Bootstrap approach for constructing confidence intervals for population pharmacokinetic parameters. II: a bootstrap modification of standard two-stage (STS) method for phase I trial

1999 ◽  
Vol 18 (5) ◽  
pp. 601-612 ◽  
Author(s):  
Akifumi Yafune ◽  
Makio Ishiguro
Keyword(s):  
Phase I ◽  
Confidence Intervals ◽  
Phase I Trial ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Two Stage ◽  
Bootstrap Approach

scholarly journals Two-Stage Priming of Allogeneic Natural Killer Cells for the Treatment of Patients with Acute Myeloid Leukemia: A Phase I Trial

PLoS ONE ◽  
2015 ◽  
Vol 10 (6) ◽  
pp. e0123416 ◽  
Author(s):  
Panagiotis D. Kottaridis ◽  
Janet North ◽  
Maria Tsirogianni ◽  
Chloe Marden ◽  
Edward R. Samuel ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Natural Killer Cells ◽  
Phase I ◽  
Natural Killer ◽  
Myeloid Leukemia ◽  
Phase I Trial ◽  
Two Stage ◽  
Killer Cells ◽  
Acute Myeloid

Population Pharmacokinetic Parameters of Gentamicin in Patients With Solid Tumors: Estimation by One- and Two-Stage Methods

1998 ◽  
Vol 20 (2) ◽  
pp. 184-190 ◽  
Author(s):  
Ana Ortega ◽  
Azucena Aldaz ◽  
Joaquín Giráldez ◽  
Antonio Brugarolas
Keyword(s):  
Solid Tumors ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Two Stage

Population Pharmacokinetics of the Novel Anticancer Agent E7070 During Four Phase I Studies: Model Building and Validation

2002 ◽  
Vol 20 (19) ◽  
pp. 4065-4073 ◽  
Author(s):  
Ch. van Kesteren ◽  
R. A.A. Mathôt ◽  
E. Raymond ◽  
J. P. Armand ◽  
Ch. Dittrich ◽  
...  
Keyword(s):  
Phase I ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Anticancer Agent ◽  
Central Compartment ◽  
Pharmacokinetic Parameters ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Data Set ◽  
Phase I Studies

PURPOSE: N-(3-Chloro-7-indolyl)-1,4-benzenedisulfonamide (E7070) is a novel sulfonamide anticancer agent currently in phase II clinical development for the treatment of solid tumors. Four phase I studies have been finalized, with E7070 administered at four different treatment schedules to identify the maximum-tolerated dose and the dose-limiting toxicities. Pharmacokinetic analyses of all studies revealed E7070 to have nonlinear pharmacokinetics. A population pharmacokinetic model was designed and validated to describe the pharmacokinetics of E7070 at all four treatment schedules and to identify the possible influences of patient characteristics on the pharmacokinetic parameters. PATIENTS AND METHODS: Plasma concentration-time data of all patients (n = 143) were fitted to several pharmacokinetic models using NONMEM. Seventeen covariables were investigated for their relation with individual pharmacokinetic parameters. A bootstrap procedure was performed to check the validity of the model. RESULTS: The data were best described using a three-compartment model with nonlinear distribution to a peripheral compartment and two parallel pathways of elimination from the central compartment: a linear and a saturable pathway. Body-surface area (BSA) was significantly correlated to both the volume of distribution of the central compartment and to the maximal elimination capacity. The fits of 500 bootstrap replicates of the data set demonstrated the robustness of the developed population pharmacokinetic model. CONCLUSION: A population pharmacokinetic model has been designed and validated that accurately describes the data of four phase I studies with E7070. Furthermore, it has been demonstrated that BSA-guided dosing for E7070 is important.

A Two-Stage Phase I Trial of Evolence30 Collagen for Soft-Tissue Contour Correction

2007 ◽  
Vol 120 (1) ◽  
pp. 303-311 ◽  
Author(s):  
Stan J. Monstrey ◽  
Sandu Pitaru ◽  
Moustapha Hamdi ◽  
Koen Van Landuyt ◽  
Phillip Blondeel ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Phase I ◽  
Phase I Trial ◽  
Two Stage

scholarly journals Phase I Trial and Pharmacokinetic Study of Ixabepilone Administered Daily for 5 Days in Children and Adolescents With Refractory Solid Tumors

2009 ◽  
Vol 27 (4) ◽  
pp. 550-556 ◽  
Author(s):  
Brigitte C. Widemann ◽  
Wendy Goodspeed ◽  
Anne Goodwin ◽  
Tito Fojo ◽  
Frank M. Balis ◽  
...  
Keyword(s):  
Phase I ◽  
Children And Adolescents ◽  
Solid Tumors ◽  
Phase I Trial ◽  
Maximum Tolerated Dose ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Phase Ii Trials ◽  
Eligibility Criteria ◽  
Dose Levels

