An Interim Evaluation of Systemic F-Ara-a Exposure in Pediatric Allogeneic Hematopoietic Cell Transplant (alloHCT) Recipients Using An Optimal Sampling Design

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1962-1962
Author(s):  
Janel R Long-Boyle ◽  
Shirley Yan ◽  
Christopher C. Dvorak ◽  
Biljana N. Horn ◽  
Morton Jerome Cowan ◽  
...  
Keyword(s):  
Interim Analysis ◽  
Sampling Strategy ◽  
Volume Of Distribution ◽  
Exploratory Analysis ◽  
Accurate Estimation ◽  
Cell Transplant ◽  
Optimal Sampling ◽  
Exposure Response ◽  
Relative Standard ◽  
Population Pk

Abstract Abstract 1962 Background Fludarabine is a purine analogue used in the preparative regimens of pediatric alloHCT to enhance stem cell engraftment. Administered intravenously as a prodrug, fludarabine (f-ara-AMP) undergoes rapid dephosphorylation in the plasma to the systemically circulating compound, f-ara-a. Despite widespread use, there are no published pharmacokinetic-pharmacodynamic (PK-PD) studies of fludarabine in children undergoing alloHCT. Using an optimal sampling strategy (OSS), we designed a prospective study to evaluate the PK-PD of fludarabine in pediatric alloHCT recipients. We report the year-1 interim PK analysis of this 3-year exposure-response study. Methods Utilizing prior f-ara-a PK data available in adults and D-optimal sampling methods (PFIM software), we designed an OSS for f-ara-a in children. Based on the OSS, the relative standard errors (RSE), representing the precision of estimated PK parameters, were predicted to be less than 20% in a total of 45 children. An interim analysis was planned after year 1 to ensure the sample collection times selected by the OSS were sufficiently informative. Patients were eligible to participate in PK sampling if they were between 0 to 17 years of age, met protocol specific criteria for alloHCT, and would be receiving fludarabine as part of their preparative regimen. All patients underwent PK sampling with dose 1 of fludarabine. Fludarabine was infused per protocol over 30–60 minutes and 1 mL of whole blood was obtained at 2, 4, 8, and 24 h after the start of infusion. PK sampling was repeated following a subsequent dose of fludarabine (dose 2, 3, 4 or 5) at 2 and 24 h. Plasma samples were analyzed by LC-tandem MS and the assay was linear in the range of 5–500 ng/mL. PK model development using f-ara-a concentration-time data was carried out using standard population PK methodologies (NONMEM 7.2 software). Further development of a 2-compartment open model was based on exploratory analysis, diagnostic plots and changes in objective function value (OFV). The addition of allometric scaling, with weight built into the base model scaled to a reference patient having the median weight of the population, resulted in a significant drop in the OFV. No other covariates were tested based on exploratory analysis and plots. The model was parameterized in terms of clearance (CL), volume of distribution-central compartment (Vc), volume of distribution-peripheral compartment (Vp), and inter-compartmental clearance (Q). Residual unexplained variability was modeled as being proportional to the predicted concentrations. Area-under-the-curve (AUC) of f-ara-a was derived from the empirical Bayes estimates of individual CL. Results A total of 94 quantifiable concentrations from 16 subjects (10 male, 6 female) were available for interim PK modeling. Most patients received fludarabine 30–40mg/m2 daily over 3 to 5 days (n=13). In the 3 smallest children (<10kg), fludarabine was dosed at 1.33mg/kg/day for 3 to 4 days. Median age and weight of subjects was 6.5 years (range, 0.3–17) and 23.4kg (6.8-82.3), respectively. Markers for renal function were within normal age limits for all subjects. A 2-compartment model with linear elimination well described the PK of f-ara-a. The population PK estimates for CL, Vc, Vp, Q, and their RSE (%) were 9.0 (6.3%), 30 (8.9%), 34 (6.4%), and 7.7 (11%), respectively. The final model of this interim analysis estimated f-ara-a CL (L/h) = 9.0 * (WT/23.4)0.67. This model predicts f-ara-a CL (%CV) to be lower for children < 10kg (n=3), 3.8 L/h (11.3%) compared to those >10kg, 12.4 L/h (42%). Correspondingly, dose-normalized AUC was predicted to be approximately 2.8 times higher in patients < 10kg. Between-patient variability of CL was estimated to be 23% and the residual variability of concentrations 25%. Conclusion The optimal sampling strategy based on adult prior data allows for accurate estimation of f-ara-a population PK parameters in our study of 16 pediatric alloHCT recipients. These interim results suggest body weight may be used to predict f-ara-a clearance, as well as suggest the need for close evaluation of weight-based dosing to prevent over-exposure in very small children. Over the next 2 years we will continue to enroll children in this PK-PD study to confirm the interim PK results and identify exposure-response relationships to inform optimal dosing of fludarabine in pediatric alloHCT. Disclosures: Off Label Use: Fludarabine (Fludara) has no offical FDA indication for use in children.

