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1.
Adv Drug Deliv Rev ; 154-155: 2-12, 2020.
Article in English | MEDLINE | ID: mdl-32707149

ABSTRACT

In the 1980s, the center of entrepreneurial activity for the application of liposome science to medicine took the form of a company called Vestar Inc. (which became NeXstar Pharmaceuticals Inc., and eventually a division of Gilead Sciences, with merger and acquisition activity). This company was formed from science initially developed at the California Institute of Technology and the City of Hope, and involving several other local academic and treatment centers. This company eventually produced two commercial liposomal therapeutics, and created a particular paradigm of formulation goals, formulation development, characterization, and production unique among the set of companies that emerged around the same time. A number of clinical candidates were also developed, but failed to achieve commercialization. Nevertheless, several of these provide still relevant lessons and guidance for the field. Key adaptations of this technology to lower cost applications have also been carried out and are examined.


Subject(s)
Liposomes , Animals , Anti-Bacterial Agents/administration & dosage , Antineoplastic Agents/administration & dosage , Communicable Diseases/drug therapy , Humans , Neoplasms/drug therapy
2.
J Liposome Res ; 27(3): 173-179, 2017 Sep.
Article in English | MEDLINE | ID: mdl-28967274

ABSTRACT

AmBisome (liposomal amphotericin B) is among the earliest approved liposomal therapeutics, and has been in commercial use since the early 1990s. This review provides examples of non-clinical, regulatory, clinical label expansion, adverse event management, and supply chain control reflecting the real world challenges of a commercial liposomal therapeutic. We review examples of post-approval clinical development in severe lung infections, development of US and European guidance documents around liposomal therapeutics, the creation of a suitable placebo for blinded clinical trials, response to findings of a possible new category of adverse event (what turned out to be pseudohyperphosphatemia), challenges in handling the finished product in a setting with high risk of exposure of the product to temperatures outside of the established label storage conditions, and elements of continuingly increased aseptic processing requirements for manufacturing.


Subject(s)
Amphotericin B/therapeutic use , Antifungal Agents/therapeutic use , Amphotericin B/administration & dosage , Amphotericin B/adverse effects , Antifungal Agents/administration & dosage , Antifungal Agents/adverse effects , Drug Stability , Humans , Liposomes , Temperature
3.
Clin Chim Acta ; 411(23-24): 1900-5, 2010 Dec 14.
Article in English | MEDLINE | ID: mdl-20655888

ABSTRACT

BACKGROUND: Hyperphosphatemia is not an expected consequence of dosing with amphotericin B formulations. However, hyperphosphatemia or pseudohyperphosphatemia (erroneously high phosphorous measurements) has been variously reported in a number of recent case studies associated with liposomal amphotericin B (L-AmB, AmBisome®). In some of these cases, hyperphosphatemia was assumed to obtain, and direct treatment or alterations to antifungal therapy were carried out. In other cases, pseudohyperphosphatemia was assumed to obtain. METHODS: Using two different Beckman-Coulter measurement platforms (Synchron® LX20 with PHOSm or PHS chemistry systems) phosphorus values were obtained in human serum titrated with L-AmB or L-AmB placebo (identical composition to L-AmB, but without the drug molecule present). RESULTS: We demonstrate an L-AmB specific assay interference with the PHOSm chemistry system resulting in a linear (in amphotericin B) upward shift in phosphorus values (pseudohyperphosphatemia) and owing to an L-AmB specific interference with the mannitol containing assay system. Interference is not seen with L-AmB placebo. The PHS chemistry exhibits a minor interference from L-AmB, and it is in the form of lower assay values. L-AmB spiked sera treated with LipoClear* or subjected to ultrafiltration exhibit correct phosphorous values. CONCLUSION: We demonstrate L-AmB specific assay interference with the PHOSm chemistry system resulting in pseudohyperphosphatemia and owing to an L-AmB dependent alteration in the kinetic performance of the reagent system. The PHS chemistry system exhibits lesser interference from L-AmB, and it is in the form of lower assay values. Two methods of generating reliable phosphorus data (use of LipoClear or the Microcon-30) are provided.


