scholarly journals Population Pharmacokinetics of Liposomal Amphotericin B in Immunocompromised Children

2016 ◽  
pp. AAC.01427-16 ◽  
Author(s):  
Jodi M. Lestner ◽  
Andreas H. Groll ◽  
Ghaith Aljayyoussi ◽  
Nita L. Seibel ◽  
Aziza Shad ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
High Performance ◽  
Drug Exposure ◽  
Compartment Model ◽  
Invasive Fungal Disease ◽  
Volume Of Distribution ◽  
Liposomal Amphotericin B ◽  
Time Curve ◽  
Maximum Serum

BackgroundLiposomal amphotericin B (LAmB) is widely used in the treatment of invasive fungal disease (IFD) in adults and children. There are relatively limited PK data to inform optimal dosing in children that achieves systemic drug exposures comparable to those of adults.ObjectivesTo describe the pharmacokinetics of LAmB in children aged 1-17 years with suspected or documented IFD.MethodsThirty-five children were treated with LAmB at dosages of 2.5-10 mg kg-1daily. Samples were taken at baseline and at 0.5-2.0 hourly intervals for twenty-four hours after receipt of the first dose (n=35 patients) and on the final day of therapy (n=25 patients). LAmB was measured using high performance liquid chromatography (HPLC). The relationship between drug exposure and development of toxicity was explored.ResultsAn evolution in PK was observed during the course of therapy resulting in a proportion of patients (n=13) having significantly higher maximum serum concentration (Cmax) and area under the concentration time curve (AUC0-24) later in the course of therapy, without evidence of drug accumulation (Cminaccumulation ratio, AR < 1.2). The fit of a 2-compartment model incorporating weight and an exponential decay function describing volume of distribution best described the data. There was a statistically significant relationship between mean AUC0-24and probability of nephrotoxicity (OR 2.37; 95% CI 1.84-3.22, p=0.004).ConclusionsLAmB exhibits nonlinear pharmacokinetics. A third of children appear to experience a time-dependent change in PK, which is not explained by weight, maturation or observed clinical factors.

scholarly journals Population Pharmacokinetics of Liposomal Amphotericin B and Caspofungin in Allogeneic Hematopoietic Stem Cell Recipients

2011 ◽  
Vol 56 (1) ◽  
pp. 536-543 ◽  
Author(s):  
Gudrun Würthwein ◽  
Charlotte Young ◽  
Claudia Lanvers-Kaminsky ◽  
Georg Hempel ◽  
Mirjam N. Trame ◽  
...  
Keyword(s):  
Stem Cell ◽  
Amphotericin B ◽  
Hematopoietic Stem Cell ◽  
Liposomal Amphotericin ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Concentration Data ◽  
Hematopoietic Stem ◽  
Two Compartment Model ◽  
Proportional Error Model

ABSTRACTLiposomal amphotericin B (LAMB) and caspofungin (CAS) are important antifungal agents in allogeneic hematopoietic stem cell transplant (aHSCT) recipients. Little is known, however, about the pharmacokinetics (PK) of both agents and their combination in this population. The PK of LAMB and CAS and the potential for PK interactions between both agents were investigated within a risk-stratified, randomized phase II clinical trial in 53 adult aHSCT recipients with granulocytopenia and refractory fever. Patients received either LAMB (n= 17; 3 mg/kg once a day [QD]), CAS (n= 19; 50 mg QD; day 1, 70 mg), or the combination of both (CAS-LAMB;n= 17) for a median duration of 10 to 13 days (range, 4 to 28 days) until defervescence and granulocyte recovery. PK sampling was performed on days 1 and 4. Drug concentrations in plasma (LAMB, 405 samples; CAS, 458 samples) were quantified by high-pressure liquid chromatography and were analyzed using population pharmacokinetic modeling. CAS concentration data best fitted a two-compartment model with a proportional error model and interindividual variability (IIV) for clearance (CL) and central volume of distribution (V1) (CL, 0.462 liter/h ± 25%;V1, 8.33 liters ± 29%; intercompartmental clearance [Q], 1.25 liters/h; peripheral volume of distribution [V2], 3.59 liters). Concentration data for LAMB best fitted a two-compartment model with a proportional error model and IIV for all parameters (CL, 1.22 liters/h ± 64%;V1, 19.2 liters ± 38%;Q, 2.18 liters/h ± 47%;V2, 52.8 liters ± 84%). Internal model validation showed predictability and robustness of both models. None of the covariates tested (LAMB or CAS comedication, gender, body weight, age, body surface area, serum bilirubin, and creatinine clearance) further improved the models. In summary, the disposition of LAMB and CAS was best described by two-compartment models. Drug exposures in aHSCT patients were comparable to those in other populations, and no PK interactions were observed between the two compounds.

