Population pharmacokinetic (PPK) analysis for 5-FU, tegafur (FT), gimeracil (CDHP), and oteracil potassium (Oxo) in the eight clinical studies of S-1 in Western patients with advanced solid tumors.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 53-53 ◽  
Author(s):  
K. Yoshida ◽  
K. Ikeda ◽  
K. Yoshisue ◽  
W. Rodriguez ◽  
G. Bodoky ◽  
...  
Keyword(s):  
Renal Function ◽  
Model Simulation ◽  
Visual Predictive Check ◽  
Compartment Model ◽  
Phase Iii ◽  
Population Pharmacokinetic ◽  
Extrinsic Factors ◽  
Minimal Impact ◽  
Two Compartment Model ◽  
Number Of Patients

53 Background: This analysis was performed to establish the PPK model of S-1, and to identify the intrinsic or extrinsic factors that influence S-1 exposure in the Western patients with advanced solid tumor. Methods: PK data obtained in seven phase I and one phase III (FLAGS) studies were combined for PPK analysis. The total number of patients was 315, and the number of data points for FT, CDHP, 5-FU and Oxo were 2,860, 2,625, 2,492, and 2,484, respectively. The two-compartment model was used for FT, CDHP and Oxo, whereas for 5-FU, inhibitory effect of CDHP on 5-FU clearance was incorporated into a two-compartment model to describe its non-linear PK. The final models were validated by visual predictive check and bootstrapping. Results: The individual fit and the stability of four models were acceptable. The predicted daily AUCs (at steady state) were calculated to evaluate the effect of covariates. The daily AUC of 5-FU strongly correlated with oral clearance (CL/F) of CDHP, but not with that of FT. The ethnic difference in exposure to 5-FU was not apparent despite the significantly lower CL/F of FT observed in the Asian patients. Co-administration with food delayed the absorption of S-1 but exhibited no or limited effect on the AUC of FT, CDHP and 5-FU, whereas the bioavailability of Oxo decreased to approximately 30%. Renal function primarily influenced CDHP exposure and, in turn, 5-FU. The model simulation suggested that the S-1 dosages of 30, 25 and 20 mg/m2 BID could achieve similar daily AUC of 5-FU in the Western patients with normal renal function (CLcr>80 mL/min), mild (50-80 mL/min) and moderate (30-50 mL/min) renal impairment, respectively. Other factors such as age, gender, liver function, serum albumin, PS, gastric cancer, gastrectomy, combination with cisplatin and liver metastasis, had little or minimal impact on the daily AUC of 5-FU. Conclusions: This analysis suggests that the daily AUC of 5-FU after S-1 administration is primarily affected by the CDHP levels, and hence renal function remains the primary factor for 5-FU PK in patients. Other factors as well as CL/F of FT had little impact on 5-FU. [Table: see text]

scholarly journals Population Pharmacokinetic Analysis of Fevipiprant in Healthy Subjects and Asthma Patients using a Tukey’s g-and-h Distribution

Drug Research ◽  
2021 ◽  
Author(s):  
Xinting Wang ◽  
Christian Bartels ◽  
Swarupa Kulkarni ◽  
Ramachandra Sangana ◽  
Monish Jain ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Compartment Model ◽  
Skewed Distribution ◽  
Phase Iii ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Concentration Data ◽  
First Order ◽  
Two Compartment Model ◽  
Asthma Patients

Abstract Aim The objective of this analysis was to characterize the population pharmacokinetics (PK) of fevipiprant in asthma patients and to evaluate the effect of baseline covariates on the PK of fevipiprant. Methods PK data from 1281 healthy subjects or asthma patients were available after single or once daily dosing of fevipiprant. Population PK analysis was conducted to describe fevipiprant plasma concentration data using a non-linear mixed effect modeling approach. Results Fevipiprant PK was described by a two-compartment model with first-order absorption and first-order elimination. Exploration of fevipiprant PK in the population from the phase III studies revealed an over-dispersed and skewed distribution. This unusual distribution was described using Tukey’s g-and-h distribution (TGH) on the between-subject variability of apparent clearance (CL/F). The model identified a significant impact of disease status on CL/F, with the value in healthy subjects being 62% higher than that in asthma patients. Bodyweight, age and renal function showed statistically significant impact on fevipiprant clearance; however, compared with a typical asthma patient, the simulated difference in steady-state exposure was at most 16%. Conclusion Fevipiprant PK was described by a two-compartment model with first-order absorption and first-order elimination. The TGH distribution was appropriate to describe the over-dispersed and skewed PK data as observed in the current studies. Asthma patients had approximately 37% higher exposure than healthy subjects did. Other covariates changed exposure by at most 16%.

