scholarly journals Population Pharmacokinetics of Eryaspase in Patients with Acute Lymphoblastic Leukemia or Pancreatic Adenocarcinoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 1-2
Author(s):  
Frank Hoke ◽  
Kara Schmelzer ◽  
Jianping Zhang ◽  
Philip Lorenzi ◽  
Iman El-Hariry
Keyword(s):  
Body Weight ◽  
Acute Lymphoblastic Leukemia ◽  
Population Pharmacokinetics ◽  
Pancreatic Adenocarcinoma ◽  
Lymphoblastic Leukemia ◽  
Volume Of Distribution ◽  
Parameter Estimates ◽  
Model Parameters ◽  
Bootstrap Analysis ◽  
Final Model

L-asparaginase (ASNase) is a microbial enzyme and a chemotherapeutic agent that has been a standard component of multi-agent chemotherapy for the treatment of acute lymphoblastic leukemia (ALL). Eryaspase, ASNase encapsulated in red blood cells, is being developed with an improved pharmacokinetic profile compared to some other ASNase products. The purpose of the present analysis was to describe the population pharmacokinetics (Pop PK) of eryaspase and sources of variability in two patient populations - ALL or pancreatic adenocarcinoma (PAC). Eryaspase was administered intravenously at doses of 50, 100, and 150 U/kg to patients enrolled in Phase 1-3 clinical trials in combination with chemotherapy. Either serial or sparse pharmacokinetic sampling was performed in each study. A Pop PK model was fit to the data using Nonlinear Mixed Effects Modeling (NONMEM®) software, and included an assessment of covariates, e.g., demography, disease type, formulation, and immunogenicity. The adequacy of the final Pop PK model and parameter estimates was investigated with a visual predictive check (VPC) and non-parametric bootstrap analysis. Using the final Pop PK model, a simulation was performed for eryaspase 100 U/kg every 2 weeks and included a target trough reference ASNase level of 100 U/L. The Pop PK analysis included 162 patients (94 ALL and 68 PAC) with median age of 56.5 years (range of 2-84 years). Eryaspase concentration-time data were best described by a one compartment model with first order elimination. Population clearance and volume of distribution were 0.29 L/day and 6.12 L, respectively. That equates to a terminal half-life of approximately 15 days. Both clearance and volume of distribution were found to increase with increasing body weight. No other covariate tested was found to influence eryaspase pharmacokinetics, including patient age and gender, patient population (ALL vs PAC), and formulation (native vs recombinant ASNase). VPC showed the final model well captured the data; furthermore, the final model parameters and bootstrap results were in accordance. The effect of positive presence of neutralizing antibodies on eryaspase clearance was inconclusive because of variability within and across studies. The figure below displays the median (solid line) and 95% prediction interval (blue shaded region) of simulated ASNase concentrations with a reference line of 100 U/L. The simulation shows that approximately 95% of patients would exceed the target trough level of 100 U/L following the first and subsequent infusions following administration of 100 U/kg every 2 weeks. In conclusion, the Pop PK analysis provided valuable information in the characterization of eryaspase and factors that influence its variability. As expected for an RBC-type product, the clearance was low, and the volume of distribution was consistent with blood volume. Terminal phase t1/2 was approximately 15 days, and body weight was a significant covariate for both clearance and volume of distribution. Based on simulation, an eryaspase dosing regimen of 100 U/kg every 2 weeks would provide trough ASNase activity levels above 100 U/L for approximately 95% of patients. Eryaspase is currently being investigated in ALL patients with hypersensitivity reactions, as well as a phase 3 clinical study in PAC (Trybeca-1) and a phase 2 study in Triple Negative Breast Cancer (Trybeca-2). Figure Disclosures Hoke: Erytech: Current Employment. Lorenzi:Precision Pathways: Consultancy. El-Hariry:Erytech: Current Employment.

scholarly journals Population Pharmacokinetics and Dosing Optimization of Linezolid in Pediatric Patients

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Si-Chan Li ◽  
Qi Ye ◽  
Hua Xu ◽  
Long Zhang ◽  
Yang Wang
Keyword(s):  
Body Weight ◽  
Population Pharmacokinetics ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Pediatric Patients ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Nonparametric Bootstrap ◽  
Bootstrap Analysis ◽  
Final Model

ABSTRACT Linezolid is a synthetic antibiotic very effective in the treatment of infections caused by Gram-positive pathogens. Although the clinical application of linezolid in children has increased progressively, data on linezolid pharmacokinetics in pediatric patients are very limited. The aim of this study was to develop a population pharmacokinetic model for linezolid in children and optimize the dosing strategy in order to improve therapeutic efficacy. We performed a prospective pharmacokinetic study of pediatric patients aged 0 to 12 years. The population pharmacokinetic model was developed using the NONMEM program. Goodness-of-fit plots, nonparametric bootstrap analysis, normalized prediction distribution errors, and a visual predictive check were employed to evaluate the final model. The dosing regimen was optimized based on the final model. The pharmacokinetic data from 112 pediatric patients ages 0.03 to 11.9 years were analyzed. The pharmacokinetics could best be described by a one-compartment model with first-order elimination along with body weight and the estimated glomerular filtration rate as significant covariates. Simulations demonstrated that the currently approved dosage of 10 mg/kg of body weight every 8 h (q8h) would lead to a high risk of underdosing for children in the presence of bacteria with MICs of ≥2 mg/liter. To reach the pharmacokinetic target, an elevated dosage of 15 or 20 mg/kg q8h may be required for them. The population pharmacokinetics of linezolid were characterized in pediatric patients, and simulations provide an evidence-based approach for linezolid dosage individualization.

scholarly journals Population Pharmacokinetics of Pyronaridine in Pediatric Malaria Patients

2015 ◽  
Vol 60 (3) ◽  
pp. 1450-1458 ◽  
Author(s):  
Amal Ayyoub ◽  
Janthima Methaneethorn ◽  
Michael Ramharter ◽  
Abdoulaye A. Djimde ◽  
Mamadou Tekete ◽  
...  
Keyword(s):  
Population Pharmacokinetics ◽  
Uncomplicated Malaria ◽  
Pediatric Patients ◽  
Visual Predictive Check ◽  
Volume Of Distribution ◽  
Phase Iii ◽  
Parameter Estimates ◽  
Final Model ◽  
Content Type ◽  
Granule Formulation

Pyramax is a pyronaridine (PYR)-artesunate (PA) combination for the treatment of uncomplicated malaria in adult and pediatric patients. A granule formulation of this combination is being developed for treatment of uncomplicatedP. falciparumandP. vivaxmalaria in pediatric patients. The aims of this study were to describe the pharmacokinetics of PYR using a total of 1,085 blood PYR concentrations available from 349 malaria patients younger than 16 years of age with mild to moderate uncomplicated malaria and to confirm the dosing regimen for the pediatric granule formulation. Nonlinear mixed-effects modeling using NONMEM software was used to obtain the pharmacokinetic and inter- and intraindividual variability parameter estimates. The population pharmacokinetics of PYR were described by a two-compartment model with first-order absorption and elimination. Allometric scaling was implemented to address the effect of body weight on clearance and volume parameters. The final parameter estimates of PYR apparent clearance (CL/F), central volume of distribution (V2/F), peripheral volume of distribution (V3/F), intercompartmental clearance (Q/F), and absorption rate constant (Ka) were 377 liters/day, 2,230 liters, 3,230 liters, 804 liters/day and 17.9 day−1, respectively. Covariate model building conducted using forward addition (P< 0.05) followed by backward elimination (P< 0.001) yielded two significant covariate-parameter relationships, i.e., age onV2/Fand formulation onKa. Evaluation of bootstrapping, visual predictive check, and condition number indicated that the final model displayed satisfactory robustness, predictive power, and stability. Simulations of PYR concentration-time profiles generated from the final model show similar exposures across pediatric weight ranges, supporting the proposed labeling for weight-based dosing of Pyramax granules. (These studies have been registered at ClinicalTrials.gov under registration no. NCT00331136 [phase II study] and NCT00541385, NCT00403260, NCT00422084, and NCT00440999 [phase III studies]. The most recent phase III study was registered at pactr.org under registration no. PACTR201105000286876.)