scholarly journals Population Pharmacokinetics of Fluconazole in Young Infants

2008 ◽  
Vol 52 (11) ◽  
pp. 4043-4049 ◽  
Author(s):  
K. C. Wade ◽  
D. Wu ◽  
D. A. Kaufman ◽  
R. M. Ward ◽  
D. K. Benjamin ◽  
...  
Keyword(s):  
Fixed Effects ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Relative Standard Error ◽  
Data Set ◽  
Mixed Effect ◽  
Young Infants ◽  
Relative Standard ◽  
Population Pk ◽  
The Impact

ABSTRACT Fluconazole is being increasingly used to prevent and treat invasive candidiasis in neonates, yet dosing is largely empirical due to the lack of adequate pharmacokinetic (PK) data. We performed a multicenter population PK study of fluconazole in 23- to 40-week-gestation infants less than 120 days of age. We developed a population PK model using nonlinear mixed effect modeling (NONMEM) with the NONMEM algorithm. Covariate effects were predefined and evaluated based on estimation precision and clinical significance. We studied fluconazole PK in 55 infants who at enrollment had a median (range) weight of 1.02 (0.440 to 7.125) kg, a gestational age at birth (BGA) of 26 (23 to 40) weeks, and a postnatal age (PNA) of 2.3 (0.14 to 12.6) weeks. The final data set contained 357 samples; 217/357 (61%) were collected prospectively at prespecified time intervals, and 140/357 (39%) were scavenged from discarded clinical specimens. Fluconazole population PK was best described by a one-compartment model with covariates normalized to median values. The population mean clearance (CL) can be derived for this population by the equation CL (liter/h) equals 0.015 · (weight/1)0.75 · (BGA/26)1.739 · (PNA/2)0.237 · serum creatinine (SCRT)−4.896 (when SCRT is >1.0 mg/dl), and using a volume of distribution (V) (liter) of 1.024 · (weight/1). The relative standard error around the fixed effects point estimates ranged from 3 to 24%. CL doubles between birth and 28 days of age from 0.008 to 0.016 and from 0.010 to 0.022 liter/kg/h for typical 24- and 32-week-gestation infants, respectively. This population PK model of fluconazole discriminated the impact of BGA, PNA, and creatinine on drug CL. Our data suggest that dosing in young infants will require adjustment for BGA and PNA to achieve targeted systemic drug exposures.

scholarly journals SAT-432 Pharmacokinetics (PK) and Exposure-Response Relationship of Teprotumumab, an Insulin-Like Growth Factor-1 Receptor (IGF-1R) Blocking Antibody, in Active Thyroid Eye Disease (TED)

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Yan Xin ◽  
Fengyan Xu ◽  
Yuying Gao ◽  
Nivedita Bhatt ◽  
Jason Chamberlain ◽  
...  
Keyword(s):  
Dose Regimen ◽  
Volume Of Distribution ◽  
Systemic Clearance ◽  
Phase 2 ◽  
Response Relationship ◽  
Exposure Response ◽  
Elimination Half ◽  
Population Pk ◽  
Igg1 Mabs ◽  
Low Volume

