AMPHOTEC

AMPHOTEC- amphotericin b injection, lipid complex
InterMune, Inc.

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 (1R *,3S *,5R *,6R *,9R *,11R *, 15S *,16R *,17R *,18S *,19E ,21E ,23E ,25E ,27E ,29E ,31E ,33R *,35S *,36R *,37S *)]-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:

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The molecular formula of the drug is C47 H73 NO17 ; 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] 3 4
[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) 3.8 4.1
CLt (L/h/kg) 0.105 0.112
Distribution Half-Life (minutes) 3.5 3.5
Elimination Half-Life (hours) 27.5 28.2
Cmax (μg/mL) 2.6 2.9
AUCss (μg/mL•h) 29 36

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.

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