Phosphorus Fluxes in Limnetic Cladocerans: Coupling of Allometry and Compartmental Analysis

1994 ◽  
Vol 51 (5) ◽  
pp. 1055-1064 ◽  
Author(s):  
Yuan Hua Wen ◽  
Alain Vézina ◽  
Robert Henry Peters
Keyword(s):  
Body Weight ◽  
Steady State ◽  
Body Size ◽  
Time Course ◽  
Compartmental Analysis ◽  
Compartment Model ◽  
Size Dependent ◽  
Two Compartment Model ◽  
Metabolic Activities ◽  
Total P

A size-dependent two-compartment model was developed for estimation of 32P turnover and fluxes by limnetic cladocerans in steady state. After feeding on radioactively labelled food, uniformly labelled animals were fed unlabelled cells and the time course of release of tracer followed. Rates of turnover and size-specific fluxes were subsequently fitted to a two-compartment model. The model predicted that steady-state turnover and size-specific fluxes for 32P excretion declined with body weight and that the exponent of weight did not significantly differ from −0.25, suggesting the relationships between total P turnover or flux rates and body size in cladocerans follow the same allometry observed for other organisms and other metabolic activities. However, rate constants for intercompartmental exchanges declined faster than weight−0.25, indicating that their turnover and flux declined much faster with increasing body size than would be expected from general allometry. Size-specific ingestion and assimilation rates of 32P by cladocerans decreased with increasing body size with a slope of the allometric function similar to −0.25.

Estimation of the rate of appearance in the non-steady state with a two-compartment model

1992 ◽  
Vol 263 (2) ◽  
pp. E400-E415 ◽  
Author(s):  
A. Mari
Keyword(s):  
Steady State ◽  
Time Course ◽  
Specific Activity ◽  
Glucose Production ◽  
Compartment Model ◽  
New Method ◽  
Two Compartment Model ◽  
Glucose Clamp Technique ◽  
Glucose Output ◽  
The Relationship

A simple tracer-based method for calculating the rate of appearance of endogenous substances in the non-steady state, free from the inconsistencies of Steele's equation, is still lacking. This paper presents a method based on a two-compartment model by which the rate of appearance can be calculated with only a modest increase in complexity over Steele's approach. An equation is developed where the rate of appearance is expressed as a sum of three terms: a steady-state term, a term for the first compartment, and a term for the second compartment. The formula employs three parameters and makes the relationship between rate of appearance and specific activity changes explicit. An equation is also provided for estimating the error of the method in each individual run. The algorithm can be implemented with a spreadsheet on a personal computer. Simulated and experimental data obtained by the hyperinsulinemic euglycemic glucose clamp technique were used as a test. The accuracy with which the time course of glucose production could be reconstructed was clearly better than that using Steele's equation. Marked negative values for endogenous glucose output were calculated with Steele's equation but not with the new method. The characteristics of generality, simplicity, and accuracy and the availability of an error estimate make this new method suitable for routine application to non-steady-state tracer analysis.

scholarly journals Population Pharmacokinetics of Oseltamivir: Pediatrics through Geriatrics

2013 ◽  
Vol 57 (8) ◽  
pp. 3470-3477 ◽  
Author(s):  
Mohamed A. Kamal ◽  
Scott A. Van Wart ◽  
Craig R. Rayner ◽  
Vishak Subramoney ◽  
Daniel K. Reynolds ◽  
...  
Keyword(s):  
Steady State ◽  
Time Course ◽  
Demographic Data ◽  
Visual Predictive Check ◽  
Compartment Model ◽  
Plasma Drug ◽  
First Order ◽  
Drug Concentrations ◽  
Population Pk ◽  
The Impact