scholarly journals Population Pharmacokinetic Analysis of Voriconazole and Anidulafungin in Adult Patients with Invasive Aspergillosis

2014 ◽  
Vol 58 (8) ◽  
pp. 4718-4726 ◽  
Author(s):  
Ping Liu ◽  
Diane R. Mould
Keyword(s):  
Invasive Aspergillosis ◽  
Area Under The Curve ◽  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Institutional Review Boards ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
First Order ◽  
Two Compartment Model

ABSTRACTTo assess the pharmacokinetics (PK) of voriconazole and anidulafungin in patients with invasive aspergillosis (IA) in comparison with other populations, sparse PK data were obtained for 305 adults from a prospective phase 3 study comparing voriconazole and anidulafungin in combination versus voriconazole monotherapy (voriconazole, 6 mg/kg intravenously [IV] every 12 h [q12h] for 24 h followed by 4 mg/kg IV q12h, switched to 300 mg orally q12h as appropriate; with placebo or anidulafungin IV, a 200-mg loading dose followed by 100 mg q24h). Voriconazole PK was described by a two-compartment model with first-order absorption and mixed linear and time-dependent nonlinear (Michaelis-Menten) elimination; anidulafungin PK was described by a two-compartment model with first-order elimination. For voriconazole, the normal inverse Wishart prior approach was implemented to stabilize the model. Compared to previous models, no new covariates were identified for voriconazole or anidulafungin. PK parameter estimates of voriconazole and anidulafungin are in agreement with those reported previously except for voriconazole clearance (the nonlinear clearance component became minimal). At a 4-mg/kg IV dose, voriconazole exposure tended to increase slightly as age, weight, or body mass index increased, but the difference was not considered clinically relevant. Estimated voriconazole exposures in IA patients at 4 mg/kg IV were higher than those reported for healthy adults (e.g., the average area under the curve over a 12-hour dosing interval [AUC0–12] at steady state was 46% higher); while it is not definitive, age and concomitant medications may impact this difference. Estimated anidulafungin exposures in IA patients were comparable to those reported for the general patient population. This study was approved by the appropriate institutional review boards or ethics committees and registered on ClinicalTrials.gov (NCT00531479).

Population pharmacokinetic modeling and dosing simulations of tobramycin in pediatric patients with cystic fibrosis

2021 ◽  
Author(s):  
Antonin Praet ◽  
Laurent Bourguignon ◽  
Florence Vetele ◽  
Valentine Breant ◽  
Charlotte Genestet ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Dose Adjustment ◽  
Total Body Weight ◽  
Compartment Model ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Time Curve ◽  
Population Pharmacokinetic Modeling ◽  
Two Compartment Model ◽  
Total Body

Initial dosing and dose adjustment of intravenous tobramycin in cystic fibrosis children is challenging. The objectives of this study were to develop nonparametric population pharmacokinetic (PK) models of tobramycin in children with CF to be used for dosage design and model-guided therapeutic drug monitoring. We performed a retrospective analysis of tobramycin PK data in our CF children center. The Pmetrics package was used for nonparametric population PK analysis and dosing simulations. Both the maximal concentration over the MIC (Cmax/MIC) and daily area under the concentration-time curve to the MIC (AUC 24 /MIC) ratios were considered as efficacy target. Trough concentration (Cmin) was considered as the safety target. A total of 2884 tobramycin concentrations collected in 195 patients over 9 years were analyzed. A two-compartment model including total body weight, body surface area and creatinine clearance as covariates best described the data. A simpler model was also derived for implementation into the BestDose software to perform Bayesian dose adjustment. Both models were externally validated. PK/PD simulations with the final model suggest that an initial dose of tobramycin of 15 to 17.5 mg/kg/day was necessary to achieve Cmax/MIC ≥ 10 values for MIC values up to 2 mg/L in most patients. The AUC 24 /MIC target was associated with larger dosage requirements and higher Cmin. A daily dose of 12.5 mg/kg would optimize both efficacy and safety target attainment. We recommend to perform tobramycin TDM, model-based dose adjustment, and MIC determination to individualize intravenous tobramycin therapy in children with CF.

