LAmB is a standard of care for a wide range of medically important opportunistic fungal pathogens. Despite nearly 20 years of clinical use, the pharmacokinetics and pharmacodynamics of this agent, which differ considerably from DAmB, remain relatively poorly understood and underutilized in the clinical setting. The molecular pharmacology, preclinical and clinical pharmacokinetics, and clinical experience with LAmB for the most commonly encountered fungal pathogens are reviewed. In vitro , experimental animal models and human clinical trial data are summarized, and novel routes of administration and dosing schedules are discussed.
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LAmB is a standard of care for a wide range of medically important opportunistic fungal pathogens. Despite nearly 20 years of clinical use, the pharmacokinetics and pharmacodynamics of this agent, which differ considerably from DAmB, remain relatively poorly understood and underutilized in the clinical setting. The molecular pharmacology, preclinical and clinical pharmacokinetics, and clinical experience with LAmB for the most commonly encountered fungal pathogens are reviewed.
In vitro , experimental animal models and human clinical trial data are summarized, and novel routes of administration and dosing schedules are discussed. LAmB is a formulation that results in reduced toxicity as compared with DAmB while retaining the antifungal effect of the active agent. Its long terminal half-life and retention in tissues suggest that single or intermittent dosing regimens are feasible, and these should be actively investigated in both preclinical models and in clinical trials.
Significant gaps remain in knowledge of pharmacokinetics and pharmacodynamics in special populations such as neonates and children, pregnant women and obese patients. Amphotericin B is a polyene antifungal agent with a broad range of activity against yeasts and molds, as well as the protozoan parasite Leishmania spp.
LAmB binds to ergosterol in the fungal cell membrane leading to ion leakage and cell death. The initial formulation was amphotericin B deoxycholate DAmB , which was developed in the s.
For many decades DAmB was the only antifungal agent available for the treatment of invasive fungal diseases. However, the significant dose-limiting toxicity of DAmB most notably nephrotoxicity and infusion-related reactions provided the impetus to develop new less toxic formulations.
While the antifungal activity of amphotericin B is retained following its incorporation into a liposome bilayer, its toxicity is significantly reduced [ 1 ]. The drug exposure-effect relationships for LAmB differ significantly from DAmB and remain relatively poorly understood. This review summarizes the available information on the pharmacokinetic and pharmacodynamic relationships of LAmB from both a clinical and preclinical perspective.
Since their first description in [ 2 ], liposomes have been extensively investigated for use in drug delivery. They are spherical vesicles characterized by an aqueous core surrounded by a lipid bilayer.
The composition of the liposome has a significant impact on the resultant pharmacokinetic properties. Liposomes can be engineered to maximize antifungal activity and minimize drug related toxicity.
The liposome specifically used in LAmB was designed to enable parenteral administration, facilitate the stability of amphotericin B within the liposome, yet enable the active compound to engage with the fungus when encountered within various tissue sites [ 3 ].
The unilamellar lipid structure of LAmB has three major components. The first is hydrogenated soy phosphatidylcholine, which comprises the majority of the lipid bilayer. Secondly, distearoylphosphatidyl glycerol was selected as its fatty acid chain is similar in length to that of the hydrophobic region of amphotericin B and has a net negative charge.
Under the slightly acidic conditions used to prepare liposomes, the amino group of amphotericin B, with its net positive charge, forms an ionic complex with the disteareoylphosphatidyl glycerol thus promoting the retention of amphotericin B within the liposomal bilayer [ 5 , 6 ].
The third component, cholesterol, was added as it binds amphotericin B and further facilitates the retention of amphotericin B within the liposome bilayer. Currently available lipid formulations of amphotericin B are not orally bioavailable, although early efforts to develop a lipid formulation suitable for oral administration are promising [ 7 ].
These formulations have significantly different compositions and therefore pharmacokinetic characteristics. ABLC is composed of flattened, ribbon-like multilamellar structures with particles - nm in size, resulting in a greater volume of distribution, perhaps from sequestration in the liver and spleen.
ABCD is a complex of amphotericin B and cholesteryl sulphate that forms thin disc shaped structures that are approximately nm in diameter, which are rapidly removed from the circulation by the reticulendothelial system [ 8 , 9 ].