PurposeThe objectives of this phase I trial were to determine the maximum-tolerated dose (MTD), toxicity profile, dose-limiting toxicities (DLTs), pharmacokinetics, and preliminary response rate for ixabepilone, a microtubule-stabilizing agent, administered intravenously daily for 5 days in children and adolescents.Patients and MethodsPatients ≥ 2 and ≤ 18 years with relapsed or refractory solid tumors were enrolled onto sequential cohorts to the following five dose levels: 3.0 (n = 3), 4.5 (n = 4), 6.0 (n = 3), 8.0 (n = 6), and 10 (n = 3) mg/m2/d. Eligibility criteria, dose levels, definitions of DLT and MTD, and pharmacokinetic sampling times were designed to be as similar as possible to the adult phase I trial of ixabepilone on the same schedule.ResultsNineteen children (median age, 10 years; range, 2 to 18 years) were enrolled, and 18 (12 with sarcomas) were assessable for toxicity. DLTs (grade 4 neutropenia for > 5 days and grade 3 fatigue) were observed in two of three patients receiving 10 mg/m2/d. The MTD of ixabepilone administered daily for 5 days every 21 days was 8 mg/m2/d. Myelosuppression, GI, and hepatic toxicities were common non-DLTs. Peripheral neuropathy was uncommon. Ixabepilone clearance was 475 ± 247 mL/min/m2, volume of distribution at steady-state was 12.2 ± 5.4 L/kg, and half-life was 14 hours.ConclusionThe recommended dose of ixabepilone for phase II trials in solid tumors is 8 mg/m2/d daily for 5 days every 21 days. This dose is 33% higher than the MTD in adults receiving the same dosing schedule. Pharmacokinetic parameters in children and adolescents were highly variable but similar to adults.

scholarly journals Standard Two-Stage Method Determination of Population Pharmacokinetic Parameters of Methotrexate.

1995 ◽  
Vol 21 (5) ◽  
pp. 375-383
Author(s):  
SABURO YOSHIOKA ◽  
TOYOHISA TSUKAMOTO ◽  
MISAO NAKANO
Keyword(s):  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Two Stage

Population Pharmacokinetic Model for Topotecan Derived From Phase I Clinical Trials

2000 ◽  
Vol 18 (12) ◽  
pp. 2459-2467 ◽  
Author(s):  
James M. Gallo ◽  
Paul B. Laub ◽  
Eric K. Rowinsky ◽  
Louise B. Grochow ◽  
Sharyn D. Baker
Keyword(s):  
Phase I ◽  
Population Model ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Plasma Concentrations ◽  
Pharmacokinetic Parameters ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Total Clearance ◽  
Phase I Clinical Trials

PURPOSE: To characterize the pharmacokinetics of topotecan in a population model that would identify patient variables or covariates that appreciably impacted on its disposition. PATIENTS AND METHODS: All data were collected from 82 patients entered in four different phase I trials that were previously reported as separate studies from 1992 to 1996. All patients received topotecan as a 30-minute constant-rate infusion on a daily-times-five schedule and were selected for this study because their daily dose did not exceed 2.0 mg/m2. Among the 82 patients were 30 patients classified as having renal insufficiency and 13 patients with hepatic dysfunction. The population pharmacokinetic model was built in sequential manner, starting with a covariate-free model and progressing to a covariate model with the aid of generalized additive modeling. RESULTS: A linear two-compartment model characterized total topotecan plasma concentrations (n = 899). Four primary pharmacokinetic parameters (total clearance, volume of the central compartment, distributional clearance, and volume of the peripheral compartment) were related to various combinations of covariates. The relationship for total clearance (TVCL [L/h] = 32.0 + [0.356(WT − 71) + 0.308(HT − 168.5) − 8.42(SCR − 1.1)] × [1 + 0.671 sex]) was dependent on the patients’ weight (WT), height (HT), serum creatinine (SCR), and sex and had a moderate ability to predict (r2 = 0.64) each patient’s individual clearance value. The addition of covariates to the population model improved the prediction errors, particularly for clearance. Removal of 10 outlying patients from the analysis improved the ability of the model to predict individual clearance values (r2 = 0.77). CONCLUSION: A population pharmacokinetic model for total topotecan has been developed that incorporates measures of body size and renal function to predict total clearance. The model can be used prospectively to obtain a revised and validated model that can then be used to design individualized dosing regimens.

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