scholarly journals A modified two-compartment model for measurement of renal function using dynamic contrast-enhanced computed tomography

PLoS ONE ◽  
2019 ◽  
Vol 14 (7) ◽  
pp. e0219605 ◽  
Author(s):  
Kai Jiang ◽  
Christopher M. Ferguson ◽  
Abdelrhman Abumoawad ◽  
Ahmed Saad ◽  
Stephen C. Textor ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Renal Function ◽  
Compartment Model ◽  
Dynamic Contrast Enhanced ◽  
Two Compartment Model ◽  
Contrast Enhanced ◽  
Enhanced Computed Tomography ◽  
Contrast Enhanced Computed Tomography

scholarly journals Population pharmacokinetic meta-analysis of individual data to design the first randomized efficacy trial of vancomycin in neonates and young infants

2019 ◽  
Vol 74 (8) ◽  
pp. 2128-2138 ◽  
Author(s):  
Evelyne Jacqz-Aigrain ◽  
Stéphanie Leroux ◽  
Alison H Thomson ◽  
Karel Allegaert ◽  
Edmund V Capparelli ◽  
...  
Keyword(s):  
Meta Analysis ◽  
Intermittent Infusion ◽  
Compartment Model ◽  
Population Pharmacokinetic ◽  
Dosing Regimen ◽  
Blue Book ◽  
Young Infants ◽  
Optimal Dosing ◽  
Two Compartment Model ◽  
Postmenstrual Age

Abstract Objectives In the absence of consensus, the present meta-analysis was performed to determine an optimal dosing regimen of vancomycin for neonates. Methods A ‘meta-model’ with 4894 concentrations from 1631 neonates was built using NONMEM, and Monte Carlo simulations were performed to design an optimal intermittent infusion, aiming to reach a target AUC0–24 of 400 mg·h/L at steady-state in at least 80% of neonates. Results A two-compartment model best fitted the data. Current weight, postmenstrual age (PMA) and serum creatinine were the significant covariates for CL. After model validation, simulations showed that a loading dose (25 mg/kg) and a maintenance dose (15 mg/kg q12h if <35 weeks PMA and 15 mg/kg q8h if ≥35 weeks PMA) achieved the AUC0–24 target earlier than a standard ‘Blue Book’ dosage regimen in >89% of the treated patients. Conclusions The results of a population meta-analysis of vancomycin data have been used to develop a new dosing regimen for neonatal use and to assist in the design of the model-based, multinational European trial, NeoVanc.

A two-compartment model of pulmonary nitric oxide exchange dynamics

1998 ◽  
Vol 85 (2) ◽  
pp. 653-666 ◽  
Author(s):  
Nikolaos M. Tsoukias ◽  
Steven C. George
Keyword(s):  
Nitric Oxide ◽  
Elimination Rate ◽  
Compartment Model ◽  
Phase Iii ◽  
Exhaled Breath ◽  
Dynamic Relationship ◽  
Exhaled No ◽  
Two Compartment Model ◽  
Conducting Airways ◽  
The Relationship

The relatively recent detection of nitric oxide (NO) in the exhaled breath has prompted a great deal of experimentation in an effort to understand the pulmonary exchange dynamics. There has been very little progress in theoretical studies to assist in the interpretation of the experimental results. We have developed a two-compartment model of the lungs in an effort to explain several fundamental experimental observations. The model consists of a nonexpansile compartment representing the conducting airways and an expansile compartment representing the alveolar region of the lungs. Each compartment is surrounded by a layer of tissue that is capable of producing and consuming NO. Beyond the tissue barrier in each compartment is a layer of blood representing the bronchial circulation or the pulmonary circulation, which are both considered an infinite sink for NO. All parameters were estimated from data in the literature, including the production rates of NO in the tissue layers, which were estimated from experimental plots of the elimination rate of NO at end exhalation (ENO) vs. the exhalation flow rate (V˙E). The model is able to simulate the shape of the NO exhalation profile and to successfully simulate the following experimental features of endogenous NO exchange: 1) an inverse relationship between exhaled NO concentration and V˙E, 2) the dynamic relationship between the phase III slope andV˙E, and 3) the positive relationship between ENO andV˙E. The model predicts that these relationships can be explained by significant contributions of NO in the exhaled breath from the nonexpansile airways and the expansile alveoli. In addition, the model predicts that the relationship between ENO and V˙E can be used as an index of the relative contributions of the airways and the alveoli to exhaled NO.

