Pharmacological & Clinical Aspects Of Nadifloxacin

Aspekk Farmakologi A F k l i & Klinis & Kli i Nadifloxacin Abraham Simatupang Abraham Simatupang Bagian Farmakologi FK UKI

Isi: • Aspek Farmakologik (Farmakokinetik,  (Farmakokinetik Farmakodinamik) • Aspek Farmakoterapi (Uji klinik)

Absorption Drug concentration in  systemic circulation

Distribution

Dose in tissues of distribution

Pharmaccokinetics

Dose of Drug administered

Drug metabolised or  excreted

Drug concentration  at site of action t it f ti

Pharmacodynaamics

Elimination Pharmacologic effect Clinical response Toxicity

Efficacy

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

Struktur k Nadifloxacin difl i

Termasuk fluorokuinolon topikal yang menghambat konfigurasi supercoiled DNA dengan menghambat DNA‐gyrase. Spektrum‐luas terhadap bakteria Gr+, termasuk coagulase‐negative Staph. Spp dan Propionibacterium acnes et granulosum.

Kadar obat dalam plasma

Ek Eksresi i lewat l t urin i

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

Percutaneus application:  application: • kulit normal: 7.4 mg/kg (rat), Cmax = 36  ng.eq/mL dan menghilang 4 jam kemudian 4 jam kemudian dengan T½el. = 1.3 jam • Stripped skin: Cmax Stripped skin: Cmax = 1416 ng.eq/mL 1416 ng.eq/mL , Tmax , Tmax 20 menit dan menghilang dalam waktu 4 jam  dgn T½el. = 1.5 jam. • Bila diberikan berturut‐turut 7 hari, kadar dan pola di hari 1 dan 7 identik.

Kadar radioaktifitas OPC Kadar radioaktifitas OPC‐7251 7251

Mekanisme kerja • Antibiotika (menghambat DNA DNA‐gyrase) gyrase) • Berpengaruh terhadap sitokin (Kuwahara et al. J.  Dermatol. Sci., 38, 47‐55 Dermatol. Sci., 38, 47 55 2005 2005): 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.

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

Inhibition of Cytokine Production in vitro

Effects of nadifloxacin on the production of cytokines by heat-killed P. acnes-treated PBMC in vitro

Relative m mRNA concen ntration (% of standard)

○: Control 20 IL-1α 15 10 5 0 40 IL-8 30 20 10 0 15 IFN-γ 10 5 0

0

4

8

12

16

20

24

20 IL-1β 16 12 8 4 0 40 IL-10 30 20 10 0 60 TNF-α 50 40 30 20 10 0 0 4 8

12

16

20

24

●: Nadifloxacin（NDFX)

10 IL-6 8 6 4 2 0 500 IL-12 p40 400 300 200 100 0 20 GM-CSF 15 10 5 0 0 4 8 12

16

20

Hours after P. acnes stimulation

▪ Cytokine productions were up-regulated by the treatment of PBMC with heat-killed P. acnes. ▪ Nadifloxacin inhibited the production of IL-12p IL 12p 40 and IFN IFN-γ. γ ▪ Nadifloxacin did not inhibit IL-1α and TNF-α production. Kuwahara, K. et al.:J. Dermatol. Sci., 38, 47-55, 2005

24

Inhibition of Cytokine Production in vitro

Effects of nadifloxacin on the production of cytokines by heat-killed P. acnes-treated PBMC in vitro

Relative m mRNA concen ntration (% of standard)

○: Control 20 IL-1α 15 10 5 0 40 IL-8 30 20 10 0 15 IFN-γ 10 5 0

0

4

8

12

16

20

24

20 IL-1β 16 12 8 4 0 40 IL-10 30 20 10 0 60 TNF-α 50 40 30 20 10 0 0 4 8

12

16

20

24

●: Nadifloxacin（NDFX)

10 IL-6 8 6 4 2 0 500 IL-12 p40 400 300 200 100 0 20 GM-CSF 15 10 5 0 0 4 8 12

16

20

Hours after P. acnes stimulation

▪ Cytokine productions were up-regulated by the treatment of PBMC with heat-killed P. acnes. ▪ Nadifloxacin inhibited the production of IL-12p IL 12p 40 and IFN IFN-γ. γ ▪ Nadifloxacin did not inhibit IL-1α and TNF-α production. Kuwahara, K. et al.:J. Dermatol. Sci., 38, 47-55, 2005