Subject(s)
Amphotericin B/therapeutic use , Artifacts , Blood Chemical Analysis/methods , Diagnostic Errors , Hyperphosphatemia/blood , Hyperphosphatemia/diagnosis , Amphotericin B/blood , Humans , Phosphorus/blood , Phosphorus/chemistry
4.
Antimicrob Agents Chemother ; 54(8): 3432-41, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20439615

ABSTRACT

The pharmacodynamic and pharmacokinetic (PK-PD) properties of amphotericin B (AmB) formulations against invasive pulmonary aspergillosis (IPA) are not well understood. We used an in vitro model of IPA to further elucidate the PK-PD of amphotericin B deoxycholate (DAmB), liposomal amphotericin B (LAmB) and amphotericin B lipid complex (ABLC). The pharmacokinetics of these formulations for endovascular fluid, endothelial cells, and alveolar cells were estimated. Pharmacodynamic relationships were defined by measuring concentrations of galactomannan in endovascular and alveolar compartments. Confocal microscopy was used to visualize fungal biomass. A mathematical model was used to calculate the area under the concentration-time curve (AUC) in each compartment and estimate the extent of drug penetration. The interaction of LAmB with host cells and hyphae was visualized using sulforhodamine B-labeled liposomes. The MICs for the pure compound and the three formulations were comparable (0.125 to 0.25 mg/liter). For all formulations, concentrations of AmB progressively declined in the endovascular fluid as the drug distributed into the cellular bilayer. Depending on the formulation, the AUCs for AmB were 10 to 300 times higher within the cells than within endovascular fluid. The concentrations producing a 50% maximal effect (EC50) in the endovascular compartment were 0.12, 1.03, and 4.41 mg/liter for DAmB, LAmB, and ABLC, respectively, whereas, the EC50 in the alveolar compartment were 0.17, 7.76, and 39.34 mg/liter, respectively. Confocal microscopy suggested that liposomes interacted directly with hyphae and host cells. The PK-PD relationships of the three most widely used formulations of AmB differ markedly within an in vitro lung model of IPA.


Subject(s)
Amphotericin B/pharmacokinetics , Antifungal Agents , Deoxycholic Acid/pharmacokinetics , Invasive Pulmonary Aspergillosis/drug therapy , Models, Biological , Amphotericin B/therapeutic use , Antifungal Agents/pharmacokinetics , Antifungal Agents/therapeutic use , Area Under Curve , Cell Line , Deoxycholic Acid/therapeutic use , Drug Combinations , Endothelial Cells/microbiology , Endothelial Cells/ultrastructure , Epithelial Cells/microbiology , Epithelial Cells/ultrastructure , Humans , Invasive Pulmonary Aspergillosis/microbiology , Invasive Pulmonary Aspergillosis/pathology , Lung Diseases, Fungal/drug therapy , Lung Diseases, Fungal/microbiology , Lung Diseases, Fungal/pathology , Microbial Sensitivity Tests , Pulmonary Alveoli/cytology , Pulmonary Alveoli/microbiology , Pulmonary Alveoli/ultrastructure
5.
Antimicrob Agents Chemother ; 52(1): 259-68, 2008 Jan.
Article in English | MEDLINE | ID: mdl-17967910

ABSTRACT

Small unilamellar amphotericin B liposomes can reduce the toxicity of amphotericin B. In this study, we compared the physical, antifungal, pharmocokinetic, and toxic properties of two liposomal amphotericin B products, AmBisome and Anfogen, that have the same chemical composition but are manufactured differently. In vitro tests included determinations of the MICs and the concentrations causing the release of 50% of the intracellular potassium from red blood cells (K50 values) to assess toxicity. The 50% lethal dose (LD50) was evaluated by using uninfected C57BL/6 mice and single intravenous (i.v.) doses of 1 to 100 mg/kg of body weight. Multiple i.v. dosing over 18 days was performed with 0.5, 1.0, or 5.0 mg of Anfogen/kg or 1.0, 5.0, or 25 mg of AmBisome/kg to evaluate chronic toxicity. DBA/2 mice were infected intranasally with 2.5 x 10(6) Aspergillus fumigatus conidia, treated for 3 or 4 days with 3.0, 5.0, or 7.5 mg of Anfogen/kg or 3, 5, 7.5, or 15 mg of AmBisome/kg, and evaluated to assess the toxicity of the drugs to the kidneys (by measurement of blood urea nitrogen and creatinine levels and histopathology) and the drug efficacy. The median particle size was 77.8 nm for AmBisome and 111.5 nm for Anfogen. In vitro K(50) values were significantly lower for Anfogen (0.9 mug/ml) than for AmBisome (20 microg/ml), and the LD50 of AmBisome was >100 mg/kg, versus 10 mg of Anfogen/kg. There was significant renal tubular necrosis in uninfected and infected mice given Anfogen but no tubular necrosis in AmBisome-treated mice. AmBisome at 7.5 or 15 mg/kg was also more efficacious than 7.5 mg of Anfogen/kg for the treatment of pulmonary aspergillosis, based on survival and weight loss data and numbers of CFU per gram of lung. In conclusion, the efficacy and toxicity of these two liposomal amphotericin B products were significantly different, and thus, the products were not comparable.


