A k F k l i & Kli iAspek Farmakologi & KlinisNadifloxacinNadifloxacin

Abraham SimatupangAbraham Simatupang

Bagian Farmakologi FK UKI

Isi:Isi:

• Aspek Farmakologik (FarmakokinetikAspek Farmakologik (Farmakokinetik, Farmakodinamik)

• Aspek Farmakoterapi (Uji klinik)• Aspek Farmakoterapi (Uji klinik)

Dose of Drugadministered

Absorption Distribution

cokine

tics

Drug concentration in systemic circulation

Dose in tissuesof distribution

Pharmac

Drug concentration t it f ti

Drug metabolised or excreted

at site of actionElimination

amics

Pharmacologic effect

Clinical response rmacod

yna

Toxicity Efficacy

Pha

k difl i

Report No. 005434. Study  No. 006650. Pharmacokinetics and safety evaluation of OPC‐7251 cream after topical  Application in healthy volunteers.

Struktur Nadifloxacin

Termasuk fluorokuinolon topikal yang menghambat konfigurasi supercoiledDNA dengan menghambat DNA‐gyrase.

Spektrum‐luas terhadap bakteria Gr+, termasuk coagulase‐negative Staph. Spp danPropionibacterium acnes et granulosum.

Kadar obat dalam plasma

Ek i l t iEksresi lewat urin

Absorption, distribution and excretion of 14C‐labeled OPC‐7251 l ti i t7251 lotion in rats (Fujio N et al. Jpn Pharmacol Ther 1998; 26: 1119‐ 32)

Percutaneus application:Percutaneus application: • kulit normal: 7.4 mg/kg (rat), Cmax = 36 ng.eq/mL dan menghilang 4 jam kemudianng.eq/mL dan menghilang 4 jam kemudiandengan T½el. = 1.3 jam

• Stripped skin: Cmax = 1416 ng.eq/mL , TmaxStripped skin: Cmax  1416 ng.eq/mL , Tmax20 menit dan menghilang dalam waktu 4 jam dgn T½el. = 1.5 jam.

• Bila diberikan berturut‐turut 7 hari, kadar danpola di hari 1 dan 7 identik.

Kadar radioaktifitas OPC‐7251Kadar radioaktifitas OPC 7251

Mekanisme kerjaMekanisme kerja

• Antibiotika (menghambat DNA‐gyrase)Antibiotika (menghambat DNA gyrase)

• Berpengaruh terhadap sitokin (Kuwahara et al. J. Dermatol. Sci., 38, 47‐55 2005 2005):Dermatol. Sci., 38, 47 55 2005 2005):

1. Inhibits the up-regulation of IL-12 and IFN-γ in PBMC stimulated by P. acnes.

2. Inhibits pro-inflammatory cytokine productions by epidermal keratinocytes stimulated with IFN-γ plus IL-1β.

A ti d i ti it f difl i• Anti‐androgenic activity of nadifloxacin (Inui, S. et al.:J. Dermatol. Sci., 36, 97‐101, 2004).

Effects of nadifloxacin on the production of cytokines by Inhibition of Cytokine Production in vitro

heat-killed P. acnes-treated PBMC in vitro

○: Control ●: Nadifloxacin（NDFX)

IL-1α

5

10

15

20 IL-1β

48

121620

ntra

tion

IL-6

2468

10

○: Control ●: Nadifloxacin（NDFX)

0 0

mR

NA

con

cen

ndar

d)

0

IL-8

10

20

30

40 IL-10

10

20

30

40 IL-12 p40

100200300400500

Rel

ativ

e m

(% o

f sta 0 0 0

100

IFN-γ

5

10

15 TNF-α

102030405060 GM-CSF

5

10

15

20

00 4 8 12 16 20 24 0

10

0 4 8 12 16 20 24

Hours after P. acnes stimulation

00 4 8 12 16 20 24

▪ Cytokine productions were up-regulated by the treatment of PBMC with heat-killed P. acnes.Nadifloxacin inhibited the production of IL 12p 40 and IFN γ▪ Nadifloxacin inhibited the production of IL-12p 40 and IFN-γ.

▪ Nadifloxacin did not inhibit IL-1α and TNF-α production.

Kuwahara, K. et al.:J. Dermatol. Sci., 38, 47-55, 2005

Effects of nadifloxacin on the production of cytokines by Inhibition of Cytokine Production in vitro

heat-killed P. acnes-treated PBMC in vitro

○: Control ●: Nadifloxacin（NDFX)

IL-1α

5

10

15

20 IL-1β

48

121620

ntra

tion

IL-6

2468

10

○: Control ●: Nadifloxacin（NDFX)

0 0

mR

NA

con

cen

ndar

d)

0

IL-8

10

20

30

40 IL-10

10

20

30

40 IL-12 p40

100200300400500

Rel

ativ

e m

(% o

f sta 0 0 0

100

IFN-γ

5

10

15 TNF-α

102030405060 GM-CSF

5

10

15

20

00 4 8 12 16 20 24 0

10

0 4 8 12 16 20 24

Hours after P. acnes stimulation

00 4 8 12 16 20 24

▪ Cytokine productions were up-regulated by the treatment of PBMC with heat-killed P. acnes.Nadifloxacin inhibited the production of IL 12p 40 and IFN γ▪ Nadifloxacin inhibited the production of IL-12p 40 and IFN-γ.