ABSTRACTOseltamivir is a potent inhibitor of influenza virus neuraminidase enzymes essential for viral replication. This study aimed to investigate the impact of covariates on pharmacokinetic (PK) variability of oseltamivir and its active metabolite form, oseltamivir carboxylate (OC). Dosing history, plasma drug concentrations, and demographic information were pooled from 13 clinical trials providing data for 390 healthy and infected subjects ranging in age from 1 to 78 years and given oseltamivir doses of 20 to 1,000 mg. Candidate population PK models simultaneously characterizing the time course of oseltamivir and OC in plasma were evaluated by using the NONMEM software program, and subject covariates were assessed using stepwise forward selection (α = 0.01) and backward elimination (α = 0.001). A two-compartment model with first-order absorption of oseltamivir and first-order conversion of oseltamivir to OC and a one-compartment model with first-order elimination of OC were utilized. Body weight when evaluated using a power function was a significant predictor of the apparent oseltamivir clearance and both apparent OC clearance (CLm/F) and central volume of distribution (Vcm/F). Creatinine clearance was a significant predictor of CLm/F, while Vcm/F also decreased linearly with age. A visual predictive check indicated that the final model described oseltamivir and OC concentrations in plasma adequately across dose regimens and subject covariate ranges. Concordance of population mean and individualpost hocpredictions of maximum concentration of drug at steady state (Cmax) and area under the plasma drug concentration-time curve from 0 to 24 h at steady state (AUC0–24) was high (r2= 0.81 and 0.71, respectively). In conclusion, a comprehensive population PK model was constructed to bridge the adult to pediatric oseltamivir PK data, allowing for reasonable estimation of the PK of OC using subject demographic data alone.

Distribution and metabolism of adrenocorticotropin in the rat

1979 ◽  
Vol 57 (9) ◽  
pp. 1024-1027 ◽  
Author(s):  
Maurice Normand ◽  
Josee Lalonde
Keyword(s):  
Standard Error ◽  
Time Course ◽  
Compartment Model ◽  
Sprague Dawley ◽  
Mean Values ◽  
Sprague Dawley Rats ◽  
Two Compartment Model ◽  
Rapid Fall ◽  
Significant Difference ◽  
Endogenous Release

The time course of plasma bioactive adrenocorticotropin (ACTH) concentrations measured following two rapid injections of the hormone at doses of 7.5 and 22.5 mU/100 g, iv, and one infusion over a period of 80 min at a rate of 1.3 mU/min per 100 g, to male Sprague–Dawley rats whose endogenous release of ACTH had been blocked, leads to the conclusion that the hormone is distributed in two compartments. Indeed, the rapid fall of plasma ACTH concentrations in the early minutes following either the injections or the stop of the infusion is followed by a much slower phase. There is no significant difference between the measurements and the two-compartment model outputs. The model represents, on the average, the mean values of the measurements plus or minus 1 standard error for the single injections and plus or minus 1.2 standard error for the infusion.

scholarly journals Estimation of Pharmacokinetic Parameters of Continuous Intravenous Flucloxacillin infusion in the Outpatient Settings (PKFLUCLOX)

2018 ◽  
Author(s):  
Nilar Lwin ◽  
Zheng Liu ◽  
Mark Loewenthal ◽  
Pauline Dobson ◽  
Ji Woong Yoo ◽  
...  
Keyword(s):  
Steady State ◽  
Continuous Infusion ◽  
Time Course ◽  
Plasma Concentrations ◽  
Compartment Model ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Device Removal ◽  
Standard Dosage

Flucloxacillin, a beta-lactam antibiotic of the penicillin class, is considered first line therapy for methicillin sensitive Staphylococcus aureus (MSSA) in Australia. At our tertiary referral hospital in the home (HITH) program, it has been prescribed in a standard dosage of 8 grams per day by continuous infusion for more than 20 years. The aim of this observational study was to characterize the pharmacokinetic profile of flucloxacillin in patients who receive continuous infusion in the HITH setting, and to undertake population pharmacokinetic analysis performed with NONMEM software by comparing various structural models. This study utilised flucloxacillin concentrations from 44 separate specimens obtained from 23 patients. Twenty-five of these were collected immediately after elastomeric device removal, representing steady-state concentrations, and the remaining 19 were each collected at least 45 minutes after device removal to determine clearance of the drug. Plasma concentrations ranged from 13 to 194 mg/L with median steady-state concentration of 51.5 mg/L and inter-quartile range of 24.6 mg/L. The time-course of flucloxacillin was best described by a 1-compartment model. The best three covariates, CrCL (ΔOFV= -11.7), eGFR (ΔOFV= -5.9) and serum albumin (ΔOFV= -5.8) were found to be equivalent in terms of decreasing the OFV. CrCL was superior in explaining inter individual variability. The best model for flucloxacillin clearance was a one compartment model with CrCL as the sole covariate. The estimated population parameters were 9.5 L for volume of distribution and 8.1 L/h for flucloxacillin clearance.