Given the significant differences between the various formulations of amphotericin B conclusions from one compound cannot be necessarily extrapolated to another.
Amphotericin B binds to ergosterol in the fungal cell membrane, which leads to the formation of pores, ion leakage and ultimately fungal cell death. In contrast binding of amphotericin B containing liposomes results in fungal cell death [ 10 ]suggesting that binding results in liposomal disruption and release of amphotericin B, which is then free to exert its fungicidal activity by binding to ergosterol in the fungal cell membrane Figure 1.
Free, protein bound and liposome-associated amphotericin B circulate in the bloodstream following the administration of LAmB. The liposomes preferentially attach to the fungal cell wall.
The active amphotericin B molecule is released and transfers to the cell membrane where it can exert its activity, forming pores and leading to ion leakage and cell death. The precise mechanism by which amphotericin B is transferred from the liposome through the fungal cell wall to the fungal membrane is not known. It is likely that the process is facilitated by the higher binding affinity of amphotericin B for ergosterol the sterol present in fungal cell membranes compared with cholesterol, which is the principal lipid component of the liposome [ 13 ].
Temperature also appears to be important in the transfer of amphotericin B between the liposome and the fungus and occurs most efficiently at body temperature [ 14 ]. The assay has a significant impact on what exactly is being measured i. Caution, therefore, is required with the interpretation of drug concentrations. Extraction of amphotericin B from the liposome is a critical step in the bioanalysis of LAmB.
Destruction of the liposome with release of active drug can be achieved with organic solvents such as methanol or DMSO. Assays have been developed to measure both free and liposome-bound amphotericin B.
Failure to completely disrupt the liposome results in an underestimation of the total concentration of amphotericin B within the matrix. The current understanding of the pharmacokinetic and pharmacodynamic properties of LAmB is largely based on measurement of total concentrations of amphotericin B in both plasma and tissues.
However, only a fraction of total amphotericin B concentrations in any matrix is biologically active: some is liposome-associated, and fractions that are not liposome-associated may be bound to plasma proteins or tissues or exist as free drug.
Moreover, measuring concentrations from tissue homogenates has the inherent limitation of being unable to distinguish which specific sub-compartment the drug is residing in, and therefore how much biologically active drug is available at the site of infection [ 15 ].
The preclinical pharmacokinetics of LAmB have been extensively characterized in a number of experimental model systems. This body of work can be summarized as follows:. Studies in mice, rats, and rabbits all suggest that the plasma pharmacokinetics of LAmB are linear [ 16 , 17 ], however tissue pharmacokinetics of LAmB are more complex.
Generally, there is a dose-dependent increase in tissue concentrations, although there also appear to be situations where changes in tissue concentrations do not appear to be linear. This nonlinearity is dependent on the organ and the species of laboratory animal [ 17 , 18 ]. For example, in one murine study, hepatosplenic uptake at 12 hours following 0. The importance of the reticuloendothelial system RES has been confirmed in a number of laboratory animal species including rats [ 21 ] rabbits [ 22 ] and canines [ 23 ].
A possible explanation for accumulation of LAmB within the liver and spleen is the large numbers of macrophages in these organs. Macrophages readily phagocytose liposomes, which may also be beneficial in treating fungi residing within macrophages, such as Cryptococcus neoformans [ 24 ].
LAmB exhibits prolonged mean residence times in tissues, with some variation according to the tissue bed. In one study in rats much of the drug remained in the organs of uninfected animals at 72h post dosing. The majority of LAmB remains concentrated in the spleen and liver following intravenous administration; whereas, LAmB concentrations in the kidneys and lungs declines [ 25 ]. LAmB penetrates the central nervous system. As with DAmB, low concentrations of amphotericin B are found in CSF, while concentrations in cerebrum are approximately fold higher.
The extent and rate of penetration into these sub-compartments has not been rigorously quantified i. As in laboratory animals, circulating LAmB probably largely consists of intact liposomes [ 28 ]. There are also likely to be pools of relatively low concentrations of non-liposomal associated drug that is bound to human serum albumin HSA and alpha 1-acid glycoprotein AAG as well as smaller pool of free drug. Several population pharmacokinetic models have been developed to describe the pharmacokinetics of LAmB in immunocompromised patients [ 29 — 31 ].