Abstract Introduction: Teprotumumab treatment resulted in statistically and clinically meaningful improvements across multiple facets of active TED and was generally well-tolerated in Phase 2 and 3 trials.1,2 An initial intravenous infusion of 10 mg/kg followed by 20 mg/kg every 3 weeks was selected based on in vitro activity and clinical PK profile, to maintain pharmacologically active exposures and &gt;90% saturation of IGF-1R over dosing intervals and to achieve efficacy at a well-tolerated dose for this vision-threatening disease. Methods: Population PK analysis were performed on data from a Phase 1 oncology study (n=60)3 and Phase 2 and 3 trials in active TED (N=83)2,3 and covariate effect on PK was assessed. Exposure-response relationship was evaluated in TED studies for key efficacy endpoints (proptosis response rate, % patients with a clinical activity score value of 0 or 1, and diplopia responder rate) and selected safety variables (hyperglycemia and muscle spasms). Results: Teprotumumab PK was linear in TED patients and consistent with other immunoglobulin G1 monoclonal antibodies (IgG1 mAbs), with low systemic clearance (0.334 L/day), low volume of distribution (3.9 L for central compartment and 4.2 L for peripheral compartment), and long elimination half-life (19.9 days). 4,5 Model-predicted mean (± standard deviation) steady-state area under the concentration curve (AUCss), peak (Cmax,ss), and trough (Cmin,ss) concentrations in TED patients were 131 (± 30.9) mg∙hr/mL, 643 (± 130) µg/mL and 157 (± 50.6) µg/mL, respectively, suggesting low inter-subject variability. Population PK analysis indicated no significant impact of baseline age, gender, race, weight, smoking status, renal impairment (mild/moderate), and hepatic function (total bilirubin, aspartate and alanine aminotransferases) on teprotumumab PK. Female patients had 15% higher Cmax,ss but similar AUC compared to male patients, which is not considered clinically relevant. Exposure-response analysis from the TED dose regimen indicated no meaningful correlations between exposures (AUCss, Cmax,ss and Cmin,ss) and key efficacy endpoints or selected safety variables, supporting the demonstrated, favorable benefit-risk profile of the TED dose regimen.2 Conclusion: Teprotumumab PK was characterized in TED patients by long elimination half-life, low systemic clearance and low volume of distribution, consistent with other IgG1 mAbs. There was no meaningful exposure-response relationship at the selected TED dose regimen for both efficacy and safety endpoints, supporting the teprotumumab dose regimen used in TED patients. Reference: (1) Smith TJ, et al. N Engl J Med 2017;376:1748-1761. (2) Douglas RS, et al. AACE 2019 late-breaking abstract. (3) ClinicalTrials.gov: NCT00400361. (4) Dirks NL et al. Clin Pharmacokinet. 2010;49(10):633-59. (5) Ryman JT et al. CPT Pharmacometrics Syst Pharmacol. 2017;6(9):576-88.

scholarly journals Population pharmacokinetics of ceftazidime in cystic fibrosis patients analyzed by using a nonparametric algorithm and optimal sampling strategy.

1996 ◽  
Vol 40 (5) ◽  
pp. 1091-1097 ◽  
Author(s):  
A A Vinks ◽  
J W Mouton ◽  
D J Touw ◽  
H G Heijerman ◽  
M Danhof ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Population Modeling ◽  
Sampling Strategy ◽  
Volume Of Distribution ◽  
Population Models ◽  
Posteriori Probability ◽  
Parameter Estimates ◽  
Data Sets ◽  
Optimal Sampling ◽  
Two Stage