scholarly journals Population Pharmacokinetics of Fluconazole in Premature Infants with Birth Weights Less than 750 Grams

2016 ◽  
Vol 60 (9) ◽  
pp. 5539-5545 ◽  
Author(s):  
Jeremiah D. Momper ◽  
Edmund V. Capparelli ◽  
Kelly C. Wade ◽  
Anand Kantak ◽  
Ramasubbareddy Dhanireddy ◽  
...  
Keyword(s):  
Body Weight ◽  
Serum Creatinine ◽  
Population Pharmacokinetics ◽  
Premature Infants ◽  
Invasive Candidiasis ◽  
Parameter Estimates ◽  
Population Parameter ◽  
Weekly Dose ◽  
Final Model ◽  
Population Pk

ABSTRACTFluconazole is an effective agent for prophylaxis of invasive candidiasis in premature infants. The objective of this study was to characterize the population pharmacokinetics (PK) and dosing requirements of fluconazole in infants with birth weights of <750 g. As part of a randomized clinical trial, infants born at <750 g birth weight received intravenous (i.v.) or oral fluconazole at 6 mg/kg of body weight twice weekly. Fluconazole plasma concentrations from samples obtained by either scheduled or scavenged sampling were measured using a liquid chromatography-tandem mass spectrometry assay. Population PK analysis was conducted using NONMEM 7.2. Population PK parameters were allometrically scaled by body weight. Covariates were evaluated by univariable screening followed by multivariable assessment. Fluconazole exposures were simulated in premature infants using the final PK model. A population PK model was developed from 141 infants using 604 plasma samples. Plasma fluconazole PK were best described by a one-compartment model with first-order elimination. Only serum creatinine was an independent predictor for clearance in the final model. The typical population parameter estimate for oral bioavailability in the final model was 99.5%. Scavenged samples did not bias the parameter estimates and were as informative as scheduled samples. Simulations indicated that the study dose maintained fluconazole troughs of >2,000 ng/ml in 80% of simulated infants at week 1 and 59% at week 4 of treatment. Developmental changes in fluconazole clearance are best predicted by serum creatinine in this population. A twice-weekly dose of 6 mg/kg achieves appropriate levels for prevention of invasive candidiasis in extremely premature infants.

scholarly journals Pharmacokinetics, Microbial Response, and Pulmonary Outcomes of Multidose Intravenous Azithromycin in Preterm Infants at Risk for Ureaplasma Respiratory Colonization

2014 ◽  
Vol 59 (1) ◽  
pp. 570-578 ◽  
Author(s):  
L. Marcela Merchan ◽  
Hazem E. Hassan ◽  
Michael L. Terrin ◽  
Ken B. Waites ◽  
David A. Kaufman ◽  
...  
Keyword(s):  
At Risk ◽  
Body Weight ◽  
Population Pharmacokinetics ◽  
Preterm Infants ◽  
Volume Of Distribution ◽  
Preterm Neonates ◽  
Parameter Estimates ◽  
Pharmacokinetic Data ◽  
Mixed Effect ◽  
Content Type

