Dataset Information

Population pharmacokinetics of amphotericin B lipid complex in neonates.

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 x WT(0.75) (interindividual variability, 35%) and V (liters) = 10.5 x 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 microg/ml, and those in CSF ranged from undetectable to 0.074 microg/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.

SUBMITTER: Wurthwein G

PROVIDER: S-EPMC1315949 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:ObjectivesTo develop a population pharmacokinetic model for IV phenobarbital in neonates following cardiac surgery and perform simulations to identify optimal dosing regimens.DesignRetrospective single-center pharmacokinetic study.SettingCardiac ICU at Children's Hospital of Philadelphia.PatientsConsecutive neonates who received greater than or equal to one dose of IV phenobarbital and had greater than or equal to one phenobarbital concentration drawn per standard of care from June 15, 2012, to October 15, 2018.InterventionsNone.Measurements and main resultsA population pharmacokinetic model was developed using nonlinear mixed-effects modeling. Simulations were performed using the final model variables. Optimal phenobarbital loading doses were determined based on attainment of peak and maintenance concentrations between 20 and 40 mg/L. A total of 37 neonates contributed 159 pharmacokinetic samples. The median (range) weight, postmenstrual age, and postnatal age were 3.2 kg (1.3-3.8), 39 2/7 weeks (28 2/7 to 42 6/7), and 5 days (0-26 d), respectively. Twelve patients (32%) were on extracorporeal membrane oxygenation. An one-compartment model best described the data. The final population pharmacokinetic model included (1) weight and postnatal age for clearance and (2) weight, extracorporeal membrane oxygenation, and albumin for volume of distribution. In neonates not on extracorporeal membrane oxygenation, loading doses of 30 and 20 mg/kg reached goal concentration with albumin values less than or equal to 3 and 3.5 mg/dL, respectively. Loading doses of 30 mg/kg reached goal concentration on extracorporeal membrane oxygenation regardless of albumin values. Maintenance doses of 4-5 mg/kg/d reached goal concentration in all neonates.ConclusionsIn neonates following cardiac surgery, phenobarbital clearance increased with postnatal age. Volume of distribution increased with extracorporeal membrane oxygenation and lower albumin values. Loading doses of 30 mg/kg on extracorporeal membrane oxygenation and 20-30 mg/kg without extracorporeal membrane oxygenation were needed to reach goal concentration based on simulations.

Project description:Liposomal 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 (V(1)) (CL, 0.462 liter/h ± 25%; V(1), 8.33 liters ± 29%; intercompartmental clearance [Q], 1.25 liters/h; peripheral volume of distribution [V(2)], 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%; V(1), 19.2 liters ± 38%; Q, 2.18 liters/h ± 47%; V(2), 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.

Project description:BackgroundThere is a major need for information on pharmacokinetics (PK) of benznidazole (BNZ) in children with Chagas disease (CD). We conducted a multicentre population PK, safety and efficacy study in children, infants and neonates with CD treated with BNZ (formulated in 100 mg tablets or 12.5 mg dispersible tablets, developed by the pharmaceutical company LAFEPE, in a collaboration with DNDi).Methods81 children 0-12 years old were enrolled at 5 pediatric centers in Argentina. Diagnosis of T. cruzi infection was confirmed by direct microscopic examination, or at least two positive conventional serological tests. Subject enrolment was stratified by age: newborns to 2 years (minimum of 10 newborns) and >2-12 years. BNZ 7.5 mg/kg/d was administered in two daily doses for 60 days. Five blood samples per child were obtained at random times within pre-defined time windows at Day 0 at 2-5 h post-dose; during steady state, one sample at Day 7 and at Day 30; and two samples at 12-24 h after final BNZ dose at Day 60. The primary efficacy endpoint was parasitological clearance by qualitative PCR at the end of treatment.ResultsForty-one (51%) patients were under 2 years of age (including 14 newborns <1 month of age). Median age at enrolment was 22 months (mean: 43.2; interquartile range (IQR) 7-72 months). The median measured BNZ Cmax was 8.32 mg/L (IQR 5.95-11.8; range 1.79-19.38). Median observed BNZ Cmin (trough) concentration was 2 mg/L (IQR 1.25-3.77; range 0.14-7.08). Overall median simulated Css was 6.3 mg/L (IQR 4.7-8.5 mg/L). CL/F increased quickly during the first month of postnatal life and reached adult levels after approximately 10 years of age. Negative qPCR was observed at the end of treatment in all 76 patients who completed the treatment. Five patients discontinued treatment (3 due to AEs and 2 due to lack of compliance).ConclusionWe observed lower BNZ plasma concentrations in infants and children than those previously reported in adults treated with comparable mg/kg doses. Despite these lower concentrations, pediatric treatment was well tolerated and universally effective, with a high response rate and infrequent, mild AEs.Trial registrationRegistered in clinicaltrials.gov #NCT01549236.

Dataset Information

Population pharmacokinetics of amphotericin B lipid complex in neonates.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets