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Amphotec (Amphotericin B) - Description and Clinical Pharmacology

 
 



AMPHOTEC®
Amphotericin B Cholesteryl Sulfate
Complex for Injection

DESCRIPTION

AMPHOTEC® is a sterile, pyrogen-free, lyophilized powder for reconstitution and intravenous (IV) administration. AMPHOTEC consists of a 1:1 (molar ratio) complex of amphotericin B and cholesteryl sulfate. Upon reconstitution, AMPHOTEC forms a colloidal dispersion of microscopic disc-shaped particles.

Note: Liposomal encapsulation or incorporation into a lipid complex can substantially affect a drug’s functional properties relative to those of the unencapsulated drug or non-lipid associated drug. In addition, different liposomal or lipid-complex products with a common active ingredient may vary from one another in the chemical composition and physical form of the lipid component. Such differences may affect the functional properties of these drug products.

Amphotericin B is an antifungal polyene antibiotic produced by a strain of Streptomyces nodosus.

Amphotericin B, which is the established name for [1R (1 R *,3 S *,5 R *,6 R *,9 R *,11 R *, 15 S *,16 R *,17 R *,18 S *,19 E,21 E,23 E,25 E,27 E,29 E,31 E,33 R *,35 S *,36 R *,37 S *)]-33-[(3-Amino-3,6-dideoxy- ß -D-mannopyranosyl)oxy]-1,3,5,6,9,11,17,37-octahydroxy-15,16,18-trimethyl-13-oxo-14,39-dioxabicyclo[33.3.1] nonatriaconta-19,21,23,25,27, 29,31-heptaene-36-carboxylic acid, has the following structure:

The molecular formula of the drug is C47H73NO17; its molecular weight is 924.10.

AMPHOTEC is available in 50 mg and 100 mg single dose vials. Each 50 mg single dose vial contains amphotericin B, 50 mg; sodium cholesteryl sulfate, 26.4 mg; tromethamine, 5.64 mg; disodium edetate dihydrate, 0.372 mg; lactose monohydrate, 950 mg; and hydrochloric acid, qs, as a sterile, nonpyrogenic, lyophilized powder. Each 100 mg single dose vial contains amphotericin B, 100 mg; sodium cholesteryl sulfate, 52.8 mg; tromethamine, 11.28 mg; disodium edetate dihydrate, 0.744 mg; lactose monohydrate, 1900 mg; and hydrochloric acid, qs, as a sterile, nonpyrogenic, lyophilized powder.

MICROBIOLOGY

Mechanism of Action

The active ingredient of AMPHOTEC, amphotericin B, is a polyene antibiotic that acts by binding to sterols (primarily ergosterol) in cell membranes of sensitive fungi, with subsequent leakage of intracellular contents and cell death due to changes in membrane permeability. Amphotericin B also binds to the sterols (primarily cholesterol) in mammalian cell membranes, which is believed to account for its toxicity in animals and humans.

Activity in vitro and in vivo

AMPHOTEC is active in vitro against Aspergillus and Candida species. One hundred and twelve clinical isolates of four different Aspergillus species and 88 clinical isolates of five different Candida species were tested, with a majority of minimum inhibitory concentrations (MICs) < 1 μg/mL. AMPHOTEC is also active in vitro against other fungi. In vitro, AMPHOTEC is fungistatic or fungicidal, depending upon the concentration of the drug and the susceptibility of the fungal organism. However, standardized techniques for susceptibility testing for antifungal agents have not been established, and results of susceptibility studies do not necessarily correlate with clinical outcome.

AMPHOTEC is active in murine models against Aspergillus fumigatus, Candida albicans, Coccidioides immitis and Cryptococcus neoformans, and in an immunosuppressed rabbit model of aspergillosis in which endpoints were prolonged survival of infected animals and clearance of microorganisms from target organ(s). AMPHOTEC also was active in a hamster model of visceral leishmaniasis, a disease caused by infection of macrophages of the mononuclear phagocytic system by a protozoal parasite of the genus Leishmania. In this hamster model the endpoints were also prolonged survival of infected animals and clearance of microorganisms from target organ(s).

Drug Resistance

Variants with reduced susceptibility to amphotericin B have been isolated from several fungal species after serial passage in cell culture media containing the drug and from some patients receiving prolonged therapy with amphotericin B deoxycholate. Although the relevance of drug resistance to clinical outcome has not been established, fungal organisms that are resistant to amphotericin B may also be resistant to AMPHOTEC.

