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)
 Dose of Drug
administered

Pharmaccokinetics
Absorption Distribution

Drug concentration in  Dose in tissues
systemic circulation of distribution

Drug metabolised or 
Drug concentration  excreted
at site of action
t it f ti
Elimination

Pharmacodynaamics
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

○: Control ●: Nadifloxacin（NDFX)
20 IL-1α 20 IL-1β 10 IL-6
15 16 8
ntration

12 6
10
8 4
5 4 2
mRNA concen

0 0 0
40 IL-8 40 IL-10 500 IL-12 p40
30 30 400
(% of standard)

20 20 300
200
10 10
Relative m

100
0 0 0
15 IFN-γ 60 TNF-α 20 GM-CSF
50 15
10 40
30 10
5 20
10 5
0 0 0
0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24
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 γ
IFN-γ.
▪ Nadifloxacin did not inhibit IL-1α and TNF-α production.

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

 Inhibition of Cytokine Production in vitro

Effects of nadifloxacin on the production of cytokines by

heat-killed P. acnes-treated PBMC in vitro

○: Control ●: Nadifloxacin（NDFX)
20 IL-1α 20 IL-1β 10 IL-6
15 16 8
ntration

12 6
10
8 4
5 4 2
mRNA concen

0 0 0
40 IL-8 40 IL-10 500 IL-12 p40
30 30 400
(% of standard)

20 20 300
200
10 10
Relative m

100
0 0 0
15 IFN-γ 60 TNF-α 20 GM-CSF
50 15
10 40
30 10
5 20
10 5
0 0 0
0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24
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 γ
IFN-γ.
▪ Nadifloxacin did not inhibit IL-1α and TNF-α production.

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

 English version

Effects of Roxithromycin and Nadifloxacin (in vitro)

1.25 1.5
＊
n=3 ＊ n=3
1 Mean±S.D. Mean±S.D.
*p<0.05 *p<0.05
1
0.75 ｔ-test ｔ-test
RLU

RLU
0.5
05
0.5
0.25

0
0
1

6
3

5
Roxithromycin 0 0 1 5 μg/mL Nadifloxacin0 0 1 5 10 50 μg/mL
R1881 0 1nmol/L R1881 0 1nmol/L

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
Super‐ Secondarily 
Causative  Number of 
Folliculitisa infected  Impetigo Sycosis infected 
organism patients
dermatitis wound
Staph. aureus 22 7 2 8 1 4
β‐hemolytic 
2 1 1
streptococci
Staph aureus
2 1 1
+ streptococci
Coagulase‐
negative
negative  47 33 3 4 7
staph
P. acnes 1 1
P gran lat m
P. granulatum 1 1
Total 75 42 5 14 8 6
a: one patient with a furuncle was
p included in folliculitis
 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
P‐value <0.0001 <0.0001

Global assessment of therapeutic effect by physician 
and patients
and patients
Global 
Very good Moderate Slight Unchanged Aggravated
assessment
By 
51 (56.7%) 28 (31.1%) 8 (8.9%) 2 (2.2%) 1 (1.1%)
physician
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 Not  Mild Moderat Severe Total P‐value
present e
Erythema 52  38 
Pre‐treatment 0 0
(57.8%) (42.2%) 90 
<0 0001
<0.0001
28  49 13  (100%)
Post‐treatment 0
(31.1%) (54.4%) (14.5%)
Scaling 14  26  39  11 
Pre‐treatment
(15.6%) (28.9%) (43.3%) (12.2%) 90 
90
<0.0001
0 0001
64  25  1  (100%)
Post‐treatment 0
(71.1%) (27.8%) (1.1%)
Exudation 57  24 
Pre‐treatment 0 9 (10%)
(63.3%) (26.7%) 90 
90
<0.0001
61  24  1  (100%)
Post‐treatment 4 (4.4%)
(67.8%) (26.7%) (1.1%)
Erosion 3  5  56  26
Pre‐treatment
(3 3%)
(3.3%) (5 6%)
(5.6%) (62 2%)
(62.2%) (28 9%)
(28.9%) 90 
<0.0001
66  21  3  (100%)
Post‐treatment 0
(73.3%) (23.3%) (3.3%)
Swelling 7  16  49  18 
Pre‐treatment
Pre treatment
(7.8%) (17.8%) (54.4%) (20%) 90 
<0.0001
60  22  8  (100%)
Post‐treatment 0
(66.7%) (24.4%) (8.9%)
 Eradication of causative organism
Eradication of causative organism
Number of strains Eradicated/total 
Causative organism
Before treatment After treatment (%)
20/24 
Staph. aureus 24 4
(83%)
β hemolytic 
β‐hemolytic 4/4 
/
streptococci
4 0
(100%)
Coagulase‐negative  32/47
staph
47 15
(68%)
0/1
P. acnes 1 1
(0%)
1/1 
P granulatum
P. granulatum 1 0
(100%)
57/77 
Total 77 20
(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‐
Pre 20 
20 3 1
24
aureus th/ 83% 13% 4%
Post‐ 5 1
6
th/ 83% 17%
β‐ Pre‐
hemolytic  th/ 1 2 1
4
streptoco 25% 50% 25%
cci
Post‐
P 1 1
2
th/ 50% 50%
Coagulas Pre‐
46 11 1 3 1 3
e‐neg th/ 65
71% 17% 1% 5% 1% 5%
staph
Post‐ 40 13 1 1 3 2 1
61
th/ 66% 21% 2% 2% 5% 3% 2%
Pre‐ 3 6 14 8 3
P acnes
P. acnes 34
th/ 9% 18% 41% 24% 9%
Post‐ 10 13 14 12 1
50
th/ 20% 26% 28% 24% 2%
 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
Skin culture Skin score Anti‐SEA IgE Anti‐SEB IgE
G
Group
Before 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
0.3 ± 0.8 ±
Nadifloxacin 18/18a 0/18b 20 ± 4c 9 ± 3d 0.6 ± 0.4e 0.3 ± 0.1d
0.1f 0.3c
* 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 Closed comedon Inflammatory

lesions

Neutrophils/
N t hil /
NDFX Lymphocytes/
Sebum Keratinocytes
secretion Keratinization

Cytokines
P. acnes

Androgen IL‐1α

Inflammatory/Immune
response to P.
P acnes
(CD4+ T, MΦ, Keratinocyte)
Dr.med. Abraham Simatupang, MKes.
Email: farmakologiuki@yahoo.com