug resistance in M. tuberculosis isolated from patients with drug-resistant tuberculosis*
Table 9 Success rate* (Bacteriological conversion) of rifabutin in patients with drug-resistant tuberculosis* (Non-comparative study)
Table 10 Success rate* (Bacteriological conversion) by rifabutin dosage (mg/day) in non-controlled studies on non-tuberculous mycobacterial infection in AIDS patients
Resistant to;RFP INH SM EB
Frequency of resistance(Resistant /Tested)
88%(203/230)
89%(204/230)
73%(161/222)
53%(105/197)
RFP: Rifampicin, INH: Isoniazid, SM: Streptomycin, EB: Ethambutol*: The details are shown in the text.
Companion drugs: Available anti-tuberculous drugs according to susceptibility tests. RBT: Rifabutin*: The details are shown in the text.** Success rate (Bacteriological conversion) among all patients (patients with positive baseline culture) enrolled. Success was defined as two consecutive negative cultures including end of treatment and last valid observation.1) Patients with positive baseline culture2) Patients with positive baseline culture and bacteriological assessment at the target visitEOT: End of Treatment, LVO: Last Valid Observation
RBT1) Patients evaluable success2)
W12 EOT LVO W12 EOT LVO
Success rate** 34%(76/221)
21%(46/221)
33%(74/221)
48%(76/158)
37%(46/123)
34%(74/220)
RBT dosage (mg /day) 150 300 450 600
Success rate* 7%(7/103)
16%(15/93)
54%(19/35)
55%(17/31)
RBT: Rifabutin, Companion drugs: Isoniazid, Clofazimine, Ethambutol* Success was defined as two consecutive negative cultures including last valid observation.
750 結核 第85巻 第10号 2010年10月
し(注 2),投与期間は12カ月間とした。一部無作為化
試験では,RBT 150 mg,300 mg,450 mgに被験者を割り
付けた。いずれの試験においても,症例ごとに in vitroで
の感受性成績を基に,各種抗結核薬を併用した。
治験に組み入れられた症例の結核症病状の内訳は,中
等度進展例37%(77/208),高度進展例58%(121/208)で
あり,ほとんどの症例が中等度または高度進展例であっ
た。治験開始時に分離された結核菌の in vitroでの感受
性検査結果をTable 8に示す。RFPに対し88%(203/230),
INHに対し89%(204/230)の耐性化を示しており,結核
症治療の第一選択基本薬として用いられるRFPおよび
INHに対し,ほぼ90%耐性を示した。
細菌学的有効性(菌陰転率)をTable 9に示した。RBT
投与例における細菌学的有効性は,投与終了時では21%
(46/221),最終観察時点では33%(74/221)であり,有効
性評価対象例に限ると,投与終了時では37%(46/123),
最終観察時点では34%(74/220)であった。これらの試
験の投与期間は試験によって異なるが,投与終了時,最
終観察時点とも投与期間にかかわらず,ほぼ同程度の細
菌学的有効性が得られた。
(注 2)非盲検非対照試験 5試験のうち 1試験(フランスで実
施)では,試験開始時には50 kg未満の場合300 mg,50 kg以上
の場合450 mgとしたが,試験実施中にリファブチンの効果が
十分ではないと判断されたことから,50 kg未満の場合450 mg,
50 kg以上の場合600 mgに用量変更された。
( 2)NTM症治療試験
①HIV感染者
RBTのHIV感染者を対象としたNTM症治療効果を検
討した試験は,多施設共同非盲検試験が 2試験,一部無
作為化した多施設共同非盲検試験 2試験および単施設非
盲検試験 1試験の計 5試験を併合解析して評価した。対
象患者は,組み入れ時の培養・同定検査結果に基づき,
NTM症と確定診断されたか,または疑診例と判定された
HIV感染者とした。RBT投与期間は 6~24カ月とした。
投与量は試験により異なるが,150~600 mgが投与され
た。なお,治験開始時に検出された原因菌のほとんどが
MACで,その他としてM.xenopiが 5例,M.gordonaeが
1例含まれていた。また,併用薬は試験実施当時使用可
Dosage(mg/day)
Isolated Mycobacterium
No. ofsubjects
Bacteriologic response
eradication persistence
300MACM.xenopi
4 2
4 (100%) 2 (100 )
0 0
450MACM.xenopi
1610
8 ( 50 ) 5 ( 50 )
8 5
600MACM.xenopi
2 6
2 (100 ) 3 ( 50 )
0 3
TotalsMACM.xenopiTotal
221840
14 ( 64 ) 10 ( 56 ) 24 ( 60 )
8 816
Table 11 Bacteriologic response by rifabutin dosage (mg/day)
Table 12 Incidence of MAC bacteremia in patients with HIV
Table 13 Adverse events in the clinical trials of RBT development1)
RBT: Rifabutin, AE: Adverse event, −: None 1) The table enumerates adverse experiences that occurred at a frequency of 1% or greater, among the patients treated with rifabutin in studies.2) Urine may be colored brown-orange with rifabutin and some of its metabolites. Urine abnormality is a color change of urine in orange, which is generally observed in the treatment with rifabutin. This event was recorded in only the“Prophylaxis study of invasive MAC infection in HIV positive patients”, not the others, therefore, the
incidence of this event is not calculated.
New Anti-Mycobacterial Agent, Rifabutin /A.Kurashima et al. 753
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1050.50) DHHS Panel on Antiretroviral Guidelines for Adults and
Adolescents: Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescent. 2008, 1.
Abstract This is a review of non-clinical and clinical study results of rifabutin (Mycobutin®, RBT) which was approved as a new anti-mycobacterial agent 38 years after rifampicin (RFP) was approved in Japan. The anti-bacterial actions of RBT were similar to those of RFP, but its potency was stronger (4 to 32 times in MIC90). RBT showed excellent penetration in cells (9 times in neutrophil, 15 times in monocyte, against plasma concentration) and in tissues (5 to 10 times in pulmonary tissue). Clinical efficacy of RBT (150 mg, as well as 300 mg daily) was comparable to that of RFP 600 mg daily, in the treatment of newly diagnosed tuberculosis, drug-resistant tuberculosis, and the NTM diseases. In addition, RBT 300 mg showed significant prophylactic effect on the development of disseminated MAC infection in HIV positive subjects. Most of the adverse events of RBT were the same as those of RFP, including drug-drug interactions related to the induction of CYP3A4. The concomitant use of RBT (over 450 mg) with
clarithromycin induces uveitis, which warrants special atten- tion. It is expected that the efficacy and safety of RBT in Japanese subjects will be evaluated in Japan through the accumulation of clinical experience.
Key words : Rifabutin, Anti-mycobacterial agent, Tuberculo- sis, Non-tuberculous mycobacteriosis, AIDS, HIV infection
1Fukujuji Hospital, Japan Anti-Tuberculosis Association (JATA), 2Research Institute of Tuberculosis, JATA, 3Clinical Research, Development Japan, and, 4Drug Safety Research & Development, Pfizer Japan Inc.
Correspondence to: Masaaki Abe, Clinical Research, Devel- opment Japan, Pfizer Japan, 3_22_7, Yoyogi, Shibuya-ku, Tokyo 151_8589 Japan. (E-mail : masaaki.abe@pfizer.com)