CLINICAL PHARMACOLOGY

Pharmacokinetics

The pharmacokinetics of amphotericin B, administered as AMPHOTEC, were studied in 51 bone marrow transplant patients with systemic fungal infections. The median (range) age and weight of those patients were 32 (3 to 52) years and 69.5 (14 to 116) kg, respectively. AMPHOTEC doses ranged from 0.5 to 8.0 mg/kg/day. The assay used in this study to measure amphotericin B in plasma does not distinguish amphotericin B that is complexed with cholesteryl sulfate from uncomplexed amphotericin B. A population modeling approach was used to estimate pharmacokinetic parameters (see table). The pharmacokinetics of amphotericin B, administered as AMPHOTEC, were best described by an open, two compartment structural model. The pharmacokinetics of amphotericin B, administered as AMPHOTEC, were nonlinear. Steady state volume of distribution (Vss) and total plasma clearance (CLt) increased with escalating doses, resulting in less than proportional increases in plasma concentration over a dose range of 0.5 to 8.0 mg/kg/day. The increased volume of distribution probably reflected uptake by tissues. The covariates of body weight and dose level accounted for a substantial portion of the variability of the pharmacokinetic estimates between patients. The unexplained variability in clearance was 26%. Based on the population model developed for these patients, pharmacokinetic parameters were predicted for two doses of AMPHOTEC and are provided in the following table:

Predicted Pharmacokinetic Parameters of Amphotericin B after Administration of Multiple Doses of AMPHOTEC [a]
AMPHOTEC (mg/kg/day)
Mean Pharmacokinetic Parameter [b]34
[a] Data obtained using population modeling in 51 bone marrow transplant patients. The modeling assumes amphotericin B pharmacokinetics after administration of AMPHOTEC is best described by a 2-compartment model. Infusion rate = 1 mg/kg/hour.
[b] Definitions: Vss - Volume of distribution at steady state, CLt - Total plasma clearance, Cmax - Maximum plasma concentration achieved at the end of an infusion, AUCss – Area under the plasma concentration time curve at steady-state.
Vss (L/kg) 3.84.1
CLt (L/h/kg) 0.1050.112
Distribution Half-Life (minutes) 3.53.5
Elimination Half-Life (hours) 27.528.2
Cmax (μg/mL) 2.62.9
AUCss (μg/mL•h)2936

In addition, the pharmacokinetics of amphotericin B, administered as amphotericin B deoxycholate, were studied in 15 patients in whom amphotericin B deoxycholate was administered for the treatment of aspergillus infections or empirical therapy. The median (range) age and weight for these patients were 21 (4 to 66) years and 60 (19 to 117) kg, respectively. A population modeling approach was used to estimate the pharmacokinetic parameters. The pharmacokinetics of amphotericin B, administered as amphotericin B deoxycholate, was best described as an open, two-compartment model with linear elimination.

The predicted pharmacokinetic parameters are provided in the following table:

Predicted Pharmacokinetic Parameters of Amphotericin B after Administration of Multiple Doses of 1 mg/kg Amphotericin B Deoxycholate [a]
Mean Pharmacokinetic Parameter [b]Values
[a] Data obtained using population modeling in 15 patients in whom amphotericin B deoxycholate was administered for treatment of aspergillus infection or empiric therapy. The modeling assumes amphotericin B pharmacokinetics after administration of amphotericin B deoxycholate are best described by a 2-compartment model. Infusion rate = 0.25 mg/kg/hour.
[b] Definitions: Vss - Volume of distribution at steady state, CLt - Total plasma clearance, Cmax - Maximum plasma concentration achieved at the end of an infusion, AUCss - Area under the plasma concentration time curve at steady-state.
Vss (L/kg) 1.1
CLt (L/h/kg) 0.028
Distribution Half-Life (minutes) 38
Elimination Half-Life (hours) 39
Cmax (μg/mL) 2.9
AUCss (μg/mL•h)36

An analytical assay that is able to distinguish between amphotericin B in the AMPHOTEC complex and amphotericin B which is not complexed to cholesteryl sulfate was used to analyze samples from a study of 25 patients who were either immunocompromised with aspergillosis or both febrile and neutropenic. Following a 1 mg/kg/hour infusion, 25 ± 18% (mean ± SD) of the total amphotericin B concentration measured in plasma was in the AMPHOTEC complex, dropping to 9.3 ± 7.9% at 1 hour and 7.5 ± 9.3% at 24 hours after the end of the infusion.