▪ Nadifloxacin did not inhibit IL-1α and TNF-α production.

Kuwahara, K. et al.:J. Dermatol. Sci., 38, 47-55, 2005

Effects of Roxithromycin and Nadifloxacin (in vitro)

English version

Effects of Roxithromycin and Nadifloxacin (in vitro)

1.25 1.5

n=3Mean±S.D.*p<0.05

1.25

1

＊ n=3Mean±S.D.*p<0.05

1.5

1

＊

ｔ-test0.75

0.5

RLU ｔ-test

1

0 5

RLU

0.25

0

4

0.5

0

Roxithromycin

R1881

0

0

0 1 5

1nmol/L

μg/mL

1 2 3 4 0

1 2 3 4 5 6

Nadifloxacin

R1881

0

0

0 1 5

1nmol/L

μg/mL10 50

R1881: synthetic androgen

Inui, S. et al.:J. Dermatol. Sci., 36, 97-101, 2004

Topical quinolone nadifloxacin (OPC‐7251) in bacterial skin disease: clinical evaluation in a multicenter open trial and in 

vitro antimicrobial susceptibility testing(J Dermatologic Treatment 1997; 8: 87‐92)

• Desain: Open phase II pilot study, melihat efikasi dantolerabilitas nadifloxacin pada infeksi kulit superfisial.

• 101 pasien (70 pria 31 wanita) usia: 18 65 tahun• 101 pasien (70 pria, 31 wanita), usia: 18‐65 tahundirekrut dari 9 center. 9 DO, 2 dikeluarkan krnmenyalahi protokol.

• Kriteria inklusi: folikulitis/sycosis vulgaris, impetigo contagiosa, impetiginized dermatitis (mis. atopic dermatitis) atau ada gejala‐gejala: sekurang‐kurangnyadermatitis) atau ada gejala‐gejala: sekurang‐kurangnya5 lesi/krusta, eritema sedang s.d. berat, moderate to severe scaling, moderate to severe erosion and 

llswelling.

• Infeksi kulit sekunder: mengandung 3 dari 5 g ggejala: moderate to severe erythema, moderate to severe scaling, moderate to severe exudation, moderate to severe erosion moderate to severemoderate to severe erosion, moderate to severe swelling.

• Kriteria eksklusi: folikulitis berat, sycosis vulgaris, impetigo contagiosa, dan infeksi kulit ygmemerlukan ab sistemik. Alergi terhadapkuinolon alkoholismus atau drug‐abusekuinolon, alkoholismus atau drug abuse.

• Obat uji: Nadifloxacin 1% topical cream (Otsuka, Japan)

Causative bacteria classified by diagnosisCausative organism

Number of patients

FolliculitisaSuper‐infected dermatitis

Impetigo SycosisSecondarily infected wound

Staph. aureus 22 7 2 8 1 4

β‐hemolytic streptococci

2 1 1

Staph aureus+ streptococci

2 1 1

Coagulase‐negative 47 33 3 4 7negative staph

47 33 3 4 7

P. acnes 1 1

P gran lat mP. granulatum 1 1

Total 75 42 5 14 8 6

a: one patient with a furuncle was included in folliculitisp

Lesions & crusts counting per patient before and after t t t ith difl itreatment with nadifloxacin

Number of patients Lesions (mean) Crust (mean)

P t t t 82 15 87 6 45Pre‐treatment 82 15.87 6.45

Post‐treatment 81 5.70 2.10

P‐value <0.0001 <0.0001

Global assessment of therapeutic effect by physician and patients

Global assessment

Very good Moderate Slight Unchanged Aggravated

and patients

By physician

51 (56.7%) 28 (31.1%) 8 (8.9%) 2 (2.2%) 1 (1.1%)

By patient 50 (57%) 26 (30%) 9 (10%) 1 (1%) 2 (2%)By patient 50 (57%) 26 (30%) 9 (10%) 1 (1%) 2 (2%)

Judgment of objective symptoms pre‐ and after treatment with nadifloxacin

Symptom Not present

Mild Moderate

Severe Total P‐value

ErythemaPre‐treatment 0 0

52 (57.8%)

38 (42.2%) 90 

<0 0001(100%)

