12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Anidulafungin is an anti-fungal drug [see Microbiology (12.4)].
General Pharmacokinetic Characteristics
The pharmacokinetics of anidulafungin following intravenous (IV) administration of ERAXIS have been characterized in healthy subjects, special populations and patients. Systemic exposures of anidulafungin are dose-proportional and have low inter-subject variability (coefficient of variation <25%) as shown in Table 5. The steady state was achieved on the first day after a loading dose (twice the daily maintenance dose) and the estimated plasma accumulation factor at steady state is approximately 2.
|Anidulafungin IV Dosing Regimen (LD/MD, mg)*|
|Cmax, ss = the steady state peak concentration|
|AUCss = the steady state area under concentration vs. time curve|
|CL = clearance|
|t1/2 = the terminal elimination half-life|
|Cmax, ss [mg/L]||3.55 (13.2)||8.6 (16.2)||10.9 (11.7)|
|AUCss [mg∙h/L]||42.3 (14.5)||111.8 (24.9)||168.9 (10.8)|
|CL [L/h]||0.84 (13.5)||0.94 (24.0)||0.78 (11.3)|
|t1/2 [h]||43.2 (17.7)||52.0 (11.7)||50.3 (9.7)|
The clearance of anidulafungin is about 1 L/h and anidulafungin has a terminal elimination half-life of 40–50 hours.
The pharmacokinetics of anidulafungin following IV administration are characterized by a short distribution half-life (0.5–1 hour) and a volume of distribution of 30–50 L that is similar to total body fluid volume. Anidulafungin is extensively bound (>99%) to human plasma proteins.
Hepatic metabolism of anidulafungin has not been observed. Anidulafungin is not a clinically relevant substrate, inducer, or inhibitor of cytochrome P450 (CYP450) isoenzymes. It is unlikely that anidulafungin will have clinically relevant effects on the metabolism of drugs metabolized by CYP450 isoenzymes.
Anidulafungin undergoes slow chemical degradation at physiologic temperature and pH to a ring-opened peptide that lacks antifungal activity. The in vitro degradation half-life of anidulafungin under physiologic conditions is about 24 hours. In vivo, the ring-opened product is subsequently converted to peptidic degradants and eliminated.
In a single-dose clinical study, radiolabeled (14C) anidulafungin was administered to healthy subjects. Approximately 30% of the administered radioactive dose was eliminated in the feces over 9 days, of which less than 10% was intact drug. Less than 1% of the administered radioactive dose was excreted in the urine. Anidulafungin concentrations fell below the lower limits of quantitation 6 days post-dose. Negligible amounts of drug-derived radioactivity were recovered in blood, urine, and feces 8 weeks post-dose.
Patients with fungal infections
Population pharmacokinetic analyses from four clinical trials including 107 male and 118 female patients with fungal infections showed that the pharmacokinetic parameters of anidulafungin are not affected by age, race, or the presence of concomitant medications which are known metabolic substrates, inhibitors or inducers.
The pharmacokinetics of anidulafungin in patients with fungal infections are similar to those observed in healthy subjects. The pharmacokinetic parameters of anidulafungin estimated using population pharmacokinetic modeling following IV administration of a maintenance dose of 50 mg/day or 100 mg/day (following a loading dose) of ERAXIS are presented in Table 6.
|PK Parameter*||ERAXIS IV Dosing Regimen (LD/MD, mg)†|
|Cmax, ss [mg/L]||4.2 (22.4)||7.2 (23.3)|
|Cmin, ss [mg/L]||1.6 (42.1)||3.3 (41.8)|
|AUCss [mg∙h/L]||55.2 (32.5)||110.3 (32.5)|
|CL [L/h]||1.0 (33.5)|
|t1/2, β [h] ‡||26.5 (28.5)|
Dosage adjustments are not required based on gender. Plasma concentrations of anidulafungin in healthy men and women were similar. In multiple-dose patient studies, drug clearance was slightly faster (approximately 22%) in men.
Dosage adjustments are not required for geriatric patients. The population pharmacokinetic analysis showed that median clearance differed slightly between the elderly group (patients ≥65, median CL=1.07 L/h) and the non-elderly group (patients <65, median CL=1.22 L/h) and the range of clearance was similar.
Dosage adjustments are not required based on race. Anidulafungin pharmacokinetics were similar among Whites, Blacks, Asians, and Hispanics.
Dosage adjustments are not required based on HIV status, irrespective of concomitant anti-retroviral therapy.
Anidulafungin is not hepatically metabolized. Anidulafungin pharmacokinetics were examined in subjects with Child-Pugh class A, B or C hepatic insufficiency. Anidulafungin concentrations were not increased in subjects with any degree of hepatic insufficiency. Though a slight decrease in AUC was observed in patients with Child-Pugh C hepatic insufficiency, it was within the range of population estimates noted for healthy subjects [see Use in Specific Populations (8.6)].
Anidulafungin has negligible renal clearance. In a clinical study of subjects with mild, moderate, severe or end stage (dialysis-dependent) renal insufficiency, anidulafungin pharmacokinetics were similar to those observed in subjects with normal renal function. Anidulafungin is not dialyzable and may be administered without regard to the timing of hemodialysis [see Use in Specific Populations (8.7)].
