항진균제 Antifungal agents (2) : 항진균제의 종류별 특징, Amphotericin B, Azoles, Echinocandins, 5-FC, 부작용
1. Amphotericin B
- Polyene 계열
- AmBd, LAmB, ABLC, ABCD 가 있다.
- Broad spectrum 을 가지고 있다. : Candida, Cryptococcus, Aspergillus, Mucorales
- Fungicidal for both CAndidia and Aspergillus
- AmBd 의 infusion 시 toxicity 로 LAmB 가 개발되었다.
* UTI 때는 Amphotericin B deoxycholate 를 사용해야 함. (urine penetration 이 높기때문)
| PK parameter | AmBd | Liposomal AmB | ABLC | ABCD |
| administration route | IV | IV | IV | IV |
| dosage (mg/kg/day) | 0.6~1 | 3~5 | 5 | 4 |
| oral bioavailablity (%) | <5 | <5 | <5 | <5 |
| food effect | N/A | N/A | N/A | N/A |
| Distribution - Cmax (mcg/mL) - AUC (mg h/L) - Protein binding (%) - CSF penetration (%) - Vitreal penetration (%) - Urine penetration (%) |
0.5~2.0 17 >95 0~4 0~38 3~20 |
83 555 >95 <5 0~38 5 |
1.7 14 >95 <5 0~38 <5 |
4 43 >95 <5 0~38 <5 |
| metabolism | minor heptic | unknown | unknown | unknown |
| elimination | urine, feces | unknown | unknown | unknown |
| half-life (hour) | 50 | 100~153 | 173 | 30 |
2. Azoles
- Fluconazole, Itraconazole, Voriconazole, Isavuconazole, Posaconazole
- Spectrum :
→ Fluconazole : only yeasts
→ Itraconazole, Voriconazole : yeasts, Aspergilllus
→ Posaconazole : yeasts, Aspergillus, Mucorales
- Fungistatic for Candida, Fungicidal for Aspergillus
- 경구약이 있다.
- Fluconazole 을 제외하면 TDM 을 해야 한다.
- Drug to Drug interaction 에 유의해야 한다.
Azole 투여시 특정 약물의 농도를 증가시킬 수 있다. (via cyt P450)
→ alprazolam, 경구혈당강하제, Tacrolimus, Theophylline 의 농도를 높일 수 있으므로 유의!
| PK parameter | Fluconazole | Itraconazole | Posaconazole | Voriconazole |
| administration route | IV, tablet oral solution |
IV, capsule, tablet, oral solution |
IV, tablet oral suspension |
IV, tablet |
| dosage | 6~12 mg/kg/day | 200 mg twice daily (PO) |
600~800 mg/day (in divided dose) |
6 mg/kg q12hr for 2 doses then 4 mg/kg q12h |
| oral bioavailablity (%) | >90 | 50 | 50 | >90 |
| food effect | None | capsule, tablet : ~55% with food oral solution ~75% w/o food |
tablet : ~54% with food oral suspension : variable (optimal : with high fat meal) |
Decreased >30% with food |
| Distribution - Cmax (mcg/mL) - AUC (mg h/L) - Protein binding (%) - CSF penetration (%) - Vitreal penetration (%) - Urine penetration (%) |
6~20 400~800 10 >60 28~75 90 |
0.5~2.3 29.2 99.8 <10 10 1~10 |
1.5~2.2 8.9 99 ND 26 <2 |
3.0~4.6 20.3 58 60 38 <2 |
| metabolism | minor heptic | hepatic | modest hepatic | hepatic |
| elimination | urine | hepatic | feces | urine |
| half-life (hour) | 31 | 24 | 25 | 6 |
3. Echinocandins
- Anidulafungin, Caspofungin, Micafungin
- Spectrum : only Candida and Aspergillus
- Fungicidal for Candidia, Fungistatic for Aspergillus
- 신기능에 따른 용량 조절이 불필요함.
- CNS 와 EYE, Urine 으로의 Penetration 이 Poor 하다.
* 신장으로의 배설이 거의 되지 않으므로, 신기능에 따른 Dose modification 이 불필요 하다.
* Echinocandin 의 3가지 약제의 특성이 모두 동일하지는 않다.
| PK parameter | Anidulafungin | Caspofungin | Micafungin |
| administration route | IV | IV | IV |
| dosage | 200 mg/d for 1 dose then 100 mg/d |
70 mg/d for 1 dose then 50 mg/d |
100~150 mg/d (prophylaxis : 50mg/d) |
| oral bioavailablity (%) | <5 | <5 | <5 |
| food effect | N/A | N/A | N/A |
| Distribution - Cmax (mcg/mL) - AUC (mg h/L) - Protein binding (%) - CSF penetration (%) - Vitreal penetration (%) - Urine penetration (%) |
6~7.0 99 84 <5 0 <2 |
8~10 119 97 <5 0 <2 |
10~16 158 99 <5 <1 <2 |
| metabolism | none | hepatic | hepatic |
| elimination | feces | feces | feces |
| half-life (hour) | 26 | 30 | 15 |
4. 5-FC
- Spectrum : Candida (Except C. krusei), Cryptococcus
- Fungistatic for candida
- 경구 흡수가 좋다. CNS 침투가 좋은 편
- 반감기가 짧다.
- 부작용 : rash, GI, BM suppression (Leukopenia, Thrombocytopenia)
주요 부작용
Amphotericin B : renal toxicity, Infusion reactions
Voriconazole : Photopsia
Itraconazole : GI sx.
Azoles : QT prolongation
5-FC : Bone marrow suppression
In vitro PD charcteristics
| Antifungal class | Candida | Aspergillus |
| Polyenes | fungicidal | fungicidal |
| Flucytosine | fungistatic | N/A |
| Triazoles | fungistatic | fungicidal |
| Echinocandins | fungicidal | fungistatic |
TDM (Therapeutic drug monitoring)
- PK behavior 가 unpredictable 하다.
- Therapeutic index 가 Narrow 하다.
- Safety 와 Efficacy 를 만족하는 정의된 용량
| Drug | Timing | Target (mg/L) |
| 5-FC | Trough or peak < 3days | Trough > 20~40 Peak < 100 |
| Itraconazole | Trough 5~7 days | > 0.5 |
| Voriconazole | Trough 5~7 days | 1~5.5 |
| Posaconazole | Trough 5~7 days | Prophylaxis > 0.7 Treatment >1 |
※ 항진균제 antifungal agent 시리즈