Time course and kinetics of proximal tubular processing of insulin

1992 ◽  
Vol 262 (5) ◽  
pp. F813-F822 ◽  
Author(s):  
S. Nielsen
Keyword(s):  
Steady State ◽  
Time Course ◽  
Accumulation Rate ◽  
Compartmental Analysis ◽  
Proximal Tubules ◽  
Hydrolysis Rate ◽  
Time Courses ◽  
High Concentrations ◽  
Kinetics Of

The present study was undertaken to determine the time courses and kinetics of the subcellular processing of 125I-insulin in isolated and in vitro perfused proximal tubules. Morphometric analysis demonstrated well-preserved ultrastructure after 90 min of perfusion. After luminal perfusion for 90 min the absorption was constant with time and reached steady state within 5 min (177 +/- 7 fg.min-1.mm-1). Also the hydrolysis rate and tubular accumulation rate were constant and averaged 84 +/- 8 and 93 +/- 10 fg.min-1.mm-1, respectively. Free 125I appeared already within 5 min of perfusion and reached steady state within 10 min. From proximal tubules perfused with 125I-insulin for 30 min and chased for 60 min, a compartmental analysis revealed two compartments; half time (t1/2) for delivery of insulin to the lysosomes was determined to be 8.5 min, and t1/2 for lysosomal degradation was 72 min. The results demonstrated that internalization by endocytic invaginations, incorporation in endocytic vacuoles, fusion with lysosomes, and hydrolysis were rapid processes and reached maximum rates within few minutes. A significant transtubular transport of insulin to the peritubular compartment was determined to be a constant rate of 11.2 +/- 0.7 fg.min-1.mm-1. Perfusion of tubules with insulin at high concentrations in the perfusate revealed that the transport was dependent on the absorbed amount and not on the perfused load, compatible with transport through the cells and not via a paracellular mechanism. The intactness of the tight junctions was supported by the following: 1) [14C]inulin leak did not increase with time and 2) enzyme-free intercellular spaces were evident after perfusion for only 5 min with microperoxidase (mol wt of 1,700). The transported 125I-insulin was trichloroacetic acid precipitable and immunoprecipitable.

Steady-State Pharmacokinetics of Cefoperazone and Sulbactam in Patients with Acute Appendicitis

1994 ◽  
Vol 28 (6) ◽  
pp. 703-707
Author(s):  
Larry H. Danziger ◽  
Stephen C. Piscitelli ◽  
Donna J. Occhipinti ◽  
Daniel J. Resnick ◽  
Keith A. Rodvold
Keyword(s):  
Steady State ◽  
Acute Appendicitis ◽  
Dosage Reduction ◽  
Area Under The Curve ◽  
Compartment Model ◽  
Hepatic Function ◽  
Volume Of Distribution ◽  
Two Compartment Model ◽  
Elimination Half ◽  
G Prior

OBJECTIVE: To determine the steady-state pharmacokinetics of intravenously administered cefoperazone and sulbactam when given in combination to patients with acute appendicitis. METHODS: Six patients with normal renal and hepatic function received cefoperazone 2 g with sulbactam 1 g prior to appendectomy and then every 12 hours. Serial blood samples were collected after each patient received at least three doses of cefoperazone/sulbactam. RESULTS: Cefoperazone and sulbactam could be best described by a two-compartment model. Mean ± SD values for cefoperazone steady-state volume of distribution (Vssd), elimination half-life (t1/2β), clearance (Cl), and area under the curve (AUC0-t) were 19.8 ± 8.0 L, 3.97 ± 1.06 h, 62.6 ± 16.3 mL/min, and 556.9 ± 122.0 mg·h/L, respectively. Sulbactam Vssd, t1/2β, Cl, and AUC0-t were 34.7 ± 13.9 L, 1.39 ± 0.4 h, 288.6 ± 68.2 mL/min, and 64.8 ± 24.5 mg·h/L, respectively. CONCLUSIONS: Compared with data from healthy volunteers, cefoperazone exhibited a decreased Cl and increased Vssd and t1/2β in patients with acute appendicitis. An increased Vssd also was observed for sulbactam. The disposition of cefoperazone/sulbactam is altered in this group of patients; however, these changes are not likely to warrant a dosage reduction.