24

English version

Effects of Roxithromycin and Nadifloxacin (in vitro) 1.5

1.25 ＊

n=3 Mean±S.D. *p<0.05 ｔ-test

0.75

1

RLU

RLU

1

n=3 Mean±S.D. *p<0.05 ｔ-test

＊

0.5

05 0.5 0.25

1

6

0

5 10 1nmol/L

50

4

0 R1881 0

Nadifloxacin

5

μg/mL

3

1 5 1nmol/L

2

3

0

0 1

2

0 R1881 0

Roxithromycin

4

1

0

μg/mL

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 dan tolerabilitas nadifloxacin pada infeksi kulit superfisial. • 101 pasien 101 pasien (70 pria, 31 wanita), usia: 18‐65 tahun (70 pria 31 wanita) usia: 18 65 tahun direkrut dari 9 center. 9 DO, 2 dikeluarkan krn menyalahi protokol. • Kriteria inklusi: folikulitis/sycosis vulgaris, impetigo  contagiosa, impetiginized dermatitis (mis. atopic  dermatitis) atau ada gejala‐gejala: sekurang‐kurangnya dermatitis) atau gejala‐gejala: sekurang‐kurangnya 5 lesi/krusta, eritema sedang s.d. berat, moderate to  severe scaling, moderate to severe erosion and  swelling. ll

• Infeksi kulit sekunder: mengandung g g 3 dari 5  gejala: moderate to severe erythema, moderate  to severe scaling, moderate to severe exudation,  moderate to severe erosion moderate to severe moderate to severe erosion, moderate to severe  swelling. • Kriteria eksklusi: folikulitis berat, sycosis vulgaris,  impetigo contagiosa, dan infeksi kulit yg memerlukan ab sistemik. Alergi terhadap kuinolon alkoholismus atau drug kuinolon, alkoholismus drug‐abuse abuse. • Obat uji: Nadifloxacin 1% topical cream (Otsuka,  Japan)

Causative bacteria classified by diagnosis Causative  organism

Number of  Folliculitisa patients

Super‐ infected  dermatitis

Impetigo

Sycosis

Secondarily  infected  wound

2

8

1

4

Staph. aureus

22

β‐hemolytic  streptococci

2

1

1

Staph aureus + streptococci

2

1

1

Coagulase‐ negative negative  staph

47

33

P. acnes

1

1

P gran lat m P. granulatum

1

1

Total

75

42

7

a: one patient with a furuncle was p included in folliculitis

3

4

7

5

14

8

6

Lesions & crusts counting per patient before and after  t t treatment with nadifloxacin t ith difl i Number of patients Lesions (mean)

Crust (mean)

P t t Pre‐treatment t

82

15 87 15.87

6 45 6.45

Post‐treatment

81

5.70

2.10

<0.0001

<0.0001

P‐value

Global assessment of therapeutic effect by physician  and patients and patients Global  assessment

Very good

Moderate

Slight

Unchanged

Aggravated

By  physician

51 (56.7%)

28 (31.1%)

8 (8.9%)

2 (2.2%)

1 (1.1%)

By patient By patient

50 (57%) 50 (57%)

26 (30%) 26 (30%)

9 (10%) 9 (10%)

1 (1%) 1 (1%)

2 (2%) 2 (2%)

Judgment of objective symptoms pre‐ and after treatment with  nadifloxacin Symptom Erythema

Scaling

Exudation

Erosion

Swelling

Not  present

Mild

Moderat e

Severe

Pre‐treatment

0

0

52  (57.8%)

38  (42.2%)

Post‐treatment

28  (31.1%)

49 (54.4%)

13  (14.5%)

0

Pre‐treatment

14  (15.6%)

26  (28.9%)

39  (43.3%)

11  (12.2%)

Post‐treatment

64  (71.1%)

25  (27.8%)

1  (1.1%)