scholarly journals 1573. Population Pharmacokinetic Analyses for Cefepime in Adult and Pediatric Patients

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S574-S575
Author(s):  
Jiajun Liu ◽  
Michael Neely ◽  
Jeffrey Lipman ◽  
Fekade B Sime ◽  
Jason Roberts ◽  
...  
Keyword(s):  
Rate Constant ◽  
Pediatric Patients ◽  
Validation Cohort ◽  
External Validation ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Information Criteria ◽  
Population Pharmacokinetic ◽  
Final Model ◽  
Two Compartment Model

Abstract Background Cefepime (CEF) is commonly used for adult and pediatric infections. Several studies have examined CEF’s pharmacokinetics (PK) in various populations; however, a unifying PK model for adult and pediatric subjects does not yet exist. We developed a combined population model for adult and pediatric patients and validated the model. Methods The initial model includes adult and pediatric patients with a rich cefepime sampling design. All adults received 2 g CEF while pediatric subjects received a mean of 49 (SD 5) mg/kg. One- and two-compartment models were considered as base models and were fit using a non-parametric adaptive grid algorithm within the Pmetrics package 1.5.2 (Los Angeles, CA) for R 3.5.1. Compartmental model selection was based on Akaike information criteria (AIC). Covariate relationships with PK parameters were visually inspected and mathematically assessed. Predictive performance was evaluated using bias and imprecision of the population and individual prediction models. External validation was conducted using a separate adult cohort. Results A total of 45 subjects (n = 9 adults; n = 36 pediatrics) were included in the initial PK model build and 12 subjects in the external validation cohort. Overall, the data were best described using a two-compartment model with volume of distribution (V) normalized to total body weight (TBW/70 kg) and an allometric scaled elimination rate constant (Ke) for pediatric subjects (AIC = 4,138.36). Final model observed vs. predicted plots demonstrated good fit (population R2 = 0.87, individual R2 = 0.97, Figure 1a and b). For the final model, the population median parameter values (95% credibility interval) were V0 (total volume of distribution), 11.7 L (10.2–14.6); Ke for adult, 0.66 hour−1 (0.38–0.78), Ke for pediatrics, 0.82 hour−1 (0.64–0.85), KCP (rate constant from central to peripheral compartment), 1.4 hour−1 (1.3–1.8), KPC (rate constant from peripheral to central compartment), 1.6 hour−1 (1.2–1.8). The validation cohort has 12 subjects, and the final model fit the data well (individual R2 = 0.75). Conclusion In this diverse group of adult and pediatrics, a two-compartment model described CEF PK well and was externally validated with a unique cohort. This model can serve as a population prior for real-time PK software algorithms. Disclosures All authors: No reported disclosures.

Association of long-term exposure to circulating platinum with adverse late effects in testicular cancer survivors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4528-4528
Author(s):  
Hink Boer ◽  
Johannes H Proost ◽  
Janine Nuver ◽  
Sophie Bunskoek ◽  
Joyce Q. Gietema ◽  
...  
Keyword(s):  
Testicular Cancer ◽  
Late Effects ◽  
Compartment Model ◽  
Population Pharmacokinetic ◽  
Serum Samples ◽  
Time Points ◽  
Two Compartment Model ◽  
Testicular Cancer Survivors

4528 Background: Successful platinum(Pt)-based chemotherapy for testicular cancer (TC) comes at the price of late cardiovascular morbidity and neurotoxicity. Damage induced by circulating Pt could be an etiological mechanism. We investigated the relation between circulating Pt and late effects. Methods: In 96 consecutive TC patients (med age 29 [17-53] at chemotherapy), 3 serum samples and a 24h-urine sample were collected on several time-points med 5 yrs (1-13) after treatment. Pt concentrations ([Pt]) were measured with a sensitive voltammetric method (Lancet 2000, 355:1075). Measured [Pt] combined with cisplatin dose, age, weight and height were analyzed simultaneously to construct a population pharmacokinetic (PK) model using NONMEM. Based on the PK parameters of each patient, individual [Pt] at 1, 3, 5, 10 yrs after start and AUC were calculated. Cardiovascular status, paresthesia and markers of vascular damage were assessed after a med follow-up (FU) of 9 yrs (3-15). Results: Decay of [Pt] was best described by a two compartment model. Mean terminal T1/2 was 3.7 (±0.3) yrs. At all time-points [Pt] correlated with cisplatin dose and renal function during treatment. [Pt] at 3 yrs correlated with systolic blood pressure (BP) (r=.32, p<0.01) and creatinine clearance (CRCL) (r=-.25, p=0.02) at FU. Patients with increased BP had higher Pt AUCs than patients with normal BP (table). Pt AUCs were higher in patients with paresthesia (table). Conclusions: Known late effects of cisplatin-based chemotherapy such as hypertension and paresthesia are related to higher circulating [Pt]. Long-term exposure to Pt is involved in healthy tissue damage in TC survivors. [Table: see text]

Cetuximab (Cet) clearance and survival in patients (pts) with metastatic colorectal cancer (mCRC).

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 699-699
Author(s):  
Di Maria Jiang ◽  
Hao-Wen Sim ◽  
Lillian L. Siu ◽  
Jeremy David Shapiro ◽  
Geoffrey Liu ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Compartment Model ◽  
Phase Iii ◽  
Population Pharmacokinetic ◽  
Mean Values ◽  
Clinical Variables ◽  
Disease Characteristics ◽  
Exposure Response ◽  
Trough Blood ◽  
Grade 3

699 Background: Cet, a monoclonal antibody against EGFR, is a standard therapy for pts with RAS wild-type (WT) mCRC. Limited previous data suggest that Cet clearance correlates with progression-free survival (PFS). We performed a population pharmacokinetic (pop-pK) analysis of Cet in pts who participated in the randomized phase III NCIC CO.20 trial in KRAS WT mCRC patients. Methods: Standard Cet doses ± brivanib were administered. Using intermittent trough blood samples, pop-pK analysis was conducted to evaluate different models. Pts were divided into quartiles according to clearance parameters to assess the exposure-response relationship to response rate (RR), PFS and overall survival (OS). Clinical variables including demographic, laboratory, disease characteristics and co-administration of brivanib were evaluated as co-variates on Cet clearance. Results: In 701 pts, Cet elimination was best described as a one-compartment model with a non-linear saturable elimination process (defined by Vmax and Km). Mean values (± standard deviation) for pop-pk parameters were 2.7 ± 0.5 L/m2 for V, 2.5 ± 0.3 mg/h/m2 for Vmax, and 101.0 ± 0.05 mg/L/m2 for Km. Grouped into quartiles, Vmax and Km were significantly associated with OS, but not RR or PFS. The median OS for pts in the lowest quartile of Vmax was 12.0 ms versus (vs.) 6.9 ms for pts in the highest quartile ( p< 0.001), while the median OS was 11.6 ms in the highest Km quartile vs. 6.9 ms in the lowest Km quartile ( p< 0.001). When compared to the quartile with the combination of highest Vmax and lowest Km, pts in the quartile with the lowest Vmax and highest Km had longer PFS (5.0 vs. 3.7 ms, HR 0.75 (95% confidence interval (CI) 0.58-0.98, p= 0.032) and OS (11.7 vs. 6.6 ms, HR 0.59 (95% CI, 0.45-0.77, p< 0.001). Pts in the lower Vmax and higher Km quartiles also experienced less grade 3 toxicity. Neither clinical variables nor brivanib administration were associated with Cet clearance parameters. Conclusions: For KRAS WT mCRC, standard Cet dosing is not optimal for all pts. Pts with slower Cet clearance have significantly improved PFS and OS. Further studies are needed to optimize Cet doses based on individual pK assessments, and to identify novel factors associated with clearance.

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