Postinfusion data obtained from 17 patients with cystic fibrosis participating in two clinical trials were used to develop population models for ceftazidime pharmacokinetics during continuous infusion. Determinant (D)-optimal sampling strategy (OSS) was used to evaluate the benefits of merging four maximally informative sampling times with population modeling. Full and sparse D-optimal sampling data sets were analyzed with the nonparametric expectation maximization (NPEM) algorithm and compared with the model obtained by the traditional standard two-stage approach. Individual pharmacokinetic parameter estimates were calculated by weighted nonlinear least-squares regression and by maximum a posteriori probability Bayesian estimator. Individual parameter estimates obtained with four D-optimally timed serum samples (OSS4) showed excellent correlation with parameter estimates obtained by using full data sets. The parameters of interest, clearance and volume of distribution, showed excellent agreement (R2 = 0.89 and R2 = 0.86). The ceftazidime population models were described as two-compartment kslope models, relating elimination constants to renal function. The NPEM-OSS4 model was described by the equations kel = 0.06516+ (0.00708.CLCR) and V1 = 0.1773 +/- 0.0406 liter/kg where CLCR is creatinine clearance in milliliters per minute per 1.73 m2, V1 is the volume of distribution of the central compartment, and kel is the elimination rate constant. Predictive performance evaluation for 31 patients with data which were not part of the model data sets showed that the NPEM-ALL model performed best, with significantly better precision than that of the standard two-stage model (P < 0.001). Predictions with the NPEM-OSS4 model were as precise as those with the NPEM-ALL model but slightly biased (-2.2 mg/liter; P < 0.01). D-optimal monitoring strategies coupled with population modeling results in useful and cost-effective population models and will be of advantage in clinical practice, as it allows pharmacokinetic-pharmacodynamic modeling with sparse data, thus describing the relationship between ceftazidime exposure and response in the treatment of acute exacerbations in patients with cystic fibrosis.

scholarly journals Proposed Scheme for Dosing Venetoclax in Pediatric Patients with Relapsed/Refractory Acute Myeloid Leukemia: Analysis of Developmental Pharmacokinetics and Exposure-Response Relationships

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 11-12
Author(s):  
Mohamed A Badawi ◽  
Sathej Gopalakrishnan ◽  
Benjamin Engelhardt ◽  
Tammy L. Palenski ◽  
Su Young Kim ◽  
...  
Keyword(s):  
Allometric Scaling ◽  
Pediatric Patients ◽  
Volume Of Distribution ◽  
Pediatric Age ◽  
Publicly Traded ◽  
Dose Selection ◽  
Exposure Response ◽  
Population Pk ◽  
Weight Groups ◽  
Refractory Aml