ABSTRACTThe study objectives were to refine the population pharmacokinetics (PK) model, determine microbial clearance, and assess short-term pulmonary outcomes of multiple-dose azithromycin treatment in preterm infants at risk forUreaplasmarespiratory colonization. Fifteen subjects (7 of whom wereUreaplasmapositive) received intravenous azithromycin at 20 mg/kg of body weight every 24 h for 3 doses. Azithromycin concentrations were determined in plasma samples obtained up to 168 h post-first dose by using a validated liquid chromatography-tandem mass spectrometry method. Respiratory samples were obtained predose and at three time points post-last dose forUreaplasmaculture, PCR, antibiotic susceptibility testing, and cytokine concentration determinations. Pharmacokinetic data from these 15 subjects as well as 25 additional subjects (who received either a single 10-mg/kg dose [n= 12] or a single 20-mg/kg dose [n= 13]) were analyzed by using a nonlinear mixed-effect population modeling (NONMEM) approach. Pulmonary outcomes were assessed at 36 weeks post-menstrual age and 6 months adjusted age. A 2-compartment model with all PK parameters allometrically scaled on body weight best described the azithromycin pharmacokinetics in preterm neonates. The population pharmacokinetics parameter estimates for clearance, central volume of distribution, intercompartmental clearance, and peripheral volume of distribution were 0.15 liters/h · kg0.75, 1.88 liters · kg, 1.79 liters/h · kg0.75, and 13 liters · kg, respectively. The estimated area under the concentration-time curve over 24 h (AUC24)/MIC90value was ∼4 h. All posttreatment cultures were negative, and there were no drug-related adverse events. OneUreaplasma-positive infant died at 4 months of age, but no survivors were hospitalized for respiratory etiologies during the first 6 months (adjusted age). Thus, a 3-day course of 20 mg/kg/day intravenous azithromycin shows preliminary efficacy in eradicatingUreaplasmaspp. from the preterm respiratory tract.

scholarly journals The Population Pharmacokinetics of Meropenem in Adult Patients With Rifampicin-Sensitive Pulmonary Tuberculosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Ahmed A. Abulfathi ◽  
Veronique de Jager ◽  
Elana van Brakel ◽  
Helmuth Reuter ◽  
Nikhil Gupte ◽  
...  
Keyword(s):  
Body Weight ◽  
Creatinine Clearance ◽  
Population Pharmacokinetics ◽  
Goodness Of Fit ◽  
Compartment Model ◽  
Parameter Estimates ◽  
Final Model ◽  
Once Daily ◽  
Two Compartment Model ◽  
Relative Standard

Background: Meropenem is being investigated for repurposing as an anti-tuberculosis drug. This study aimed to develop a meropenem population pharmacokinetics model in patients with pulmonary tuberculosis and identify covariates explaining inter-individual variability.Methods: Patients were randomized to one of four treatment groups: meropenem 2 g three times daily plus oral rifampicin 20 mg/kg once daily, meropenem 2 g three times daily, meropenem 1 g three times daily, and meropenem 3 g once daily. Meropenem was administered by intravenous infusion over 0.5–1 h. All patients also received oral amoxicillin/clavulanate together with each meropenem dose, and treatments continued daily for 14 days. Intensive plasma pharmacokinetics sampling over 8 h was conducted on the 14th day of the study. Nonlinear mixed-effects modeling was used for data analysis. The best model was chosen based on likelihood metrics, goodness-of-fit plots, and parsimony. Covariates were tested stepwise.Results: A total of 404 concentration measurements from 49 patients were included in the analysis. A two-compartment model parameterized with clearance (CL), inter-compartmental clearance (Q), and central (V1) and peripheral (V2) volumes of distribution fitted the data well. Typical values of CL, Q, V1, and V2 were 11.8 L/h, 3.26 L/h, 14.2 L, and 3.12 L, respectively. The relative standard errors of the parameter estimates ranged from 3.8 to 35.4%. The covariate relations included in the final model were creatinine clearance on CL and allometric scaling with body weight on all disposition parameters. An effect of age on CL as previously reported could not be identified.Conclusion: A two-compartment model described meropenem population pharmacokinetics in patients with pulmonary tuberculosis well. Covariates found to improve model fit were creatinine clearance and body weight but not rifampicin treatment. The final model will be used for an integrated pharmacokinetics/pharmacodynamics analysis linking meropenem exposure to early bactericidal activity.