Pharmacokinetics in Special Populations

A population modeling approach was used to assess the effect of renal function, hepatic function, and age on the pharmacokinetics of AMPHOTEC in 51 patients receiving bone marrow transplants as described earlier.

Renal Impairment: The pharmacokinetics of amphotericin B, administered as AMPHOTEC, were not related to baseline serum creatinine clearance in the population studied; the median (range) creatinine clearance for this population was 74.0 (range: 35 - 202) mL/min/70 kg. The effect of more severe renal impairment on the pharmacokinetics of AMPHOTEC has not been studied.

Hepatic Impairment: The pharmacokinetics of amphotericin B, administered as AMPHOTEC, were not related to baseline liver function, as determined by liver enzymes and total bilirubin. For the population tested, the mean ± SD values for AST and total Bilirubin were 59.4 ± 70.0 IU/mL and 3.5 ± 3.7 mg/dL, respectively. The effect of more severe hepatic impairment on the pharmacokinetics of AMPHOTEC has not been studied.

Age: The pharmacokinetics of amphotericin B, administered as AMPHOTEC, were not related to the age of the patient. The median (range) age for the population in this study was 32 (3 to 52) years.

DESCRIPTION OF CLINICAL STUDIES

Clinical Studies in Aspergillosis

Data from 161 patients with proven or probable aspergillus infection were pooled from 5 non-comparative open label studies, one of which included emergency use patients. The patients were treated with AMPHOTEC because of failure to respond to amphotericin B deoxycholate (n=49), development of nephrotoxicity while receiving amphotericin B deoxycholate (n=62), preexisting renal impairment (n=25), or other reasons (n=25).

The median age of these 161 patients (92 males and 69 females) was 41 years (range 2 months to 85 years). For the 155 patients with baseline neutrophil data, 33 patients (21%) had neutrophil counts of < 500/mm3. The underlying diseases included bone marrow transplant, 69 (43%); hematological malignancy, 51(32%); solid organ transplant, 25 (15%); solid tumor, 3 (2%); and other diagnoses, 13 (8%) including surgery, 4; HIV infection, 3; immunosuppression for autoimmune disease, 3; diabetes, 2; and no known underlying disease, 1. Pulmonary involvement was the primary infection site, 118 patients (73%), followed by sinus, 14 (9%), CNS, 9 (6%), skin/wound, 9 (6%), and others, 10 (6%) including 3 with bone involvement, 2 with hepatic involvement, 2 with disseminated disease and 1 each with endocarditis, ophthalmitis, otitis, and involvement of the hard palate. The 49 patients enrolled due to failure to respond to amphotericin B had received amphotericin B deoxycholate prior to AMPHOTEC for ≤ 7 days (11 patients), 8 - 14 days (16 patients), and > 14 days (22 patients).

Patients were defined by their physicians as being refractory to amphotericin B deoxycholate therapy based on overall clinical judgment after receiving either a minimum of 7 days of amphotericin B deoxycholate or a minimum total dose of 15 mg/kg of amphotericin B deoxycholate. Nephrotoxicity was defined as a serum creatinine that had doubled from baseline, increased by ≥ 1.5 mg/dL or increased to ≥ 2.0 mg/dL. Preexisting renal impairment was defined as a serum creatinine that had increased to ≥ 2.0 mg/dL due to reasons other than amphotericin B deoxycholate administration.

Classifications of diagnosis and response were based on the definitions previously developed by the Mycoses Study Group.1 A retrospective response analysis was conducted in which a “complete response” was defined as resolution of all attributable symptoms, signs, and radiographic abnormalities present at enrollment, and a “partial response” was defined as major improvement of the abovementioned parameters. The total number of responders was the sum of the number of “complete” and “partial” responses.

Of the 161 patients, 80 were considered evaluable for response. Eighty-one (81) were excluded on the basis of inadequate diagnosis, confounding factors, or receiving ≤ 4 doses of AMPHOTEC. In the evaluable patients, the median daily dose was 4 mg/kg/day (range 0.73 - 7.5 mg/kg/day) and the cumulative median dose was 6.3 g (range 0.36 - 34.4 grams). Median duration of treatment was 24 days (range 5 - 129 days).

