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

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.

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

Frontiers in Pharmacology ◽

10.3389/fphar.2021.637618 ◽

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.

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

Blood ◽

10.1182/blood-2020-134377 ◽

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.

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Population Pharmacokinetic Modeling and Pharmacodynamic Target Attainment Simulation of Piperacillin/Tazobactam for Dosing Optimization in Late Elderly Patients with Pneumonia

Antibiotics ◽

10.3390/antibiotics9030113 ◽

2020 ◽

Vol 9 (3) ◽

pp. 113 ◽

Cited By ~ 1

Author(s):

Noriyuki Ishihara ◽

Nobuhiro Nishimura ◽

Kazuro Ikawa ◽

Fumi Karino ◽

Kiyotaka Miura ◽

...

Keyword(s):

Plasma Concentration ◽

Elderly Patients ◽

Distribution Volume ◽

Population Pharmacokinetic ◽

Parameter Estimates ◽

Target Attainment ◽

Old Patients ◽

Final Model ◽

Concentration Time ◽

Population Pk

The aim of this study was to develop a population pharmacokinetic model for piperacillin (PIPC)/tazobactam (TAZ) in late elderly patients with pneumonia and to optimize the administration planning by applying pharmacokinetic/pharmacodynamic (PK/PD) criteria. PIPC/TAZ (total dose of 2.25 or 4.5 g) was infused intravenously three times daily to Japanese patients over 75 years old. The plasma concentrations of PIPC and TAZ were determined using high-performance liquid chromatography and modeled using the NONMEM program. PK/PD analysis with a random simulation was conducted using the final population PK model to estimate the probability of target attainment (PTA) profiles for various PIPC/TAZ-regimen–minimum-inhibitory-concentration (MIC) combinations. The PTAs for PIPC and TAZ were determined as the fraction that achieved at least 50% free time > MIC and area under the free-plasma-concentration–time curve over 24 h ≥ 96 μg h/mL, respectively. A total of 18 cases, the mean age of which was 86.5 ± 6.0 (75–101) years, were investigated. The plasma-concentration–time profiles of PIPC and TAZ were characterized by a two-compartment model. The parameter estimates for the final model, namely the total clearance, central distribution volume, peripheral distribution volume, and intercompartmental clearance, were 4.58 + 0.061 × (CLcr − 37.4) L/h, 5.39 L, 6.96 L, and 20.7 L/h for PIPC, and 5.00 + 0.059 × (CLcr − 37.4) L/h, 6.29 L, 7.73 L, and 24.0 L/h for TAZ, respectively, where CLcr is the creatinine clearance. PK/PD analysis using the final model showed that in drug-resistant strains with a MIC > 8 μg/mL, 4.5 g of PIPC/TAZ every 6 h was required, even for the patients with a CLcr of 50–60 mL/min. The population PK model developed in this study, together with MIC value, can be useful for optimizing the PIPC/TAZ dosage in the over-75-year-old patients, when they are administered PIPC/TAZ. Therefore, the findings of present study may contribute to improving the efficacy and safety of the administration of PIPC/TAZ therapy in late elderly patients with pneumonia.

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Population Pharmacokinetics and Dosing Optimization of Linezolid in Pediatric Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02387-18 ◽

2019 ◽

Vol 63 (4) ◽

Cited By ~ 2

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.

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Population Pharmacokinetics of Pyronaridine in Pediatric Malaria Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02004-15 ◽

2015 ◽

Vol 60 (3) ◽

pp. 1450-1458 ◽

Cited By ~ 3

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.)

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03951-14 ◽

2014 ◽

Vol 59 (1) ◽

pp. 570-578 ◽

Cited By ~ 17

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.

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Population Pharmacokinetics of High-Dose Methotrexate in Chinese Pediatric Patients With Acute Lymphoblastic Leukemia

Frontiers in Pharmacology ◽

10.3389/fphar.2021.701452 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xuan Gao ◽

Xiao-Wen Qian ◽

Xiao-Hua Zhu ◽

Yi Yu ◽

Hui Miao ◽

...