M. Badawi and S. Gopalakrishnan equally contributed to this work Introduction: Venetoclax is a selective BCL2 inhibitor approved for patients with CLL and patients with newly diagnosed AML who are ineligible for induction chemotherapy. Venetoclax is currently being evaluated in other hematologic and solid tumors in both adult and pediatric populations. In this analysis, we characterized the pharmacokinetics and exposure response relationships of venetoclax to guide dose selection of venetoclax in combination with high dose cytarabine (HDAC) in pediatric patients with relapsed or refractory AML. Methods: A population PK model describing venetoclax PK in pediatric patients was developed using data from 121 subjects across three venetoclax studies that tested venetoclax at 400-800 mg doses across different tumors. The model accounted for the CYP3A4 developmental changes in early years of life using a maturation function and allometric scaling was also incorporated in the model to account for growth and body size effect. Individual subject average venetoclax plasma concentration (Cavg) up to the event of interest, determined based on the population PK analysis using the post-hoc empirical Bayesian parameter estimates, was used as an exposure metric to explore exposure-efficacy and exposure-safety relationships. Data from subjects with AML (database version 23-Mar-2020) who received venetoclax in combination with either azacitidine, decitabine, or cytarabine were included in the exposure-efficacy and exposure-safety analyses. The population PK model was then used to simulate venetoclax exposures in pediatric subgroups to guide dose selection for future trials. Results: Population PK estimates (clearance, volume of distribution, rate of absorption and peripheral volume of distribution) were comparable to previously reported estimates. Additionally, weight was identified as a statistically significant covariate on clearance and volume of distribution. Exposure-response analyses showed a flat relationship between venetoclax exposures and efficacy in patients with AML who received venetoclax in combination with azacitidine, decitabine, or cytarabine. Moreover, venetoclax exposures did not correlate with incidence of neutropenia. Specifically, in AML patients who received venetoclax in combination with HDAC (&gt;500-2000 mg/m2/day, n=15), higher venetoclax exposures were not associated with better clinical response. A 600 mg dose of venetoclax was selected based on high response rates observed in the clinic. Venetoclax doses for pediatric subgroups were selected based on weight (allometric scaling) for children aged ≥ 2 years old and based on weight and CYP3A ontogeny for children aged &lt; 2 years old. Table 1 presents the selected doses for the pediatric age and weight groups. Simulations of exposures (steady state area under the curve [AUCss]) using the population PK model for the pediatric age and weight groups are represented in Figure 1. Reasonable overlap in exposures was observed across the pediatric groups. Conclusions: Exposure-efficacy and exposure-safety showed lack of superiority of higher exposures and hence, 600 mg QD venetoclax in combination with HDAC was selected for pediatric patients with relapsed or refractory AML in future trials. Simulations of exposures demonstrated that the selected age- and weight-based doses would achieve exposures in pediatric subgroups comparable to that expected in adults receiving a 600 mg dose of venetoclax. Disclosures Badawi: AbbVie Inc.: Current Employment, Other: may hold stock or other options. Gopalakrishnan:AbbVie Inc.: Current Employment, Other: may hold stock or other options. Engelhardt:AbbVie Inc.: Current Employment, Other: may hold stock or other options. Palenski:AbbVie: Current Employment, Other: may hold stock or other options. Kim:AbbVie, Inc.: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Other: may hold stock or other options. Karol:AbbVie Inc.: Other: Unrelated to this study, St. Jude has received a charitable contribution from AbbVie, Inc. The charitable contribution is not being used for clinical or research activities, including any activities related to this study. . Rubnitz:AbbVie Inc.: Research Funding. Menon:AbbVie Inc.: Current Employment, Other: may hold stock or other options. Salem:AbbVie Inc.: Current Employment, Other: may hold stock or other options.

scholarly journals Development and evaluation of a Bayesian pharmacokinetic estimator and optimal, sparse sampling strategies for ceftazidime.

1996 ◽  
Vol 40 (8) ◽  
pp. 1860-1865 ◽  
Author(s):  
A D Kashuba ◽  
C H Ballow ◽  
A Forrest
Keyword(s):  
Sampling Strategy ◽  
Population Pharmacokinetic Analysis ◽  
Volume Of Distribution ◽  
Sparse Sampling ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Optimal Sampling ◽  
Sampling Strategies ◽  
Adaptive Feedback ◽  
Sampling Times

Data were gathered during an activity-controlled trial in which seriously ill, elderly patients were randomized to receive intravenous ceftazidime or ciprofloxacin and for which adaptive feedback control of drug concentrations in plasma and activity profiles was prospectively performed. The adaptive feedback control algorithm for ceftazidime used an initial population model, a maximum a posteriori (MAP)-Bayesian pharmacokinetic parameter value estimator, and an optimal, sparse sampling strategy for ceftazidime that had been derived from data in the literature obtained from volunteers. Iterative two-stage population pharmacokinetic analysis was performed to develop an unbiased MAP-Bayesian estimator and updated optimal, sparse sampling strategies. The final median values of the population parameters were follows: the volume of distribution of the central compartment was equal to 0.249 liter/kg, the volume of distribution of the peripheral compartment was equal to 0.173 liter/kg, the distributional clearance between the central and peripheral compartments was equal to 0.2251 liter/h/kg, the slope of the total clearance (CL) versus the creatinine clearance (CLCR) was equal to 0.000736 liter/h/kg of CL/1 ml/min/1.73 m2 of CLCR, and nonrenal clearance was equal to + 0.00527 liter/h/kg. Optimal sampling times were dependent on CLCR; for CLCR of > or = 30 ml/min/1.73 m2, the optimal sampling times were 0.583, 3.0, 7.0, and 16.0 h and, for CLCR of < 30 ml/min/1.73 m2, optimal sampling times were 0.583, 4.15, 11.5, and 24.0 h. The study demonstrates that because pharmacokinetic information from volunteers may often not be reflective of specialty populations such as critically ill elderly individuals, iterative two-stage population pharmacokinetic analysis, MAP-Bayesian parameter estimation, and optimal, sparse sampling strategy can be important tools in characterizing their pharmacokinetics.