Vancomycin volume of distribution estimation in adults with class III obesity

2019 ◽  
Author(s):  
Ryan D Dunn ◽  
Ryan L Crass ◽  
Joseph Hong ◽  
Manjunath P Pai ◽  
Lynne C Krop
Keyword(s):  
Body Weight ◽  
Total Body Weight ◽  
Volume Of Distribution ◽  
Patient Specific ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Parameter Estimates ◽  
Class Iii ◽  
Class Iii Obesity ◽  
Total Body

Abstract Purpose To compare methods of estimating vancomycin volume of distribution (V) in adults with class III obesity. Methods A retrospective, multicenter pharmacokinetic analysis of adults treated with vancomycin and monitored through measurement of peak and trough concentrations was performed. Individual pharmacokinetic parameter estimates were obtained via maximum a posteriori Bayesian analysis. The relationship between V and body weight was assessed using linear regression. Mean bias and root-mean-square error (RMSE) were calculated to assess the precision of multiple methods of estimating V. Results Of 241 patients included in the study sample, 159 (66.0%) had a BMI of 40.0–49.9 kg/m2, and 82 (34.0%) had a BMI of ≥50.0 kg/m2. The median (5th, 95th percentile) weight of patients was 136 (103, 204) kg, and baseline characteristics were similar between BMI groups. The mean ± S.D. V was lower in patients with a BMI of 40.0–49.9 kg/m2 than in those with a BMI of ≥50.0 kg/m2 (72.4 ± 19.6 L versus 79.3 ± 20.6 L, p = 0.009); however, body size poorly predicted V in regression analyses (R2 < 0.20). A fixed estimate of V (75 L) or use of 0.52 L/kg by total body weight yielded similar bias and error in this population. Conclusion Results of the largest analysis of vancomycin V in class III obesity to date indicated that use of a fixed V value (75 L) and use of a TBW-based estimate (0.52 L/kg) for estimation of vancomycin V in patients with a BMI of ≥40.0 kg/m2 have similar bias. Two postdistribution vancomycin concentrations are needed to accurately determine patient-specific pharmacokinetic parameters, estimate AUC, and improve the precision of vancomycin dosing in this patient population.

scholarly journals Population Pharmacokinetics of Nevirapine, Zidovudine, and Didanosine in Human Immunodeficiency Virus-Infected Patients

1999 ◽  
Vol 43 (1) ◽  
pp. 121-128 ◽  
Author(s):  
Xiao-Jian Zhou ◽  
Lewis B. Sheiner ◽  
Richard T. D’Aquila ◽  
Michael D. Hughes ◽  
Martin S. Hirsch ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Body Weight ◽  
Population Pharmacokinetics ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Zero Order ◽  
Triple Combination ◽  
Entire Study ◽  
First Order ◽  
Immunodeficiency Virus

ABSTRACT The population pharmacokinetics of nevirapine (NVP), zidovudine (ZDV), and didanosine (ddI) were evaluated in a total of 175 patients infected with human immunodeficiency virus randomized to receive either a double combination of ZDV plus ddI or a triple combination of NVP plus ZDV plus ddI as a substudy of the AIDS Clinical Trials Group Protocol 241. Levels (approximating 3.5 determinations/patient) of the three drugs in plasma were measured during 44 of a total 48 weeks of study treatment, and a set of potential covariates was available for nonlinear mixed-effect modeling analysis. A one-compartment model with zero-order input and first-order elimination was fitted to the NVP data. Individual oral clearance (CL) and volume of distribution (V) averaged 0.0533 liters/h/kg of body weight and 1.17 liters/kg, respectively. Gender was the only covariate which significantly correlated with the CL of NVP. ZDV and ddI data were described by a two-compartment model with zero-order input and first-order elimination. Individual mean oral CL,V SS (volume of distribution at steady state), and V of ZDV were 1.84 liters/h/kg and 6.68 and 2.67 liters/kg, respectively, with body weight and age as correlates of CL and body weight as a correlate of V SS. The average individual oral CL, V SS, andV of ddI were 1.64 liters/h/kg and 3.56 and 2.74 liters/kg, respectively, with body weight as a significant correlate of both CL and V SS. The relative bioavailability (F) of ZDV and ddI in the triple combination compared to that in the double combination was also evaluated. No significant effects of the combination regimens on the F of ddI were detected (F TRIPLE = 1.05 andF DOUBLE = 1 by definition), but theF of ZDV was markedly reduced by the triple combination, being only 67.7% of that of the double combination. Large (>50%) intraindividual variability was associated with both ZDV and ddI pharmacokinetics. Individual cumulative area under the plasma drug level-time curve of the three drugs was calculated for the entire study period as a measure of drug exposure based on the individual data and the final-model estimates of structural and statistical parameters.