Response Rates for Evaluable Patients
Patient Group (n)Complete ResponsePartial ResponseTotal Responders
[a]
Response
Rate
[a] Total responders = Complete responses + Partial responses.
[b] Defined, based on overall clinical judgment, after receiving a minimum of 7 days of amphotericin B deoxycholate or a minimum total dose of 15 mg/kg of amphotericin B deoxycholate.
[c] Defined as a serum creatinine that had doubled from baseline or increased by ≥ 1.5 mg/dL or increased to ≥ 2.0 mg/dL.
[d] Defined as a serum creatinine that had increased to ≥ 2.0 mg/dL due to reasons other than amphotericin B deoxycholate.
Amphotericin B deoxycholate failure (28) [b]391243%
Nephrotoxicity (36) [c]5121747%
Preexisting renal impairment (16) [d]17850%
Total (80)9283746%

There is no directly comparable control group for the patients described in the above table to be certain whether similar patients would have responded had amphotericin B deoxycholate therapy been continued. A randomized study comparing AMPHOTEC with amphotericin B deoxycholate for therapy of invasive aspergillosis is currently undergoing analysis.

Renal Function

Patients with Renal Dysfunction at Baseline

The subset of patients with aspergillosis from the above five noncomparative open label studies, who initiated treatment with AMPHOTEC when their serum creatinine was ≥ 2.0 mg/dL (n = 47) experienced a mean decline in serum creatinine during treatment. In part, this decline may be attributed to patient dropout over time from this group. A historical control group was selected by reviewing medical charts of patients from January 1990 to June 1994 at 6 medical centers (M.D. Anderson Cancer Center, Fred Hutchinson Cancer Research Center, H. Lee Moffitt Cancer Center, University of Pittsburgh, Memorial Sloan-Kettering Cancer Center, and Bone Marrow Transplant Program at Emory  University). The mean change in serum creatinine was evaluated for similar cohorts of patients from this historical control group, with the baseline for assessing change being the day each patient’s serum creatinine reached ≥ 2.0 mg/dL. As shown in the figure, serum creatinine levels were lower during treatment with AMPHOTEC when compared to the serum creatinine levels of amphotericin B deoxycholate patients in the historical control group. There is no directly comparable group to be certain whether this decline is significantly better than the results of serum creatinine levels in patients who had continued on amphotericin B deoxycholate. Since these data were obtained from two separate studies, no statistical testing of the differences between these two groups was performed.

Changes in Mean Serum Creatinine Over Time in Patients with
Aspergillosis and Baseline Serum Creatinine ≥ 2.0 mg/dL [a]

[a] These curves do not represent the clinical course of a given patient, but that of an openlabel cohort of patients.

[b] Administered as amphotericin B deoxycholate.

Patients with Normal Renal Function at Baseline

In a randomized, double-blind, multicenter study, 213 febrile neutropenic patients were given empirically either 4 mg/kg/day of AMPHOTEC or 0.8 mg/kg/day of amphotericin B deoxycholate for a maximum of 14 days. This study was primarily designed to compare the safety profiles of these two treatments. NOTE: AMPHOTEC is NOT approved for empirical treatment in febrile neutropenic patients.

In the above study, patients had largely normal renal function at baseline; median serum creatinine levels were 0.8 mg/dL for both treatment groups. The mean change in serum creatinine was evaluated for patients with baseline creatinine ≤ 1.5 mg/dL. As shown in the graph, patients in both treatment groups showed an increase in serum creatinine while on study, however AMPHOTEC patients experienced significantly less creatinine increase at each time point.

Changes in Mean Serum Creatinine Over Time in Patients with Febrile
Neutropenia, and Baseline Serum Creatinine ≤ 1.5 mg/dL [a]

[a] These curves do not represent the clinical course of a given patient, but that of a cohort of patients.

[b] Administered as amphotericin B deoxycholate.

Hypokalemia

In the same empiric study, significantly more amphotericin B deoxycholate patients had at least one laboratory result of serum potassium < 3.0 mEq/L at least one time in the study compared with AMPHOTEC patients (23% vs. 7%), although concomitant supplemental potassium was allowed in the study design. Both groups received approximately equal amounts of potassium supplementation.

Hypomagnesemia

In the same empiric study, there was no overall trend for decreasing serum magnesium in either group.

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