Subject(s)
Amphotericin B , Antifungal Agents , Aspergillosis/drug therapy , Aspergillus fumigatus/drug effects , Liposomes , Amphotericin B/administration & dosage , Amphotericin B/chemistry , Amphotericin B/pharmacology , Amphotericin B/toxicity , Animals , Antifungal Agents/administration & dosage , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Antifungal Agents/toxicity , Aspergillosis/microbiology , Aspergillus fumigatus/growth & development , Erythrocytes/drug effects , Female , Kidney/drug effects , Lethal Dose 50 , Liposomes/administration & dosage , Liposomes/chemistry , Liposomes/pharmacology , Liposomes/toxicity , Lung Diseases, Fungal/drug therapy , Lung Diseases, Fungal/microbiology , Mice , Mice, Inbred C57BL , Microbial Sensitivity Tests , Spores, Fungal/drug effects , Treatment Outcome
6.
J Liposome Res ; 17(3-4): 121-37, 2007.
Article in English | MEDLINE | ID: mdl-18027233

ABSTRACT

In the early 1980s, Vestar Inc., a company founded on the basis of science developed by the California Institute of Technology and the City of Hope, brought into development an imaging agent based on liposome encapsulated (111)In(3+). This agent, named Vescan, together with the gamma ray perturbed angular correlation spectroscopy technique to examine liposome integrity, was envisioned as a broadly applicable in vivo tumor diagnostic agent. While not ultimately commercialized, the agent was used to successfully image a variety of tumors, and was evaluated in late-stage clinical trials. Lessons learned from the formulation and process development of this product, and the wealth of non-clinical and clinical results, revealed valuable information about the properties of stable, RES avoiding conventional liposomes. This technology ultimately would lead (at NeXstar Pharmaceuticals and, later, at Gilead Sciences) to the technology that created commercialized liposomal products such as AmBisome and DaunoXome as well as other development stage product candidates.


Subject(s)
Liposomes , Drug Evaluation, Preclinical , Quality Control , Spectrum Analysis/methods
7.
Antimicrob Agents Chemother ; 50(6): 2122-31, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16723574

ABSTRACT

Invasive aspergillosis, an important cause of morbidity and mortality in immunosuppressed (IS) patients, is often treated with amphotericin B lipid formulations. In the present study, liposomal amphotericin B (L-AMB) and amphotericin B lipid complex (ABLC) were compared in treatment of murine pulmonary aspergillosis. Uninfected, IS mice were treated for 4 days with 1, 4, 8, or 12 mg L-AMB or ABLC/kg of body weight, and their lungs were analyzed by high-performance liquid chromatography for drug concentrations. IS mice intranasally challenged with Aspergillus fumigatus were treated with 12, 15, or 20 mg/kg L-AMB or ABLC and monitored for survival, fungal burden (CFU), and tissue drug concentration. Blood urea nitrogen (BUN) levels and kidney histopathology were determined for uninfected and infected mice given 15 or 20 mg/kg L-AMB or ABLC. The results showed that both drugs had therapeutic levels of drug (>3.0 microg/g) in the lungs of uninfected or infected mice, and 24 h after the last dose, ABLC levels were significantly higher than L-AMB levels (P < 0.02). L-AMB and ABLC at 12 mg/kg both produced 57% survival, but only L-AMB at 15 or 20 mg/kg further increased survival to 80 to 90%, with BUN levels and kidney morphology similar to those of controls. Survival at 15 or 20 mg/kg ABLC was not significantly different than that of controls, and BUN levels were significantly elevated, with tubular alterations in uninfected animals and acute necrosis in kidney tubules of infected animals. In conclusion, although both drugs were effective in prolonging survival at 12 mg/kg, the reduced nephrotoxicity of L-AMB increased its therapeutic index, allowing for its safe and effective use at 15 or 20 mg/kg.