Keyword(s):

Body Weight ◽

Acute Lymphoblastic Leukemia ◽

Serum Creatinine ◽

Pediatric Patients ◽

Lymphoblastic Leukemia ◽

High Dose ◽

High Dose Methotrexate ◽

Concentration Data ◽

Dose Methotrexate ◽

Population Pk

High-dose methotrexate (HD-MTX) is widely used in pediatric acute lymphoblastic leukemia (ALL) treatment regimens. In this study, we aimed to develop a population pharmacokinetic (PK) model of HD-MTX in Chinese pediatric patients with ALL for designing personalized dosage regimens. In total, 4,517 MTX serum concentration data for 311 pediatric patients with ALL, aged 0.75–15.2 years and under HD-MTX treatment, were retrospectively collected at a tertiary Children’s Hospital in China. The non-linear mixed-effect model was used to establish the population PK model, using NONMEM software. The potential covariate effects of age, body weight, and biochemical measurements (renal and liver function) on MTX PK disposition were investigated. The model was then evaluated using goodness-of-fit, visual predictive check. MTX PK disposition was described using a three-compartment model reasonable well. Body weight, implemented as a fixed allometric function on all clearance and volume of distribution parameters, showed a substantial improvement in model fit. The final population model demonstrated that the MTX clearance estimate in a typical child with body weight of 19 kg was 6.9 L/h and the central distribution of volume estimate was 20.7 L. The serum creatinine significantly affected the MTX clearance, with a 0.97% decrease in clearance per 1 μmol/L of serum creatinine. Other covariates (e.g., age, sex, bilirubin, albumin, aspartate transaminase, concomitant medication) did not significantly affect PK properties of MTX. The proposed population PK model could describe the MTX concentration data in Chinese pediatric patients with ALL. This population PK model combined with a maximum a posteriori Bayesian approach could be used to estimate individual PK parameters, and optimize personalized MTX therapy in target patients, thus aiming to reduce toxicity and improve treatment outcomes.

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Population Pharmacokinetics Study of Recommended Zidovudine Doses in HIV-1-Infected Children

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00911-13 ◽

2013 ◽

Vol 57 (10) ◽

pp. 4801-4808 ◽

Cited By ~ 4

Author(s):

Floris Fauchet ◽

Jean-Marc Treluyer ◽

Pierre Frange ◽

Saik Urien ◽

Frantz Foissac ◽

...

Keyword(s):

Body Weight ◽

Rate Constant ◽

Elimination Rate ◽

Volume Of Distribution ◽

World Health ◽

Population Pharmacokinetic ◽

Parameter Estimates ◽

Population Parameter ◽

Subject Variability ◽

Elimination Clearance

ABSTRACTThe aims of this study were to describe the pharmacokinetics of zidovudine (ZDV) and its biotransformation to its metabolite, 3*-azido-3*-deoxy-5*-glucuronylthymidine (G-ZDV), in HIV-infected children, to identify factors that influence the pharmacokinetics of ZDV, and to compare and evaluate the doses recommended by the World Health Organization (WHO) and the Food and Drug Administration (FDA). ZDV concentrations in 782 samples and G-ZDV concentrations in 554 samples from 247 children ranging in age from 0.5 to 18 years were retrospectively measured. A population pharmacokinetic model was developed with NONMEM software (version 6.2), and the pharmacokinetics of ZDV were best described by a one-compartment model with first-order absorption and elimination. The effect of body weight on the apparent elimination clearance and volume of distribution was significant. The mean population parameter estimates were as follows: absorption rate, 2.86 h−1; apparent elimination clearance, 89.7 liters · h−1(between-subject variability, 0.701 liters · h−1); apparent volume of distribution, 229 liters (between-subject variability, 0.807 liters); metabolic formation rate constant, 12.6 h−1(between-subject variability, 0.352 h−1); and elimination rate constant of G-ZDV, 2.27 h−1. On the basis of simulations with FDA and WHO dosing recommendations, the probabilities of observing efficient exposures (doses resulting in exposures of between 3 and 5 mg/liter · h) with less adverse events (doses resulting in exposures below 8.4 mg/liter · h) were higher when the FDA recommendations than when the WHO recommendations were followed. In order to improve the FDA recommendations, ZDV doses should be reconsidered for the weight band (WB) of 20 to 40 kg. The most appropriate doses should be decreased from 9 to 8 mg/kg of body weight twice a day (BID) for the WB from 20 to 29.9 kg and from 300 to 250 mg BID for the WB from 30 to 39.9 kg. The highest dose, 300 mg BID, should be started from body weights of 40 kg.

