Introduction
Amphotericin B
Adverse effects of amphotericin B
Dosage, plasma pharmacokinetics, and administration of amphotericin B deoxycholate
Preparation | Amphotericin B deoxycholate | Liposomal amphotericin B AmBisome®
|
---|---|---|
C
max (µg/mL) | 1.7–2.8 | 14–29 (90) |
AUC (µg h/mL) | 14–29 | 423 |
V
d (L/kg) | 0.5–2.0 | 0.05–2.2 |
Protein binding (%) | 95–99 | 95–99 (of amphotericin B, liberated from lipid encapsulation) |
t
1/2 (h) | 15–27 | 13–24 |
CL (mL/h/kg) | 10–30 | 1–23 |
Elimination | Bile, kidney; no metabolites identified | Bile, RES long-term disposition, final elimination not yet clear; no metabolites identified |
Renal impairment | Contra-indicated in reversible renal impairment | No dose adjustment, consider nephrotoxicity |
Hepatic impairment | No dose adjustment, consider hepatotoxicity and renal toxicity | No dose adjustment, consider hepatotoxicity |
Remark |
T
inf ≥ 4 h mandatory, continuous infusion reduces toxicity, but may decrease the efficacy |
T
inf ≥ 4 h recommended |
Continuous infusion of amphotericin B deoxycholate
Amphotericin B deoxycholate in special patient groups
Lipid formulations of amphotericin B
Dosage and plasma pharmacokinetics of lipid-formulated amphotericin B
Lipid-formulated amphotericin B in special patient groups
Safety and antifungal activity of amphotericin B lipid formulations
Target-site penetration of amphotericin B preparations
Flucytosine
Dosage and plasma pharmacokinetics of flucytosine
Standard dose (mg/kg) | 25–37.5 mg/kg four times per day |
C
max (µg/mL) | 50–100 |
V
d (L/kg) | 0.4–0.8 |
Protein binding (%) | 3–4 |
t
1/2 (h) | 3–6 |
Elimination | Glomerular filtration |
Renal impairment | Dose reduction guided by glomerular filtration rate |
Hepatic impairment | Flucytosine should be avoided because of hepatotoxicity, no effect on pharmacokinetics because of renal elimination |
Remark | Therapeutic drug monitoring strongly recommended because of toxicity |
Flucytosine in special patient groups
Drug–drug interactions involving flucytosine
Target-site penetration of flucytosine
Antifungal azoles
Ketoconazole
Dosage and plasma pharmacokinetics of ketoconazole
Drug–drug interactions involving ketoconazole
Endocrinologic effects and current indication of ketoconazole
Fluconazole
Dosage and plasma pharmacokinetics of fluconazole
Fluconazole | Voriconazole | Isavuconazole | |
---|---|---|---|
Intravenous standard dose | Loading dose 12 mg/kg once Maintenance dose 6 mg/kg once daily | Loading dose 6 mg/kg b.i.d. on day1 Maintenance dose 4 mg/kg b.i.d. | Loading dose 200 mg t.i.d. on day 1 and day 2 Maintenance dose 200 mg once daily |
Oral standard dose | Depends on clinical indication | Loading dose 400 mg b.i.d. on day1 Maintenance dose 200 mg b.i.d. | Loading dose 200 mg t.i.d. on day 1 and day 2 Maintenance dose 200 mg once daily |
C
max (µg/mL) | 9 after 400 mg i.v. | 4.4 after i.v. administration | 2.6 |
AUC (µg h/mL) | 93 (AUC0-∞ after 400 mg i.v.) | 30 (AUCτ after i.v. administration) | 34 (AUCτ after i.v. administration) |
Vd (L/kg) | 0,7 | 4.5 | ~6.5 |
Protein binding (%) | 12 | 58 | 98–99 |
t1/2 (h) | 30 | ~6 | 80–120 |
CL (mL/h/kg) | 15–24 | ~100 | ~30–70 |
Metabolism and elimination | Mainly unchanged via the kidney, tubular re-absorption | Hepatic metabolism involving 2C9, 2C19, and CYP3A4 | Hepatic metabolism involving UGT, and CYP3A4 |
Renal impairment | Dose reduction (by 50% for GFR 11-50 mL/min) | Standard dose, consider SBECD accumulation during i.v. infusion | Standard dose |
Hepatic impairment | No relevant hepatic metabolism, consider hepatotoxicity | Mild to moderate: 50% dose reduction, TDM recommended | Mild to moderate, enhanced levels, no dose reduction recommended by the manufacturer |