scholarly journals Plasma Protein Binding of Amphotericin B and Pharmacokinetics of Bound versus Unbound Amphotericin B after Administration of Intravenous Liposomal Amphotericin B (AmBisome) and Amphotericin B Deoxycholate

2002 ◽  
Vol 46 (3) ◽  
pp. 834-840 ◽  
Author(s):  
Ihor Bekersky ◽  
Robert M. Fielding ◽  
Dawna E. Dressler ◽  
Jean W. Lee ◽  
Donald N. Buell ◽  
...  
Keyword(s):  
Human Plasma ◽  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
The Body ◽  
Liposomal Amphotericin B ◽  
Time Curve ◽  
Liposomal Drug ◽  
Drug Concentrations ◽  
Unique Composition

ABSTRACT Unilamellar liposomal amphotericin B (AmBisome) (liposomal AMB) reduces the toxicity of this antifungal drug. The unique composition of liposomal AMB stabilizes the liposomes, producing higher sustained drug levels in plasma and reducing renal and hepatic excretion. When liposomes release their drug payload, unbound, protein-bound, and liposomal drug pools may exist simultaneously in the body. To determine the amounts of drug in these pools, we developed a procedure to measure unbound AMB in human plasma by ultrafiltration and then used it to characterize AMB binding in vitro and to assess the pharmacokinetics of nonliposomal pools of AMB in a phase IV study of liposomal AMB and AMB deoxycholate in healthy subjects. We confirmed that AMB is highly bound (>95%) in human plasma and showed that both human serum albumin and α1-acid glycoprotein contribute to this binding. AMB binding exhibited an unusual concentration dependence in plasma: the percentage of bound drug increased as the AMB concentration increased. This was attributed to the low solubility of AMB in plasma, which limits the unbound drug concentration to <1 μg/ml. Subjects given 2 mg of liposomal AMB/kg of body weight had lower exposures (as measured by the maximum concentration of drug in serum and the area under the concentration-time curve) to both unbound and nonliposomal drug than those receiving 0.6 mg of AMB deoxycholate/kg. Most of the AMB in plasma remained liposome associated (97% at 4 h, 55% at 168 h) after liposomal AMB administration, so that unbound drug concentrations remained at <25 ng/ml in all liposomal AMB-treated subjects. Although liposomal AMB markedly reduces the total urinary and fecal recoveries of AMB, urinary and fecal clearances based on unbound AMB were similar (94 to 121 ml h−1 kg−1) for both formulations. Unbound drug urinary clearances were equal to the glomerular filtration rate, and tubular transit rates were <16% of the urinary excretion rate, suggesting that net filtration of unbound drug, with little secretion or reabsorption, is the mechanism of renal clearance for both conventional and liposomal AMB in humans. Unbound drug fecal clearances were also similar for the two formulations. Thus, liposomal AMB increases total AMB concentrations while decreasing unbound AMB concentrations in plasma as a result of sequestration of the drug in long-circulating liposomes.

scholarly journals Pharmacokinetics of Liposomal Amphotericin B in Pleural Fluid

2010 ◽  
Vol 54 (4) ◽  
pp. 1633-1635 ◽  
Author(s):  
Brad Moriyama ◽  
Parizad Torabi-Parizi ◽  
Alexandra K. Pratt ◽  
Stacey A. Henning ◽  
Gennethel Pennick ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Pleural Fluid ◽  
Successful Treatment ◽  
Chest Tube ◽  
Liposomal Amphotericin ◽  
Chest Tube Drainage ◽  
Liposomal Amphotericin B ◽  
Time Curve ◽  
Tube Drainage ◽  
Low Level