0

Pre‐treatment

0

9 (10%)

57  (63.3%)

24  (26.7%)

Post‐treatment

61  (67.8%)

24  (26.7%)

4 (4.4%)

1  (1.1%)

Pre‐treatment

3  (3 3%) (3.3%)

5  (5 6%) (5.6%)

56  (62 2%) (62.2%)

26 (28 9%) (28.9%)

Post‐treatment

66  (73.3%)

21  (23.3%)

3  (3.3%)

0

Pre‐treatment Pre treatment

7  (7.8%)

16  (17.8%)

49  (54.4%)

18  (20%)

Post‐treatment

60  (66.7%)

22  (24.4%)

8  (8.9%)

0

Total

90  (100%)

P‐value

<0 0001 <0.0001

90  90 (100%)

<0.0001 0 0001

90  90 (100%)

<0.0001

90  (100%)

<0.0001

90  (100%)

<0.0001

Eradication of causative organism Eradication of causative organism Causative organism

Number of strains

Eradicated/total  (%)

Before treatment

After treatment

Staph. aureus

24

4

20/24  (83%)

β hemolytic  β‐hemolytic streptococci

4

0

4/4  / (100%)

Coagulase‐negative  staph

47

15

32/47 (68%)

P. acnes

1

1

0/1 (0%)

P granulatum P. granulatum

1

0

1/1  (100%)

Total

77

20

57/77  (74%)

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

Staph aureus

β‐ hemolytic  streptoco cci

MIC (μg/ml) <0.05

0.1

0.2

Pre‐ Pre th/

20  20 83%

3 13%

1 4%

Post‐ th/

5 83%

1 17%

Pre‐ th/

0.39

P acnes P. acnes

Pre‐ th/

1.56

3.13

6.25

12.5

50

≥100

Total 24 6

1 25%

2 50%

Post‐ P th/ Coagulas e‐neg staph

0.78

1 25%

4

1 50%

1 50%

1 1%

3 5%

1 1%

3 5%

65

2 3%

1 2%

61

2

46 71%

11 17%

Post‐ th/

40 66%

13 21%

1 2%

1 2%

3 5%

Pre‐ th/

3 9%

6 18%

14 41%

8 24%

3 9%

34

Post‐ th/

10 20%

13 26%

14 28%

12 24%

1 2%

50

Effect of nadifloxacin on atopic dermatitis with  methicillin‐resistant staphylococcus aureus p y in young  y g children (Kimata H. Eur J Pediatr 1999; 158: 949‐54)

• Desain open label, parallel group, pada open label parallel group pada 35  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 • Nadifl. (n=18)  : Nadifloxacin N difl ( 18) N difl i +  bufexamac b f 3 dd 1 

Effect of nadifloxacin Effect of nadifloxacin G Group Control

Skin culture

Skin score

Anti‐SEA IgE

Anti‐SEB IgE

Before After

Before After

Before

Before

17/17

17/17 19 ± 5

Nadifloxacin 18/18a 0/18b

After

After

18 ± 4 0.5  ± 0.3 0.6 ± 0.4 0.7 ± 0.4 0.8 ± 0.4

20 ± 4c 9 ± 3d

0.6 ± 0.4e

0.3 ± 0.1f

0.8 ± 0.3c

0.3 ± 0.1d

* Number of patients with MRSA/total number of patients are shown Skin score, anti‐SEA IgE and anti‐SEB IgE (OD 410 mm) are expressed as mean ± SD a 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 formation Tidak ditemukan kelainan darah dan urin Tidak ditemukan induksi fluoroquinolone‐resistant bacteria  Follow‐up 3 bulan:  tdk ditemukan MRSA 

Mechanisms of Nadifloxacin in Acne Vulgaris Open comedon Micro comedon

Sebum secretion

Closed comedon

Inflammatory lesions

NDFX Keratinization P. acnes

Androgen

IL‐1α Inflammatory/Immune response to P. P acnes (CD4+ T, MΦ, Keratinocyte)

Neutrophils/ N t hil / Lymphocytes/ Keratinocytes

Cytokines

Dr.med. Abraham Simatupang, MKes. Email: [email protected]