Remark | Strong inhibitor of CYP3A4 and 2C9, continuous renal replacement therapy requires enhanced dose | Strong inhibitor of CYP2C9 and 2C19, moderate inhibitor of CYP3A4 | Inhibitor of CYP3A4, P-gp and BCRP |
Drug–drug interactions involving fluconazole
Fluconazole in special patient groups
Target-site penetration of fluconazole
Itraconazole
Dosage and plasma pharmacokinetics of itraconazole
Itraconazole | Posaconazole, oral suspension | Posaconazole, tablet formulation | Posaconazole, intravenous | |
---|---|---|---|---|
Standard dose | Loading dose 200 mg b.i.d. Maintenance dose 200 mg once daily—200 mg b.i.d | Therapeutic dose 200 mg q.i.d. or 400 mg b.i.d Prophylaxis 200 mg t.i.d. | Loading dose 300 mg b.i.d. on day 1 Maintenance dose 300 mg once daily | Loading dose 300 mg b.i.d. on day 1 Maintenance dose 300 mg once daily |
C
max (µg/mL) | 0.3–1.3 | 0.6 | 2 | 2.6 |
V
d (L/kg) | 11 | 20 | 5 | 3.7 |
Protein binding (%) | 99.8 | 98–99 | 98–99 | 98–99 |
t
1/2 (h) | 30 | 29 | 35 | 27 |
CL (mL/h/kg) | Dose-dependent, highly variable | 485 | 130 | 100 |
Metabolism and elimination | Excessive metabolisms involving CYP3A4 | Metabolisms involving CYP3A4, P-gp substrate | ||
Renal impairment | No dose reduction, enhanced dose during continuous renal replacement therapy | No dose adjustment | No dose adjustment | Avoid because of SBECD accumulation, When GFR <50 mL/min |
Hepatic impairment | Consider dose reduction, TDM | No dose adjustment | No dose adjustment | No dose adjustment |
Remark | Variable enteral absorption, strong inhibitor of CYP3A4 causing numerous drug–drug interactions, TDM recommended | Poor, variable enteral absorption, strong inhibitor of CYP3A4 causing numerous drug–drug interactions | Strong inhibitor of CYP3A4 causing numerous drug–drug interactions | Strong inhibitor of CYP3A4 causing numerous drug–drug interactions |
Drug–drug interactions involving itraconazole
Itraconazole in special patient groups
Target-site penetration of itraconazole
Voriconazole
Dosage and plasma pharmacokinetics of voriconazole
Drug–drug interactions involving voriconazole
Voriconazole in special patient groups
Target-site penetration and pharmacokinetics of voriconazole
Posaconazole
Dosage and plasma pharmacokinetics of posaconazole
Drug–drug interactions involving posaconazole
Posaconazole in special patient populations
Target-site penetration and kinetics of posaconazole
Isavuconazole
Dosage and plasma pharmacokinetics of isavuconazole
Drug–drug interactions involving isavuconazole
Isavuconazole in special patient groups
Isavuconazole target-site concentrations
Echinocandins
Caspofungin
Dosage and plasma pharmacokinetics of caspofungin
Caspofungin | Anidulafungin | Micafungin | |
---|---|---|---|
Dose, mg once daily | Loading dose 70, maintenance dose 50 (70 if body weight >80 kg) | Loading dose 200 (T
inf, 180 min), maintenance dose 100 (T
inf, 90 min) | 50 for prophylaxis, 100 for candidaemia, 150 for oesophageal candidiasis |
C
max (µg/mL) | 10 | 7 | 18 (dose 150 mg) |
Volume of distribution (L/kg) | 0.3–2.0 | 0.6 | 0.3 |
Protein binding (%) | 92.4–96.5 | 99.0 | 99.9 |
t
1/2 (h) | 8 | 40–50 | 13–20 |
CL (mL/h/kg) | ~10 | 15 | ~12 |
Metabolism and elimination | Independent from cytochrome P-450 (CYP) | Spontaneous degradation in plasma | CYP involved |
Renal impairment | No dose adjustment | No dose adjustment | No dose adjustment |
Hepatic impairment | Enhanced exposure in moderate hepatic impairment, dose reduction | Slightly lowered concentrations, no dose adjustment recommended | Slightly lowered concentrations, contra-indicated in European SmPC |
Remark | Dose reduction in critically ill patients with liver dysfunction may cause underexposure | Potential risk for liver tumours |