These models provide measures of central tendency for the model parameter values, such as volume and clearance, as well as the extent of inter-individual variability in drug exposure for patients receiving various regimens of LAmB. A bi-or triphasic decline in total amphotericin B concentrations is observed. LAmB has a long terminal half-life in plasma approx. Total plasma concentrations of amphotericin B are higher than observed with amphotericin B deoxycholate, even following correction for the higher weight-based dosages that are used for LAmB.
The majority of circulating drug is likely to be biologically inactive. Biologically active drug is not released until there is direct contact with the fungus [ 28 ]. Urinary clearance of LAmB is 4. Similarly, fecal clearance is significantly lower than observed with DAmB. Intact liposomes are not excreted [ 32 ]. LAmB is not found in significant concentration in urine, meaning it is not a suitable agent for treating lower urinary tract infections urethritis or cystitis caused by Candida species.
This is in contrast to the significant concentration found in the kidney parenchyma [ 20 ], which makes it useful in the treatment of renal candidiasis i. As in experimental models, the distribution of LAmB, rather than its metabolism, is the primary determinant of the shape of the concentration-time profile—studies in patients have consistently failed to detect any amphotericin B metabolites [ 28 ].
In this case, tissue uptake is not saturated. Rather, dosage escalation results in activation or induction of an additional pathway that leads to accelerated clearance and lower-than-expected drug exposure [ 33 ].
Urinary excretion of free drug occurs rather than secretion, reabsorption or metabolism. Active excretion of non-liposomal amphotericin B into bile does occur, but to a lesser extent than amphotericin B deoxycholate. Amphotericin B undergoes moderate hepatic extraction and is unlikely to be affected by changes in hepatic blood flow.
Excretion of intact liposomes into the bile does not occur [ 28 ]. There are few tissue pharmacokinetic data from patients. LAmB has been quantified in liver and spleen, but also the kidney, lung, myocardium and brain in patients undergoing autopsy after receiving LAmB [ 35 ].
In one study of 14 paediatric oncology patients, amphotericin B concentrations in the CSF were approximately 0. LAmB is not removed by hemodialysis [ 37 ] and does not require dosage adjustment in this setting. The impact of weight on clearance is unclear. One study suggested that weight did not improve the fit of a model to PK data [ 29 ], while another suggested a statistically weak, but significant relationship between weight and clearance [ 31 ]. Further studies are required and studies in obese patients would be especially helpful.
The effect of obesity on the pharmacokinetics of LAmB is not well characterized and it is unclear whether dosing should be calculated using total or lean body weight. Dosing obese patients on total body weight results in a higher incidence of nephrotoxicity compared with patients with normal body weight [ 38 ], which may be due to low accumulation in fat tissue.
Dosing based on total body weight may be inappropriate and lead to relative overdosing [ 39 ]. Despite extensive use in neonates and premature infants with suspected or proven invasive fungal infection, there are no robust PK data in this population, and no good information on optimal dosing regimens. Although LAmB can cause hepatotoxicity, there is no current recommendation to reduce dosing in patients with pre-existing hepatic failure and its effects in this population remain unknown.
A single autopsy study reported enhanced pulmonary deposition in a patient with a failed liver transplant who had received LAmB for aspergillosis [ 37 ]. There are very few data regarding the use of LAmB in pregnancy. Small case series of patients with visceral leishmaniasis in pregnancy treated with LAmB have reported positive clinical outcomes without evidence of any adverse effects to the fetus [ 41 ]. LAmB is less potent on a mg-per-mg basis compared with amphotericin B deoxycholate.
Amphotericin B Liposomal Injection
Amphotericin B liposomal injection is used to treat fungal infections such as cryptococcal meningitis a fungal infection of the lining of the spinal cord and brain and visceral leishmaniasis a parasitic disease that usually affects spleen, liver, and bone marrow in certain people. It is also used to treat certain fungal infections in people who cannot receive conventional amphotericin B therapy. Amphotericin B liposomal injection is in a class of medications called antifungals. It works by slowing the growth of fungi that cause infection. Amphotericin B liposomal injection comes as a suspension liquid to be injected intravenously into a vein.