scholarly journals Population Pharmacokinetics of Amphotericin B Lipid Complex in Neonates

2005 ◽  
Vol 49 (12) ◽  
pp. 5092-5098 ◽  
Author(s):  
Gudrun Würthwein ◽  
Andreas H. Groll ◽  
Georg Hempel ◽  
Felice C. Adler-Shohet ◽  
Jay M. Lieberman ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Gestational Age ◽  
High Performance ◽  
Interindividual Variability ◽  
Age Groups ◽  
Compartment Model ◽  
Multicenter Trial ◽  
Volume Of Distribution ◽  
Lipid Complex ◽  
Amphotericin B Lipid Complex

ABSTRACT The pharmacokinetics of amphotericin B lipid complex (ABLC) were investigated in neonates with invasive candidiasis enrolled in a phase II multicenter trial. Sparse blood (153 samples; 1 to 9 per patient, 1 to 254 h after the dose) and random urine and cerebrospinal fluid (CSF) samples of 28 neonates (median weight [WT], 1.06 kg; range, 0.48 to 4.9 kg; median gestational age, 27 weeks; range, 24 to 41 weeks) were analyzed. Patients received intravenous ABLC at 2.5 (n = 15) or 5 (n = 13) mg/kg of body weight once a day over 1 or 2 h, respectively, for a median of 21 days (range, 4 to 47 days). Concentrations of amphotericin B were quantified as total drug by high-performance liquid chromatography. Blood data for time after dose (TAD) of <24 h fitted best to a one-compartment model with an additive-error model for residual variability, WT0.75 (where 0.75 is an exponent) as a covariate of clearance (CL), and WT as a covariate of volume of distribution (V). Prior amphotericin B, postnatal age, and gestational age did not further improve the model. The final model equations were CL (liters/h) = 0.399 × WT0.75 (interindividual variability, 35%) and V (liters) = 10.5 × WT (interindividual variability, 43%). Noncompartmental analysis of pooled data with a TAD of >24 h revealed a terminal half-life of 395 h. Mean concentrations in the urine after 1, 2, and 3 weeks ranged from 0.082 to 0.430 μg/ml, and those in CSF ranged from undetectable to 0.074 μg/ml. The disposition of ABLC in neonates was similar to that observed in other age groups: weight was the only factor that influenced clearance. Based on these results and previously published safety and efficacy data, we recommend a daily dosage between 2.5 and 5.0 mg/kg for treatment of invasive Candida infections in neonates.

scholarly journals Pharmacokinetic profile of ABELCET (amphotericin B lipid complex injection): combined experience from phase I and phase II studies.

1997 ◽  
Vol 41 (10) ◽  
pp. 2201-2208 ◽  
Author(s):  
A Adedoyin ◽  
J F Bernardo ◽  
C E Swenson ◽  
L E Bolsack ◽  
G Horwith ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Interindividual Variability ◽  
Pharmacokinetic Profile ◽  
Volume Of Distribution ◽  
Lipid Complex ◽  
Phase Ii Studies ◽  
Amphotericin B Lipid Complex ◽  
Trough Concentrations ◽  
Dose Limiting Toxicity ◽  
Wide Interindividual Variability

Amphotericin B (AmB) has been the most effective systemic antifungal agent, but its use is limited by the dose-limiting toxicity of the conventional micellar dispersion formulation (Fungizone). New formulations with better and improved safety profiles are being developed and include ABELCET (formerly ABLC), but their dispositions have not been well characterized; hence, the reason for their improved profiles remains unclear. This report details the pharmacokinetics of ABELCET examined in various pharmacokinetic and efficacy studies by using whole-blood measurements of AmB concentration performed by high-pressure liquid chromatography. The data indicated that the disposition of AmB after administration of ABELCET is different from that after administration of Fungizone, with a faster clearance and a larger volume of distribution. It exhibits complex and nonlinear pharmacokinetics with wide interindividual variability, extensive distribution, and low clearance. The pharmacokinetics were unusual. Clearance and volume of distribution were increased with dose, peak and trough concentrations after multiple dosings increased less than proportionately with dose, steady state appeared to have been attained in 2 to 3 days, despite an estimated half-life of up to 5 days, and there was no evidence of significant accumulation in the blood. The data are internally consistent, even though they were gathered under different conditions and circumstances. The pharmacokinetics of ABELCET suggest that lower concentrations in blood due to higher clearance and greater distribution may be responsible for its improved toxicity profile compared to those of conventional formulations.

scholarly journals Comparative Efficacies, Toxicities, and Tissue Concentrations of Amphotericin B Lipid Formulations in a Murine Pulmonary Aspergillosis Model

2006 ◽  
Vol 50 (6) ◽  
pp. 2122-2131 ◽  
Author(s):  
Jon A. Olson ◽  
Jill P. Adler-Moore ◽  
Julie Schwartz ◽  
Gerard M. Jensen ◽  
Richard T. Proffitt
Keyword(s):  
Amphotericin B ◽  
High Performance ◽  
Therapeutic Index ◽  
Pulmonary Aspergillosis ◽  
Lipid Complex ◽  
Drug Concentrations ◽  
Kidney Morphology ◽  
Amphotericin B Lipid Complex ◽  
Effective Use ◽  
Lipid Formulations

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 μg/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.