Subject(s)
Amphotericin B/administration & dosage , Amphotericin B/pharmacology , Antifungal Agents/therapeutic use , Aspergillosis/drug therapy , Lung Diseases, Fungal/drug therapy , Phosphatidylcholines/administration & dosage , Phosphatidylcholines/pharmacology , Phosphatidylglycerols/administration & dosage , Phosphatidylglycerols/pharmacology , Administration, Inhalation , Aerosols , Amphotericin B/therapeutic use , Animals , Antifungal Agents/pharmacokinetics , Antifungal Agents/pharmacology , Aspergillus fumigatus/drug effects , Aspergillus fumigatus/isolation & purification , Blood Urea Nitrogen , Colony Count, Microbial , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Combinations , Drug-Related Side Effects and Adverse Reactions/pathology , Female , Kidney Tubules/pathology , Liposomes , Mice , Mice, Inbred DBA , Phosphatidylcholines/therapeutic use , Phosphatidylglycerols/therapeutic use , Survival Analysis , Time Factors
8.
J Mol Biol ; 315(4): 845-57, 2002 Jan 25.
Article in English | MEDLINE | ID: mdl-11812152

ABSTRACT

Cavity complementation has been observed in many proteins, where an appropriate small molecule binds to a cavity-forming mutant. Here, the binding of compounds to the W191G cavity mutant of cytochrome c peroxidase is characterized by X-ray crystallography and binding thermodynamics. Unlike cavities created by removal of hydrophobic side-chains, the W191G cavity does not bind neutral or hydrophobic compounds, but displays a strong specificity for heterocyclic cations, consistent with the role of the protein to stabilize a tryptophan radical at this site. Ligand dissociation constants for the protonated cationic state ranged from 6 microM for 2-amino-5-methylthiazole to 1 mM for neutral ligands, and binding was associated with a large enthalpy-entropy compensation. X-ray structures show that each of 18 compounds with binding behavior bind specifically within the artificial cavity and not elsewhere in the protein. The compounds make multiple hydrogen bonds to the cavity walls using a subset of the interactions seen between the protein and solvent in the absence of ligand. For all ligands, every atom that is capable of making a hydrogen bond does so with either protein or solvent. The most often seen interaction is to Asp235, and most compounds bind with a specific orientation that is defined by their ability to interact with this residue. Four of the ligands do not have conventional hydrogen bonding atoms, but were nevertheless observed to orient their most polar CH bond towards Asp235. Two of the larger ligands induce disorder in a surface loop between Pro190 and Asn195 that has been identified as a mobile gate to cavity access. Despite the predominance of hydrogen bonding and electrostatic interactions, the small variation in observed binding free energies were not correlated readily with the strength, type or number of hydrogen bonds or with calculated electrostatic energies alone. Thus, as with naturally occurring binding sites, affinities to W191G are likely to be due to a subtle balance of polar, non-polar, and solvation terms. These studies demonstrate how cavity complementation and judicious choice of site can be used to produce a protein template with an unusual ligand-binding specificity.


Subject(s)
Cations/metabolism , Cytochrome-c Peroxidase/chemistry , Cytochrome-c Peroxidase/metabolism , Protein Engineering , Amino Acid Substitution/genetics , Binding Sites , Crystallization , Crystallography, X-Ray , Cytochrome-c Peroxidase/genetics , Entropy , Hydrogen Bonding , Ligands , Models, Molecular , Mutation/genetics , Protein Binding , Protons , Static Electricity , Substrate Specificity , Thermodynamics , Tryptophan/metabolism
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