scholarly journals Population Pharmacokinetics of Ropeginterferon Alfa-2b: A Comparison Between Healthy Caucasian and Chinese Subjects

2021 ◽  
Vol 12 ◽  
Author(s):  
Min Zhu ◽  
Mei-xia Wang ◽  
Zi-ran Li ◽  
Wei Wang ◽  
Xia Su ◽  
...  
Keyword(s):  
Drug Disposition ◽  
Volume Of Distribution ◽  
Population Pharmacokinetic ◽  
Relative Standard Error ◽  
Quasi Equilibrium ◽  
Phase I Clinical Trials ◽  
Two Phase ◽  
Relative Standard ◽  
Population Pk ◽  
Chinese Subjects

Objective: To develop a population pharmacokinetic (PK) model for ropeginterferon alfa-2b and to compare its PK properties between Caucasian and Chinese populations.Methods: A population PK model was developed based on data from two phase I clinical trials conducted in Caucasian and Chinese individuals, to evaluate the influence of ethnicity on the PKs of ropeginterferon alfa-2b.Results: We included 456 observations from 30 healthy Caucasian subjects and 438 observations from 27 healthy Chinese subjects in the population PK analysis. The PKs of ropeginterferon alfa-2b were best described by a one-compartment quasi-equilibrium approximated target-mediated drug disposition model with first-order absorption and absorption lag times. The typical value (relative standard error%) of apparent clearance (CL/F) and volume of distribution of ropeginterferon alfa-2b in 70-kg subjects were 0.778 (12%) L/day and 2.32 (14%) L, respectively. Body weight was the only significant factor affecting the CL/F. There were no obvious differences in the PK properties of ropeginterferon alfa-2b, and predicted steady-state exposure was similar in the Chinese and Caucasian populations.Conclusion: No significant ethnic differences in ropeginterferon alfa-2b PKs were observed between the Chinese and Caucasian populations.

scholarly journals Comparable Population Pharmacokinetics and Pharmacodynamic Breakpoints of Cefpirome in Cystic Fibrosis Patients and Healthy Volunteers

2011 ◽  
Vol 55 (6) ◽  
pp. 2927-2936 ◽  
Author(s):  
J. B. Bulitta ◽  
M. Kinzig ◽  
C. B. Landersdorfer ◽  
U. Holzgrabe ◽  
U. Stephan ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Healthy Volunteers ◽  
High Performance ◽  
Standard Dose ◽  
Total Body Weight ◽  
Volume Of Distribution ◽  
Nonparametric Bootstrap ◽  
Population Pk ◽  
Total Body ◽  
Similar Body