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 A Pharmacokinetic Study of Amphotericin B Lipid Complex Injection (Abelcet) in Patients with Definite or Probable Systemic Fungal Infections

2000 ◽  
Vol 44 (10) ◽  
pp. 2900-2902 ◽  
Author(s):  
Adedayo Adedoyin ◽  
Christine E. Swenson ◽  
Lois E. Bolcsak ◽  
Andrzej Hellmann ◽  
Danuta Radowska ◽  
...  
Keyword(s):  
Body Weight ◽  
Steady State ◽  
Amphotericin B ◽  
Fungal Infections ◽  
Volume Of Distribution ◽  
Lipid Complex ◽  
Systemic Fungal Infection ◽  
Elimination Half ◽  
Amphotericin B Lipid Complex ◽  
Pharmacokinetic Evaluation

ABSTRACT This study describes a pharmacokinetic evaluation of amphotericin B (AMB) lipid complex injection (ABLC or Abelcet) in 17 patients with systemic fungal infection administered 5 mg/kg of body weight/day by infusion for 10 to 17 days. The results showed that AMB exhibited multiexponential disposition with high clearance, large volume of distribution at steady state, and long apparent elimination half-life but no evidence of accumulation in the blood after multiple daily doses. The results confirm previous observations and further reinforce the suggestion that ABLC may exist as a depot in the tissues from which free AMB is slowly released to limit exposure.

Two-year Longitudinal Evaluation of Amphotericin B Lipid Complex Injection in a Tertiary Care Medical Center

2000 ◽  
Vol 35 (2) ◽  
pp. 176-181 ◽  
Author(s):  
Leanne D. Kennedy ◽  
Julie F. Connelly ◽  
Kevin M. Kuzma
Keyword(s):  
Serum Creatinine ◽  
Amphotericin B ◽  
Fungal Infections ◽  
Tertiary Care ◽  
Serum Creatinine Concentration ◽  
Creatinine Concentration ◽  
Lipid Complex ◽  
Tertiary Care Medical Center ◽  
Amphotericin B Lipid Complex ◽  
The Mean

A 2-year concurrent drug use evaluation was conducted in 156 patients to determine whether Abelcet (amphotericin B lipid complex injection) was being prescribed according to institution-approved guidelines and to characterize the patient population receiving Abelcet. Eighty-nine patients (57%) had fungal infections documented by chest x-ray, computed tomography, or fungal cultures. Sixty-seven (43%) had clinically suspected fungal infections. The Abelcet mean dose by weight was 5 mg/kg/day (actual body weight). Seventy-one patients (46%) met the established guidelines for use; 85 (54%) did not. Premedication was given to 64% of the patients; only 15 patients (10%) experienced documented fever and chills. A total of 72 patients (46%) died during therapy. Of the 75 patients who completed therapy in the hospital, 41 were switched to conventional amphotericin B, fluconazole, or itraconazole following a decrease in serum creatinine concentration, and 34 did not receive further antifungal therapy. The mean length of Abelcet therapy was 11 days. The mean increase in serum creatinine concentration at discontinuation of therapy was 0.2 mg/dL. Continued monitoring of Abelcet use was recommended and established guidelines were reaffirmed. Hydration with normal saline before and after dosing was suggested to help improve renal function, and dopamine was recommended to increase renal blood flow.

Amphotericin B Lipid Complex

Drugs ◽  
2004 ◽  
Vol 64 (17) ◽  
pp. 1905-1911 ◽  
Author(s):  
David R Goldsmith ◽  
Caroline M Perry
Keyword(s):  
Amphotericin B ◽  
Lipid Complex ◽  
Amphotericin B Lipid Complex

scholarly journals Combination Echinocandin-Polyene Treatment of Murine Mucormycosis

2008 ◽  
Vol 52 (4) ◽  
pp. 1556-1558 ◽  
Author(s):  
Ashraf S. Ibrahim ◽  
Teclegiorgis Gebremariam ◽  
Yue Fu ◽  
John E. Edwards ◽  
Brad Spellberg
Keyword(s):  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
Class Effect ◽  
Lipid Complex ◽  
Enhanced Activity ◽  
Amphotericin B Lipid Complex ◽  
Disseminated Mucormycosis

ABSTRACT We previously found that caspofungin synergized with amphotericin B lipid complex in treating murine mucormycosis. We now report a similarly enhanced activity of liposomal amphotericin combined with micafungin or anidulafungin in mice with disseminated mucormycosis. The efficacy of combination echinocandin-polyene therapy for mucormycosis is a class effect.

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