항진균제 Antifungal agents (2) : 항진균제의 종류별 특징, Amphotericin B, Azoles, Echinocandins, 5-FC, 부작용

Table of Contents

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