ABSTRACTCystic fibrosis (CF) patients are often reported to have higher clearances and larger volumes of distribution per kilogram of total body weight (WT) for beta-lactams than healthy volunteers. As pharmacokinetic (PK) data on cefpirome from studies of CF patients are lacking, we systematically compared its population PK and pharmacodynamic breakpoints for CF patients and healthy volunteers of similar body size. Twelve adult CF patients (median lean body mass [LBM] = 45.7 kg) and 12 healthy volunteers (LBM = 50.0 kg) received a single 10-min intravenous infusion of 2 g cefpirome. Plasma and urine concentrations were determined by high-performance liquid chromatography (HPLC). Population PK and Monte Carlo simulations were performed using NONMEM and S-ADAPT and a duration of an unbound plasma concentration above the MIC ≥ 65% of the dosing interval as a pharmacodynamic target. Unscaled clearances for CF patients were similar to those seen with healthy volunteers, and the volume of distribution was 6% lower for CF patients. Linear scaling of total clearance by WT resulted in clearance that was 20% higher (P≤ 0.001 [nonparametric bootstrap]) in CF patients. Allometric scaling by LBM explained the differences between the two subject groups with respect to average clearance and volume of distribution and reduced the unexplained between-subject variability of renal and nonrenal clearance by 10 to 14%. For the CF patients, robust (>90%) probabilities of target attainment (PTA) were achieved by the administration of a standard dose of 2 g/70 kg WT every 12 h (Q12h) given as 30-min infusions for MICs ≤ 1.5 mg/liter. As alternative dosage regimens, a 5-h infusion of 1.33 g/70 kg WT Q8h achieved robust PTAs for MICs ≤ 8 to 12 mg/liter and a continuous infusion of 4 g/day for MICs ≤ 12 mg/liter. Prolonged infusion of cefpirome is expected to be superior to short-term infusions for MICs between 2 and 12 mg/liter.

scholarly journals Quantification of Ligand PET Studies using a Reference Region with a Displaceable Fraction: Application to Occupancy Studies with [11C]-DASB as an Example

2011 ◽  
Vol 32 (1) ◽  
pp. 70-80 ◽  
Author(s):  
Federico E Turkheimer ◽  
Sudhakar Selvaraj ◽  
Rainer Hinz ◽  
Venkatesha Murthy ◽  
Zubin Bhagwagar ◽  
...  
Keyword(s):  
Specific Binding ◽  
Normal Subjects ◽  
Volume Of Distribution ◽  
Binding Potential ◽  
Accurate Estimation ◽  
Data Sets ◽  
Reference Region ◽  
Reference Tissue ◽  
Positron Emission ◽  
Definition Of

This paper aims to build novel methodology for the use of a reference region with specific binding for the quantification of brain studies with radioligands and positron emission tomography (PET). In particular: (1) we introduce a definition of binding potential BPD = DVR–1 where DVR is the volume of distribution relative to a reference tissue that contains ligand in specifically bound form, (2) we validate a numerical methodology, rank-shaping regularization of exponential spectral analysis (RS-ESA), for the calculation of BPD that can cope with a reference region with specific bound ligand, (3) we demonstrate the use of RS-ESA for the accurate estimation of drug occupancies with the use of correction factors to account for the specific binding in the reference. [11C]-DASB with cerebellum as a reference was chosen as an example to validate the methodology. Two data sets were used; four normal subjects scanned after infusion of citalopram or placebo and further six test—retest data sets. In the drug occupancy study, the use of RS-ESA with cerebellar input plus corrections produced estimates of occupancy very close the ones obtained with plasma input. Test-retest results demonstrated a tight linear relationship between BPD calculated either with plasma or with a reference input and high reproducibility.

Daratumumab (DARA) maintenance or observation (OBS) after treatment with bortezomib, thalidomide and dexamethasone (VTd) with or without DARA and autologous stem cell transplant (ASCT) in patients (pts) with newly diagnosed multiple myeloma (NDMM): CASSIOPEIA Part 2.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8004-8004
Author(s):  
Philippe Moreau ◽  
Pieter Sonneveld ◽  
Keyword(s):  
Interim Analysis ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Complete Response ◽  
Autologous Stem Cell Transplant ◽  
Second Primary ◽  
Cell Transplant ◽  
Open Label ◽  
Depth Of Response