ABSTRACT We report the penetration of liposomal amphotericin B into the pleural fluid of a patient with pulmonary zygomycosis and empyema. The ratio of area under the concentration-versus-time curve in pleural fluid (AUCpleural fluid) to that in serum (AUCserum) for liposomal amphotericin B over 24 h was 9.4%, with pleural fluid concentrations of 2.12 to 4.91 μg/ml. Given the relatively low level of intrapleural penetration of liposomal amphotericin B, chest tube drainage may be warranted for successful treatment of zygomycotic empyema.

scholarly journals Experimental Models of Short Courses of Liposomal Amphotericin B for Induction Therapy for Cryptococcal Meningitis

2017 ◽  
Vol 61 (6) ◽  
Author(s):  
Jodi Lestner ◽  
Laura McEntee ◽  
Adam Johnson ◽  
Joanne Livermore ◽  
Sarah Whalley ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Induction Therapy ◽  
Liposomal Amphotericin ◽  
Experimental Models ◽  
Liposomal Amphotericin B ◽  
Perivascular Spaces ◽  
Histopathological Changes ◽  
Time Curve ◽  
Cryptococcal Meningoencephalitis ◽  
The Brain

ABSTRACT Cryptococcal meningoencephalitis is a rapidly lethal infection in immunocompromised patients. Induction regimens are usually administered for 2 weeks. The shortest effective period of induction therapy with liposomal amphotericin B (LAMB) is unknown. The pharmacodynamics of LAMB were studied in murine and rabbit models of cryptococcal meningoencephalitis. The concentrations of LAMB in the plasma and brains of mice were measured using high-performance liquid chromatography (HPLC). Histopathological changes were determined. The penetration of LAMB into the brain was determined by immunohistochemistry using an antibody directed to amphotericin B. A dose-dependent decline in fungal burden was observed in the brains of mice, with near-maximal efficacy achieved with LAMB at 10 to 20 mg/kg/day. The terminal elimination half-life in the brain was 133 h. The pharmacodynamics of a single dose of 20 mg/kg was the same as that of 20 mg/kg/day administered for 2 weeks. Changes in quantitative counts were reflected by histopathological changes in the brain. Three doses of LAMB at 5 mg/kg/day in rabbits were required to achieve fungicidal activity in cerebrospinal fluid (cumulative area under the concentration-time curve, 2,500 mg · h/liter). Amphotericin B was visible in the intra- and perivascular spaces, the leptomeninges, and the choroid plexus. The prolonged mean residence time of amphotericin B in the brain suggests that abbreviated induction regimens of LAMB are possible for cryptococcal meningoencephalitis.

Influence of Hypovolemia on the Pharmacokinetics and Electroencephalographic Effect of γ-Hydroxybutyrate in the Rat

2002 ◽  
Vol 97 (5) ◽  
pp. 1218-1226 ◽  
Author(s):  
Diederik K. Van Sassenbroeck ◽  
Peter De Paepe ◽  
Frans M. Belpaire ◽  
Paul A. Boon ◽  
Walter A. Buylaert
Keyword(s):  
Blood Pressure ◽  
High Performance ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Control Procedure ◽  
Time Data ◽  
Time Curve ◽  
Concentration Time ◽  
Gamma Hydroxybutyrate ◽  
Significant Difference

Background Hypovolemia alters the effect of propofol in the rat by influencing the pharmacokinetics and the end organ sensitivity. We now studied the effect of hypovolemia on the anesthetic gamma-hydroxybutyrate (GHB) because in contrast with propofol it increases blood pressure. Methods Thirty-two rats were randomly assigned to undergo moderate hypovolemia or a control procedure. Each rat received either an infusion of sodium-GHB (390 mg x kg(-1) x 5 min(-1)) or the same volume of an equimolar solution of sodium chloride (6.9%). Plasma samples were taken for GHB assay (high-performance liquid chromatography) and the electroencephalography and blood pressure values were recorded. A two-compartment model with Michaelis-Menten elimination was fitted to the concentration-time data and a sigmoid E(max) model to the electroencephalographic effect effect site concentration curve allowing the study of the end organ sensitivity. Results Plasma concentration-time curves and the total volume of distribution in hypovolemic and normovolemic rats were comparable with only small but significant differences in central volume of distribution and the intercompartmental clearance. There was no significant difference either in the distribution from the plasma to the brain (k(e0)) or in the end organ sensitivity (EC50 = 335 +/- 76 microg/ml in control vs. 341 +/- 89 microg/ml in hypovolemic rats). GHB temporarily increased mean arterial pressure in both groups, which cannot be explained by the sodium salt alone. Conclusions Hypovolemia does not influence the overall concentration-time curve of GHB and induces no changes in the electroencephalographic effect of GHB in the rat. This difference with propofol may be due to the fact that it increases blood pressure but also due to its different pharmacokinetic properties.