Effective Induction of Apoptosis by Mistletoe Plant Extracts in an Acute Lymphoblastic Leukemia Model.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1880-1880
Author(s):  
Georg Seifert ◽  
Patrick Jesse ◽  
Aram Prokop ◽  
Tobias Reindl ◽  
Stephan Lobitz ◽  
...  
Keyword(s):  
Cell Death ◽  
Body Weight ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
The Body ◽  
Induction Of Apoptosis ◽  
First Time ◽  
Over Time

Abstract Mistletoe (Viscum album) is one of the most used alternative cancer therapies applied as monotherapy or in combination with conventional therapies. Anti-tumor effects of mistletoe (MT) extracts were related to cytostatic and immunomodulatory effects observed in vitro. Aqueous MT extracts contain the three mistletoe lectins I, II and III as one predominant group of biologically active agents. The MT lectins inhibit protein biosynthesis by inactivating the 60S ribosomal subunit. Mistletoe lectin-I (ML-I) is one important apoptosis inducing compound. It is a heterodimer that consists of a cytotoxic A-chain (ribosome inactivating protein, RIP type 1) linked by a carbohydrate binding B-chain for cellular lectin uptake. However, although MT is widely used, there is a lack of scientific preclinical and clinical data. Here, we describe for the first time efficacy and mechanism of MT extracts against lymphoblastic leukemia in vitro and in vivo. For this purpose, we first investigated both the cytotoxic effect and mechanism of action of two standardized aqueous MT extracts (MT obtained from fir trees (MT-A); MT obtained from pine trees (MT-P)) and isolated ML-I, in three human acute lymphoblastic leukemia (ALL) cell lines (NALM-6, sup-B-15 and REH). MT-A, MT-P and ML-I clearly inhibited cell proliferation as determined by LDH reslease assays at very low concentrations (ML-I LD50 from 0,05 ng/ml to 10 ng/ml depending on the host tree) with MT-P being the most cytotoxic extract. The mechanism of cell death was determined by DNA-fragmentation assays. These indicated dose dependent induction of apoptosis as the main mechanism of cell death. Finally, we evaluated the efficacy of MT-A and MT-P in an in vivo SCID-model of pre-B ALL (NALM-6). For this purpose, mice (n=8/group) were injected i.v. with 1 × 106NALM6 cells and treated by intraperitoneal injections four times per week for 3 weeks (day 1–4; 7–11; 14–18) at varying doses (1, 5 and 50 mg/Kg (plant weight/body weight)). Mice (n=8) treated with PBS and cyclophosphamide (100 mg/kg, once on day 1) were used as negative and positive controls, respectively. Toxicity, peripheral blood counts, bodyweight and survival was determined over time. Interestingly, both MT extracts in all tested concentrations significantly improved survival (up to 55,4 days) in contrast to controls (34,6 days). Furthermore, no hematologic side effects were observed from this treatment as indicated by completely stable blood counts. Also the body weight of treated animals remained stable over time indicating a complete absence of systemic toxicity in the selected dose range. In summary, we demonstrate for the first time efficacy and mechanism of MT extracts against ALL in vitro and in vivo and hereby provide an important base line for the design of clinical trials with these compounds.

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