Higher Doses of Rituximab May Be Required for Patients with CLL as Compared to NHL Based On Population Pharmacokinetic (PK) Modeling.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1742-1742 ◽  
Author(s):  
Jing Li ◽  
Jianguo Zhi ◽  
Michael K. Wenger ◽  
Nancy Valente ◽  
Jennifer Visich
Keyword(s):  
Steady State ◽  
Dose Regimen ◽  
Compartment Model ◽  
Rate Of Change ◽  
Phase Iii ◽  
Time Varying ◽  
Malignant Cells ◽  
Concentration Data ◽  
Two Compartment Model ◽  
Population Pk

Abstract Abstract 1742 Poster Board I-768 Introduction In the randomized Phase III study REACH, the combination of rituximab (R) (375 mg/m2 cycle 1, 500 mg/m2 cycles 2-6) and fludarabine (F) (25mg/m2 X 6 cycles) and cyclophosphamide (C) (250 mg/m2 X6 cycles) was shown to improve clinical response and prolong PFS in patients with relapsed/refractory Chronic Lymphocytic Leukemia (CLL) compared with F and C alone. The use of 500 mg/m2 as the dose of R in R-FC was guided by previous published data in CLL patients treated with R monotherapy demonstrating a probable dose-response relationship of a higher response rate at the higher dose levels (O'Brien JCO 2001, Byrd JCO 2001) and also by the data of high number of circulating malignant cells in CLL population (characteristic of CLL) which indicated that R might exhibit a higher clearance rate in CLL compared to observed clearance rates in NHL. Prior to the REACH study, the pharmacokinetics (PK) of R have not been thoroughly studied in the CLL population. As sub-study in REACH trial, a complete PK analysis of R was performed in CLL patients using a population PK analysis. This approach allowed not only the characterization of R PK in CLL patients, but also allowed for an opportunity to perform comparison of the PK differences between indications (CLL and NHL) and provided data-driven validation for the need of high R in CLL patients. Patients and Methods The PK of R were described with plasma concentrations from 21 CLL patients who received R-FC, using nonlinear mixed-effects modeling (NONMEM VI) software. A two-compartment model with time-varying clearance was validated using a bootstrap and visual predictive check method. The concentration vs. time profiles after given different dosages of R in NHL and CLL patients were predicted using the final models based on the observed data. Results R concentration data in CLL patients were well described by a two-compartment model with time-varying clearance, which has been used to describe R concentration data in NHL. Total clearance is comprised of two terms, a non-specific clearance pathway (CL1), which remains unchanged throughout treatment, and a specific clearance pathway (CL2) that decreases following a first-order decay rate from its initial value following the first infusion. The term Kdes represents the actual rate of change from the specific clearance (mediated by CD20) to the non-specific clearance (mediated by IgG1). The typical population estimates of R nonspecific clearance (CL1), and central compartment volume of distribution (V1) are similar between CLL and NHL (171 vs. 138 mL/day; 2310 vs. 2710 mL, respectively). However, the specific clearance (CL2) in CLL was much faster than that in NHL (1280 vs. 577 mL/day), and the rate of change (Kdes) from the specific clearance (mediated by CD20) to the non-specific clearance (mediated by IgG1) is two times lower for CLL patients compared to NHL patients (0.024 vs. 0.046 /day) and this suggests that it takes longer time for receptor saturation for CLL patients compared to NHL patients. The results of the simulation exercise showed that in the early cycles of the R-FC regimen, trough concentrations (Ctrough) and drug exposure (AUC) in CLL patients given 500 mg/m2 would be lower than those for NHL patients given 375 mg/m2 dose regimen. By the final cycles, the Ctrough and AUC of R are similar in NHL given 375 mg/m2 and CLL given 500 mg/m2. Conclusions Retrospective population PK analysis of R in CLL patients using non linear mixed effect modeling confirmed an increased R clearance during the early cycle of treatment as compared to NHL patients. This increased clearance is potentially due to a higher number of malignant cells in circulation for CLL patients, thus a larger dominance of the faster receptor-mediated clearance component in these patients, which overcome the lower CD20 density in CLL. The dose regimen of 500mg/m2 in CLL patients allows for reaching steady state AUC which is similar to the steady state AUC achieved with doses of 375mg/m2 given in NHL patients. Disclosures Li: Genentech: Employment. Zhi:Hoffmann-La Roche Inc.: Employment. Wenger:F. Hoffmann-La Roche Ltd: Employment. Valente:Genentech: Employment, Equity Ownership. Visich:Genentech: Employment.

Trastuzumab (T) and everolimus (E) pharmacokinetics (PK) in HER2 positive (+) primary breast cancer (BC) patients (pts): Unicancer RADHER trial results.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2599-2599
Author(s):  
Guillemette Bernadou ◽  
Keyvan Rezai ◽  
Jean-Louis Merlin ◽  
Mario Campone ◽  
Francois Lokiec ◽  
...  
Keyword(s):  
Body Weight ◽  
Half Life ◽  
Tumor Volume ◽  
Compartment Model ◽  
Her2 Positive ◽  
Elimination Half Life ◽  
A Value ◽  
Two Compartment Model ◽  
Elimination Half ◽  
The Impact

2599 Background: T has greatly modified the prognosis of HER2+ BC, but few studies have analyzed its PK. The RADHER study evaluated the interest of adding E to T as preoperative therapy for primary HER2+ BC. It also aimed at describing the PK of T and studying the impact of E with T in primary BC. Methods: Eligible pts with HER2+ operable primary BC were randomized to receive T alone (loading dose 4 mg/kg, then 2 mg/kg/week (W)) or T + E (10 mg/day (D)) for a 6-W pre-operative treatment. Blood samples were collected to measure T and E concentrations. For T, plasma samples were collected in all pts before each infusion, and at Hour (H) 1, D1, D3, W1, W2, W4, W8 and W12 after the last infusion. E concentrations were determined on whole blood collected at H0, H0.5, H1, H2, H4, H6, H12 and H24 after the first T infusion, and again after the last E intake. T and E PK were described using population compartment analyses. Results: From 82 pts randomized, 79 were evaluable for T and 22 for E PK. Mean estimated PK parameters of T were (interindividual coefficient of variation %): central (Vc) and peripheral (Vp) volumes of distribution = 2 L (24%) and 1.3 L (39%), systemic (CL) and intercompartment (Q) clearances = 0.22 L/day (19%) and 0.36 L/day, respectively. Vc increased with body weight and decreased with age, while CL increased with body weight and with tumor volume. Elimination half-life was 11 days, a value lower than that previously reported in metastatic BC (28 days). E PK was best described by a two-compartment model. Mean estimated PK parameters (RSE%) of E were: CL = 3.96 L/h (22%), Q = 29.1 L/h (7%), Vc = 119 L (11%), Vp = 1530 L (24%). E did not influence T PK. E PK was similar to that previously reported in other indications. Conclusions: This is the first study describing the PK of T and E in primary BC. Notably, T CL increases with tumor volume and the elimination half-life is only 11 days, lower than expected from previous results in metastatic BC. The differences in PK between primary and metastatic BC might lead to take a second look at trastuzumab dose regimen in primary BC. Clinical trial information: NCT00674414.

scholarly journals Population pharmacokinetic modeling of PF-06439535 (a bevacizumab biosimilar) and reference bevacizumab (Avastin®) in patients with advanced non-squamous non-small cell lung cancer

2019 ◽  
Vol 85 (3) ◽  
pp. 487-499
Author(s):  
Cheryl S. W. Li ◽  
Kevin Sweeney ◽  
Carol Cronenberger
Keyword(s):  
Lung Cancer ◽  
Body Weight ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Drug Product ◽  
Compartment Model ◽  
Small Cell ◽  
Small Cell Lung ◽  
Covariate Analysis ◽  
Two Compartment Model