scholarly journals Comparative Pharmacokinetics, Tissue Distributions, and Effects on Renal Function of Novel Polymeric Formulations of Amphotericin B and Amphotericin B-Deoxycholate in Rats

2000 ◽  
Vol 44 (4) ◽  
pp. 898-904 ◽  
Author(s):  
Iciar Echevarría ◽  
Celia Barturen ◽  
María Jesús Renedo ◽  
Iñaki F. Trocóniz ◽  
M. Carmen Dios-Viéitez
Keyword(s):  
Renal Function ◽  
Amphotericin B ◽  
High Performance ◽  
Drug Exposure ◽  
Compartment Model ◽  
Drug Uptake ◽  
Parameter Estimates ◽  
Tissue Samples ◽  
Plasma Creatinine Level ◽  
Male Wistar Rats

ABSTRACT The pharmacokinetic profiles of a traditional formulation of amphotericin B (Fungizone) and novel nanosphere and mixed micelle delivery systems developed for amphotericin B were compared and described. Six groups of male Wistar rats received intravenous injections of the different formulations. Plasma and tissue samples were obtained at 11 different times after dosing, with three animals used each time. The amphotericin B concentrations in plasma and tissues were analyzed by high-performance liquid chromatography. The plasma drug concentration-time profiles were best described by a two-compartment model. Models that described the observed single or double peak disposition kinetics in kidney, liver, and spleen were also developed. Parameter estimates from those models show that components of the formulation such as poloxamer 188, which is present in all new formulations, seem to play an important role in the rate of drug uptake by the tissues; in general, the levels of amphotericin B in tissues were increased after the administration of the new formulations compared with those after the administration of Fungizone. The increment in the baseline plasma creatinine level was used as an index of renal function. All formulations increased this baseline value, but the novel formulations exhibited fewer renal effects than Fungizone did. However, a direct relationship between drug exposure in the kidneys and development of renal damage could not be found.

scholarly journals A safety and feasibility study comparing an intermittent high dose with a daily standard dose of liposomal amphotericin B for persistent neutropenic fever

2009 ◽  
Vol 58 (11) ◽  
pp. 1474-1485 ◽  
Author(s):  
Michael Ellis ◽  
Roos Bernsen ◽  
Hussein Ali-Zadeh ◽  
Jörgen Kristensen ◽  
Ulla Hedström ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Feasibility Study ◽  
Liposomal Amphotericin ◽  
Drug Exposure ◽  
Fungal Infections ◽  
Lower Proportion ◽  
Liposomal Amphotericin B ◽  
High Dose ◽  
Group A ◽  
Group B