<0.0001

Post‐treatment28 

(31.1%)49

(54.4%)13 

(14.5%)0

ScalingPre‐treatment

14 (15.6%)

26 (28.9%)

39 (43.3%)

11 (12.2%) 90

0 000190 

(100%)<0.0001

Post‐treatment64 

(71.1%)25 

(27.8%)1 

(1.1%)0

ExudationPre‐treatment 0 9 (10%)

57 (63.3%)

24 (26.7%) 90(63.3%) (26.7%) 90 

(100%)<0.0001

Post‐treatment61 

(67.8%)24 

(26.7%)4 (4.4%)

1 (1.1%)

ErosionPre‐treatment

3 (3 3%)

5 (5 6%)

56 (62 2%)

26(28 9%)(3.3%) (5.6%) (62.2%) (28.9%) 90 

(100%)<0.0001

Post‐treatment66 

(73.3%)21 

(23.3%)3 

(3.3%)0

SwellingPre‐treatment

7  16  49  18 Pre treatment

(7.8%) (17.8%) (54.4%) (20%) 90 (100%)

<0.0001

Post‐treatment60 

(66.7%)22 

(24.4%)8 

(8.9%)0

Eradication of causative organismEradication of causative organism

Causative organismNumber of strains Eradicated/total 

(%)Before treatment After treatment

Staph. aureus 24 420/24 (83%)

β‐hemolytic 4 04/4 β hemolytic 

streptococci 4 0/

(100%)

Coagulase‐negative staph 47 15

32/47(68%)

P. acnes 1 10/1(0%)

P granulatum 1 01/1 

P. granulatum 1 0(100%)

Total 77 2057/77 (74%)

Number of bacterial strains inhibited at the concentrations of nadifloxacin shown comparing pre & post treatment

Organism MIC (μg/ml)

<0.05 0.1 0.2 0.39 0.78 1.56 3.13 6.25 12.5 50 ≥100 Total

Staph Pre 20 3 1Staphaureus

Pre‐th/

20 83%

313%

14%

24

Post‐th/

583%

117%

6

β‐hemolytic streptococci

Pre‐th/ 1

25%2

50%1

25%4

P 1 1Post‐th/

150%

150%

2

Coagulase‐negstaph

Pre‐th/

4671%

1117%

11%

35%

11%

35%

65staph

Post‐th/

4066%

1321%

12%

12%

35%

23%

12%

61

P acnesPre‐ 3 6 14 8 3

34P. acnesth/ 9% 18% 41% 24% 9%

34

Post‐th/

1020%

1326%

1428%

1224%

12%

50

Effect of nadifloxacin on atopic dermatitis with methicillin‐resistant staphylococcus aureus in young p y y g

children (Kimata H. Eur J Pediatr 1999; 158: 949‐54)

• Desain open label parallel group pada 35Desain open label, parallel group, pada 35 anak (20 laki, 15 perempuan) usia 2‐11 bulan.

• Control (n=17): NSAID ointment (bufexamac)• Control (n=17): NSAID‐ointment (bufexamac) 3 dd 1

N difl ( 18) N difl i b f• Nadifl. (n=18)  : Nadifloxacin +  bufexamac3 dd 1 

Effect of nadifloxacinEffect of nadifloxacin

GSkin culture Skin score Anti‐SEA IgE Anti‐SEB IgE

GroupBefore After Before After Before After Before After

Control 17/17 17/17 19 ± 5 18 ± 4 0.5  ± 0.3 0.6 ± 0.4 0.7 ± 0.4 0.8 ± 0.4

Nadifloxacin 18/18a 0/18b 20 ± 4c 9 ± 3d 0.6 ± 0.4e0.3 ±0.1f

0.8 ±0.3c

0.3 ± 0.1d

* Number of patients with MRSA/total number of patients are shownSkin score, anti‐SEA IgE and anti‐SEB IgE (OD 410 mm) are expressed as mean ± SDa versus b p < 0.0001 (paired sign test)c versus d p < 0.0001 (paired t‐test)e versus f p < 0.001 (paired t‐test)e versus f p < 0.001 (paired t test)

Tidak ditemukan adverse events:  Articular cartilago formationTidak ditemukan kelainan darah dan urinTidak ditemukan induksi fluoroquinolone‐resistant bacteria Follow‐up 3 bulan:  tdk ditemukan MRSA 

Mechanisms of Nadifloxacin in Acne Vulgaris

Open comedon

Micro comedon Closed comedon Inflammatorylesions

N t hil /

Sebumsecretion Keratinization

Neutrophils/Lymphocytes/Keratinocytes

NDFX

P. acnesCytokines

IL‐1αAndrogen

Inflammatory/Immuneresponse to P acnesresponse to P. acnes(CD4+ T, MΦ, Keratinocyte)

Dr.med. Abraham Simatupang, MKes.Email: farmakologiuki@yahoo.com