Abstract Purpose The objectives of this analysis were to characterize the population pharmacokinetics (PK) of PF-06439535 (a bevacizumab biosimilar) and reference bevacizumab (Avastin®) sourced from the European Union (bevacizumab-EU) in patients with advanced non-squamous non-small cell lung cancer (NSCLC), and to quantify the difference in PK parameters between the two drug products via covariate analysis. Methods Pooled PF-06439535 and bevacizumab-EU serum concentration data from a comparative clinical efficacy and safety study (NCT02364999) in patients with NSCLC (N = 719) were analyzed using a non-linear mixed-effects modeling approach. Patients received PF-06439535 plus chemotherapy or bevacizumab-EU plus chemotherapy every 21 days for 4–6 cycles, followed by monotherapy with PF-06439535 or bevacizumab-EU. PF-06439535 or bevacizumab-EU was administered intravenously at a dose of 15 mg/kg. Effects of patient and disease covariates, as well as the drug product (PF-06439535 versus bevacizumab-EU), on PK were investigated. Results Overall, 8632 serum bevacizumab concentrations from 351 patients in the PF-06439535 group and 354 patients in the bevacizumab-EU group were included in the analysis. A two-compartment model adequately described the combined data. Clearance (CL) and central volume of distribution (V1) estimates were 0.0113 L/h and 2.99 L for a typical 71-kg female patient with NSCLC administered bevacizumab-EU. CL and V1 increased with body weight and were higher in males than females even after accounting for differences in body weight. The 95% confidence intervals for the effect of drug product on CL and V1 encompassed unity. Conclusions The population PK of PF-06439535 and bevacizumab-EU were well characterized by a two-compartment model. Covariate analysis did not reveal any appreciable differences between PK parameters for PF-06439535 and bevacizumab-EU in patients with NSCLC. Clinical trial registration ClinicalTrials.gov, NCT02364999.

Effects of lung volume on clearance of solutes from the air spaces of lungs

1988 ◽  
Vol 64 (3) ◽  
pp. 1068-1075 ◽  
Author(s):  
B. T. Peterson ◽  
H. L. James ◽  
J. W. McLarty
Keyword(s):  
Human Serum Albumin ◽  
Lung Volume ◽  
Clearance Rate ◽  
Compartmental Analysis ◽  
Compartment Model ◽  
Lung Inflation ◽  
Experimental Animals ◽  
Two Compartment Model ◽  
Additional Control ◽  
Albumin Clearance

Several investigators have shown that the clearance rate of aerosolized 99mTc-labeled diethylenetriamine pentaacetate (DTPA, mol wt = 492, radius = 0.6 nm) from the air spaces of the lungs of humans and experimental animals increases with lung volume. To further investigate this phenomenon we performed a compartmental analysis of the 2-h clearance of DTPA from the lungs of anesthetized sheep using a new method to more accurately correct for the effects of DTPA recirculation. This analysis showed that the DTPA clearance in eight sheep ventilated with zero end-expired pressure was best described by a one-compartment model with a clearance rate of 0.42 ± 0.15%/min. Ventilating eight sheep with an end-expired pressure of 10 cmH2O throughout the study increased the end-expired volume 0.4 ± 0.1 liter BTPS and created a clearance curve that was best described by a two-compartment model. In these sheep 56 ± 16% of the DTPA cleared from the lungs at a rate of 7.9 ± 2.9%/min. The remainder cleared at a rate similar to that measured in the sheep ventilated with zero end-expired pressure (0.35 ± 0.18%/min). Additional control and lung inflation experiments were performed using 99mTc-labeled human serum albumin (mol wt = 66,000, radius = 3.6 nm). In six control sheep ventilated with zero end-expired pressure the albumin clearance was best described by a one-compartment model with a clearance rate of 0.06 ± 0.02%/min. The clearance rate in six sheep with increased lung volume was slightly larger (0.09 ± 0.02, P less than 0.05) but was well described by a one-compartment model.(ABSTRACT TRUNCATED AT 250 WORDS)

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