A high intermittent dose regimen (group A: 10 mg kg−1 on day 1, 5 mg kg−1 on days 3 and 6) was compared with standard dosing (group B: 3 mg kg−1 per day for 14 days) of liposomal amphotericin B (LAB) for empirical treatment of persistent febrile neutropenia. A total cumulative dose of 1275 mg (group A) and 2800 mg (group B) was administered. Infusion-related adverse drug events, mainly rigors/chills, occurred more frequently with group A (11/45, 24 % infusions) than with group B (12/201, 6 % infusions) (P=0.002), which extended the mean infusion time by 20 min (P=0.001). Creatinine levels were similar in the two regimens: the A : B ratio of the area under the curve for creatinine (AUCCREATININE) for days 2–7 was 1.09 (P=0.27) and for days 2–14 was 1.05 (P=0.51). Rises in creatinine were mild (clinical toxicity criteria 1) in all patients with elevations. Hypokalaemia tended to be less severe in group A with a lower proportion of hypokalaemic days [57/143 (39 %) vs 80/137 (58 %), P=0.21], a higher AUCPOTASSIUM (A : B ratio of 1.06, P=0.12), a lower proportion of patients with hypokalaemia at the end of study (10 vs 61 %, P=0.01) and fewer potassium-supplemented days [12/210 (6 %) vs 41/210 (19.5 %), P<0.1]. There were mildly elevated median levels of serum bilirubin, alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase, which were similar for the two regimens and were usually associated with other co-existing co-morbid conditions. The AUC for these enzymes was also similar in the two groups. No patient had discontinuation of the study drug due to toxicity. Composite success was identical for each regimen (11/15 patients, 73 %). Three of the fifteen patients in group B and none in group A developed invasive fungal infections (IFIs). β-d-Glucan levels were similar in both groups for patients without an IFI [AUCGLUCAN of 362 and 683 (P=0.36) for groups A and B, respectively]. The rate of defervescence was similar for each regimen (P=0.75). This feasibility study suggests that a short intermittent high-dose course of 10/5/5 mg LAB kg−1 on days 1, 3 and 6 may be as safe and effective as a standard 14 day course of 3 mg kg−1 per day, with drug-acquisition cost savings and reduced drug exposure. A larger study is indicated for confirmation of this.

scholarly journals Safety, Tolerance, and Pharmacokinetics of High-Dose Liposomal Amphotericin B (AmBisome) in Patients Infected withAspergillus Species and Other Filamentous Fungi: Maximum Tolerated Dose Study

2001 ◽  
Vol 45 (12) ◽  
pp. 3487-3496 ◽  
Author(s):  
Thomas J. Walsh ◽  
Jesse L. Goodman ◽  
Peter Pappas ◽  
Ihor Bekersky ◽  
Donald N. Buell ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Filamentous Fungi ◽  
Liposomal Amphotericin ◽  
Fungal Infections ◽  
Liposomal Amphotericin B ◽  
High Dose ◽  
Time Curve ◽  
Days Of Therapy ◽  
Plasma Pharmacokinetics ◽  
Intent To Treat

ABSTRACT We conducted a phase I-II study of the safety, tolerance, and plasma pharmacokinetics of liposomal amphotericin B (L-AMB; AmBisome) in order to determine its maximally tolerated dosage (MTD) in patients with infections due to Aspergillus spp. and other filamentous fungi. Dosage cohorts consisted of 7.5, 10.0, 12.5, and 15.0 mg/kg of body weight/day; a total of 44 patients were enrolled, of which 21 had a proven or probable infection (13 aspergillosis, 5 zygomycosis, 3 fusariosis). The MTD of L-AMB was at least 15 mg/kg/day. Infusion-related reactions of fever occurred in 8 (19%) and chills and/or rigors occurred in 5 (12%) of 43 patients. Three patients developed a syndrome of substernal chest tightness, dyspnea, and flank pain, which was relieved by diphenhydramine. Serum creatinine increased two times above baseline in 32% of the patients, but this was not dose related. Hepatotoxicity developed in one patient. Steady-state plasma pharmacokinetics were achieved by day 7. The maximum concentration of drug in plasma (C max) of L-AMB in the dosage cohorts of 7.5, 10.0, 12.5, and 15.0 mg/kg/day changed to 76, 120, 116, and 105 μg/ml, respectively, and the mean area under the concentration-time curve at 24 h (AUC24) changed to 692, 1,062, 860, and 554 μg · h/ml, respectively, while mean CL changed to 23, 18, 16, and 25 ml/h/kg, respectively. These data indicate that L-AMB follows dose-related changes in disposition processing (e.g., clearance) at dosages of ≥7.5 mg/kg/day. Because several extremely ill patients had early death, success was determined for both the modified intent-to-treat and evaluable (7 days of therapy) populations. Response rates (defined as complete response and partial response) were similar for proven and probable infections. Response and stabilization, respectively, were achieved in 36 and 16% of the patients in the modified intent-to-treat population (n = 43) and in 52 and 13% of the patients in the 7-day evaluable population (n = 31). These findings indicate that L-AMB at dosages as high as 15 mg/kg/day follows nonlinear saturation-like kinetics, is well tolerated, and can provide effective therapy for aspergillosis and other filamentous fungal infections.

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