8004 Background: D-VTd plus ASCT was approved for transplant-eligible (TE) NDMM based on part 1 of CASSIOPEIA. We report a prespecified interim analysis of CASSIOPEIA part 2: DARA maintenance vs OBS in pts with ≥partial response (PR) in part 1, regardless of induction/consolidation (ind/cons) treatment. Methods: CASSIOPEIA is a 2-part, randomized, open-label, phase 3 study in TE NDMM. Pts received 4 cycles ind and 2 cycles cons with D-VTd or VTd. 886 pts who achieved ≥PR were rerandomized to DARA 16 mg/kg IV Q8W for up to 2 yr (n = 442) or OBS (n = 444) until progressive disease per IMWG. Pts were stratified by ind (D-VTd vs VTd) and depth of response (minimum residual disease [MRD] status and post cons response ≥PR). Primary endpoint was progression-free survival (PFS) after second randomization. This interim analysis assessed efficacy and safety after 281 PFS events. A preplanned hierarchical procedure tested key secondary endpoints: time to progression (TTP), ≥complete response (CR), MRD negativity rates by NGS and overall survival (OS). Results: At median follow-up of 35.4 mo, median PFS was not reached (NR) with DARA and 46.7 mo with OBS (HR 0.53; 95% CI 0.42–0.68; P <0.0001). PFS advantage for DARA was consistent across most subgroups. However, a prespecified analysis showed significant interaction with ind/cons treatment arm ( P< 0.0001). PFS HR for DARA vs OBS was 0.32 (95% CI 0.23–0.46) in the VTd arm and 1.02 (0.71–1.47) in the D-VTd arm. Median TTP was NR for DARA vs 46.7 mo for OBS (HR 0.49; 95% CI 0.38–0.62; P <0.0001). More pts in the DARA vs OBS arm achieved ≥CR (72.9% vs 60.8%; OR 2.17; 95% CI 1.54–3.07; P <0.0001). MRD negativity (in ≥CR pts at 10-5) was 58.6% with DARA vs 47.1% with OBS (OR 1.80; 95% CI 1.33–2.43; P= 0.0001). Median OS was NR in either arm. Most common (≥2.5%) grade 3/4 adverse events (AEs) with DARA vs OBS were pneumonia (2.5% vs 1.4%), lymphopenia (3.6% vs 1.8%), and hypertension (3.0% vs 1.6%). Serious AEs occurred in 22.7% (DARA) vs 18.9% (OBS) of pts; the most common (≥2.5%) was pneumonia (2.5% vs 1.6%). 13 (3.0%) pts discontinued DARA due to an AE. The rate of infusion-related reactions was 54.5% (DARA-naïve pts) and 2.2% (prior DARA pts); 90% were grade 1/2.Second primary malignancies occurred in 5.5% (DARA) vs 2.7% (OBS) of pts. Conclusions: CASSIOPEIA part 2 demonstrated a clinical benefit of DARA maintenance in TE NDMM pts, with significantly longer PFS for DARA vs OBS. With current follow-up, maintenance PFS benefit appeared only in pts treated with VTd as ind/cons. Pts who received D-VTd ind/cons with or without DARA maintenance achieved similar PFS; longer follow-up is needed for PFS2 and OS. DARA significantly increased deeper response and MRD negativity rates vs OBS, and was well tolerated with no new safety signals. Clinical trial information: NCT02541383.

scholarly journals Optimal design for population pk/pd models

2012 ◽  
Vol 51 (1) ◽  
pp. 115-130
Author(s):  
Sergei Leonov ◽  
Alexander Aliev
Keyword(s):  
Optimal Design ◽  
Fisher Information ◽  
Fisher Information Matrix ◽  
Information Matrix ◽  
Optimal Sampling ◽  
Design Algorithm ◽  
Sampling Schemes ◽  
Population Pk ◽  
Different Types

ABSTRACT We provide some details of the implementation of optimal design algorithm in the PkStaMp library which is intended for constructing optimal sampling schemes for pharmacokinetic (PK) and pharmacodynamic (PD) studies. We discuss different types of approximation of individual Fisher information matrix and describe a user-defined option of the library.

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