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A Universal Pharmacokinetic Model for Dexmedetomidine in Children and Adults

Journal of Clinical Medicine ◽

10.3390/jcm9113480 ◽

2020 ◽

Vol 9 (11) ◽

pp. 3480

Author(s):

James D. Morse ◽

L. Ignacio Cortinez ◽

Brian J. Anderson

Keyword(s):

Body Weight ◽

Fat Mass ◽

Pharmacokinetic Model ◽

Total Body Weight ◽

Central Compartment ◽

Fat Free Mass ◽

Lean Body Weight ◽

Peripheral Compartment ◽

Parameter Estimates ◽

Population Parameter

A universal pharmacokinetic model was developed from pooled paediatric and adult data (40.6 postmenstrual weeks, 70.8 years, 3.1–152 kg). A three-compartment pharmacokinetic model with first-order elimination was superior to a two-compartment model to describe these pooled dexmedetomidine data. Population parameter estimates (population parameter variability%) were clearance (CL) 0.9 L/min/70 kg (36); intercompartmental clearances (Q2) 1.68 L/min/70 kg (63); Q3 0.62 L/min/70 kg (90); volume of distribution in the central compartment (V1) 25.2 L/70 kg (103.9); rapidly equilibrating peripheral compartment (V2) 34.4 L/70 kg (41.8); slow equilibrating peripheral compartment (V3) 65.4 L/70 kg (62). Obesity was best described by fat-free mass for clearances and normal fat mass for volumes with a factor for fat mass (FfatV) of 0.293. Models describing dexmedetomidine pharmacokinetics in adults can be applied to children by accounting for size (allometry) and age (maturation). This universal dexmedetomidine model is applicable to a broad range of ages and weights: neonates through to obese adults. Lean body weight is a better size descriptor for dexmedetomidine clearance than total body weight. This parameter set could be programmed into target-controlled infusion pumps for use in a broad population.

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Population pharmacokinetic and pharmacodynamic (PK-PD) parameters of Erwinia Chrysanthemi (ERW) asparaginase (ASNase) using the fused first-order elimination and Michaelis-Menten (MM) limited physiological model

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.13010 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 13010-13010

Author(s):

V. I. Avramis ◽

C. Fu

Keyword(s):

Enzymatic Reaction ◽

Prediction Method ◽

Serum Levels ◽

Population Pharmacokinetic ◽

Parameter Estimates ◽

Population Parameter ◽

Nonlinear Kinetics ◽

First Order ◽

Population Pk ◽

Better Than

13010 Background: Using the linear PK first order (FO) compartmental approach, the methodical and computational uniformity in modeling various linear systems (ERW) is the dominant characteristic of the population PK analyses. However, saturation of the enzymatic reaction results in nonlinear kinetics based on the MM equation, i.e., the deamination of ASN by ERW, which complicates the PK-PD model. The PK with FO & the MM PK-PD model is theoretically better when single dose of ERW is given. To simulate the PK-PD data and to project patient (pt) data using this model, we used simultaneous integration of the FO+MM equations. Methods: In the 1990’s, ERW was used in pediatric ALL pt (n=23, 1st cohort evaluated for PK-PD). The current study was started to assess if the parallel MM+FO (MM+FO) PK-PD model fit the limited ERW (25K) data better than the MM model, and to validate the MM+FO model and its population parameter estimates. Results: The population PK-PD model best-fitted serum ERW & ASN-time pairs obtained in 23 and from 5 pediatric pt with ALL, using nonlinear mixed-effects modeling (NONMEM). The validity of the MM+FO population PK-PD model and the estimated parameters were tested using the naive prediction method. Patients were administered ERW 6K or 25 K IU/m2 when allergy to E. coli formulations appeared. High correlation between ERW peak serum levels calculated from limited individual pt’ KM (900 μM) & Vmax values in 5 pediatric pt (2nd cohort) and the observed ERW trough levels & its substrate (ASN) were found. The T1/2 averaged 16 hr (25K ERW), and the trough level of 0.1–0.2 IU/ml was correlated with ASN <3 μM. These PK-PD parameters validated those obtained from the 1st cohort. When simulations on population parameters were conducted, the MM+FO predicted the multiple dose steady-state serum ERW & ASN levels nicely. Therefore, the MM+FO model was clearly superior to either the FO or the MM PD models. Moreover, simulations compared favorably ERW 25K Q2 days x3 doses & x2 weeks vs. Pegaspargase 2,5K Q2 weeks. Conclusions: The NONMEM PK-PD model for ERW fitted the simultaneous analyses of data from different doses and regimens better than either standard Two-stage or MM could. No significant financial relationships to disclose.

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