The pharmacokinetics of anidulafungin after daily doses were investigated in immunocompromised pediatric (2 through 11 years) and adolescent (12 through 17 years) patients with neutropenia. The steady state was achieved on the first day after administration of the loading dose (twice the maintenance dose), and the Cmax and AUCss increased in a dose-proportional manner. Concentrations and exposures following administration of maintenance doses of 0.75 and 1.5 mg/kg/day in this population were similar to those observed in adults following maintenance doses of 50 and 100 mg/day, respectively (as shown in Table 7).
|ERAXIS IV Dosing Regimen|
|Age Group||2–11 years|
(N = 6)
(N = 6)
(N = 6)
(N = 6)
|Cmax, ss [mg/L]||3.32 (50.0)||4.35 (22.5)||7.57 (34.2)||6.88 (24.3)|
|AUCss [mg∙h/L]||41.1 (38.4)||56.2 (27.8)||96.1 (39.5)||102.9 (28.2)|
The pharmacokinetics of anidulafungin were also investigated in 66 pediatric patients (1 month to <18 years) with candidemia/invasive candidiasis (ICC) in a prospective, open-label, non-comparative pediatric study following administration of ERAXIS of 3 mg/kg loading dose on Day 1 and followed by 1.5 mg/kg once daily maintenance dose [see Clinical Studies (14.1)]. Based on population pharmacokinetic analysis of combined data from adult and pediatric patients with ICC, the mean steady state exposure parameters (AUC0–24,,ss Cmin,,ss and Cmax,ss) across age groups in the overall pediatric patients (Table 8) were comparable to those in adults receiving 200 mg loading dose and 100 mg once daily maintenance dose.
|PK Parameter||ERAXIS IV Dosing Regimen |
(3 mg/kg LD/1.5 mg/kg MD)*
|Age Group||1 month to <2 years|
(N = 17)
|2 to < 5 years|
(N = 19)
|5 to <18 years|
(N = 30)
|Cmax, ss [mg/L]||6.7 (28.3)||7.1 (39.4)||6.5 (29.2)|
|Cmin, ss [mg/L]||2.0 (29)||2.5 (44)||2.5 (38.4)|
|AUCss [mg∙h/L]||69.9 (25.3)||82.8 (38.5)||86.8 (35.8)|
In vitro studies showed that anidulafungin is not metabolized by human cytochrome P450 or by isolated human hepatocytes and does not significantly inhibit the activities of human CYP isoforms (1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A) in clinically relevant concentrations. No clinically relevant drug-drug interactions were observed with drugs likely to be co-administered with anidulafungin.
Cyclosporine (CYP3A4 substrate)
In a study in which 12 healthy adult subjects received 100 mg/day maintenance dose of anidulafungin following a 200 mg loading dose (on Days 1 to 8) and in combination with 1.25 mg/kg oral cyclosporine twice daily (on Days 5 to 8), the steady state Cmax of anidulafungin was not significantly altered by cyclosporine; the steady state AUC of anidulafungin was increased by 22%. A separate in vitro study showed that anidulafungin has no effect on the metabolism of cyclosporine [see Drug Interactions (7.1)].
Voriconazole (CYP2C19, CYP2C9, CYP3A4 inhibitor and substrate)
In a study in which 17 healthy subjects received 100 mg/day maintenance dose of anidulafungin following a 200 mg loading dose, 200 mg twice daily oral voriconazole (following two 400 mg loading doses) and both in combination, the steady state Cmax and AUC of anidulafungin and voriconazole were not significantly altered by co-administration [see Drug Interactions (7.2)].
Tacrolimus (CYP3A4 substrate)
In a study in which 35 healthy subjects received a single oral dose of 5 mg tacrolimus (on Day 1), 100 mg/day maintenance dose of anidulafungin following a 200 mg loading dose (on Days 4 to 12) and both in combination (on Day 13), the steady state Cmax and AUC of anidulafungin and tacrolimus were not significantly altered by co-administration [see Drug Interactions (7.3)].
Rifampin (potent CYP450 inducer)
The pharmacokinetics of anidulafungin were examined in 27 patients that were co-administered anidulafungin and rifampin. The population pharmacokinetic analysis showed that when compared to data from patients that did not receive rifampin, the pharmacokinetics of anidulafungin were not significantly altered by co-administration with rifampin [see Drug Interactions (7.4)].
Amphotericin B liposome for injection
The pharmacokinetics of anidulafungin were examined in 27 patients that were co-administered liposomal amphotericin B. The population pharmacokinetic analysis showed that when compared to data from patients that did not receive amphotericin B, the pharmacokinetics of anidulafungin were not significantly altered by co-administration with amphotericin B [see Drug Interactions (7.5)].
Mechanism of Action
Anidulafungin is a semi-synthetic echinocandin with antifungal activity. Anidulafungin inhibits glucan synthase, an enzyme present in fungal, but not mammalian cells. This results in inhibition of the formation of 1,3-β-D-glucan, an essential component of the fungal cell wall.
Echinocandin resistance is due to point mutations within the genes (FKS1 and FKS2) encoding for subunits in the glucan synthase enzyme complex. There have been reports of Candida isolates with reduced susceptibility to anidulafungin, suggesting a potential for development of drug resistance. The clinical significance of this observation is not fully understood.
Anidulafungin has been shown to be active against most isolates of the following microorganisms both in vitro and in clinical infections:
The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following fungi exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for anidulafungin against isolates of the following Candida species. However, the effectiveness of anidulafungin in treating clinical infections due to these fungi has not been established in adequate and well-controlled clinical trials: