Infliximab Efficacy May Be Linked to Full TNF-α Blockade in Peripheral Compartment—A Double Central-Peripheral Target-Mediated Drug Disposition (TMDD) Model

Infliximab is an anti-TNF-α monoclonal antibody approved in chronic inflammatory bowel diseases (IBD). This study aimed at providing an in-depth description of infliximab target-mediated pharmacokinetics in 133 IBD patients treated with 5 mg/kg infliximab at weeks 0, 2, 14, and 22. A two-compartment model with double target-mediated drug disposition (TMDD) in both central and peripheral compartments was developed, using a rich database of 26 ankylosing spondylitis patients as a reference for linear elimination kinetics. Population approach and quasi-steady-state (QSS) approximation were used. Concentration-time data were satisfactorily described using the double-TMDD model. Target-mediated parameters of central and peripheral compartments were respectively baseline TNF concentrations (RC0 = 3.3 nM and RP0 = 0.46 nM), steady-stated dissociation rates (KCSS = 15.4 nM and KPSS = 0.49 nM), and first-order elimination rates of complexes (kCint = 0.17 day−1 and kPint = 0.0079 day−1). This model showed slower turnover of targets and infliximab-TNF complex elimination rate in peripheral compartment than in central compartment. This study allowed a better understanding of the multi-scale target-mediated pharmacokinetics of infliximab. This model could be useful to improve model-based therapeutic drug monitoring of infliximab in IBD patients.

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Effect of polyaspartic acid on pharmacokinetics of gentamicin after single intravenous dose in the dog.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.5.1237 ◽

1996 ◽

Vol 40 (5) ◽

pp. 1237-1241 ◽

Cited By ~ 8

Author(s):

T Whittem ◽

K Parton ◽

K Turner

Keyword(s):

Aspartic Acid ◽

Elimination Rate ◽

Volume Of Distribution ◽

Intravenous Dose ◽

Pharmacokinetic Parameters ◽

Therapeutic Drug ◽

Peripheral Compartment ◽

Single Intravenous Dose ◽

Polyaspartic Acid ◽

Peripheral Tissues

The effects of poly-L-aspartic acid on the pharmacokinetics of gentamicin were examined by using a randomized crossover trial design with the dog. When analyzed according to a three-compartment open model, poly-L-aspartic acid reduced some first-order rate equation constants (A3, lambda 1, and lambda 3), the deep peripheral compartment exit microconstant (k31), the elimination rate constant (k(el)), and the area under the concentration-time curve from 0 to 480 h (AUC0-480) (0.21-, 0.60-, 0.26-, 0.27-, 0.72-, and 0.76-fold, respectively; P < 0.05) but increased the volume of distribution at steady state (Vss), the volume of distribution calculated by the area method (V(area)), the apparent volume of the peripheral compartment (Vp), and all mean time parameters. These results suggested that poly-L-aspartic acid increased the distribution of gentamicin to or binding within the deep peripheral compartment and that poly-L-aspartic acid may have delayed gentamicin transit through the peripheral tissues. In contrast, poly-L-aspartic acid did not alter pharmacokinetic parameters relevant to the central or shallow peripheral compartments to a clinically significant extent. Although gentamicin's pharmacokinetic parameters of relevance to therapeutic drug monitoring were not directly altered, this study has provided pharmacokinetic evidence that poly-L-aspartic acid alters the peripheral distribution of gentamicin. This pharmacokinetic interaction occurred after a single intravenous dose of each drug. Therefore, this interaction should be investigated further, before polyaspartic acid can be considered for use as a clinical nephroprotectant.

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Real Life Population Pharmacokinetics Modelling of Eight Factors VIII in Patients with Severe Haemophilia A: Is It Always Relevant to Switch to an Extended Half-Life?

Pharmaceutics ◽

10.3390/pharmaceutics12040380 ◽

2020 ◽

Vol 12 (4) ◽

pp. 380 ◽

Cited By ~ 2

Author(s):

Quentin Allard ◽

Zoubir Djerada ◽

Claire Pouplard ◽

Yohann Repessé ◽

Dominique Desprez ◽

...

Keyword(s):

Half Life ◽

Random Effect ◽

Real Life ◽

Compartment Model ◽

Central Compartment ◽

Peripheral Compartment ◽

Population Pharmacokinetic ◽

Severe Haemophilia ◽

Fviii Activity ◽

Data Files

We retrospectively analysed the data files of 171 adults and 87 children/adolescents with severe haemophilia, except for 14 patients (moderate; minor) (1), to develop a global population pharmacokinetic (PK) model for eight factors VIII (FVIII) that could estimate individual PK parameters for targeting the desired level of FVIII activity (FVIII:C); and (2) to compare half-life (HL) in patients switching from a standard half-life (SHL) to an extended half-life (EHL) and evaluate the relevance of the switch. One-stage clotting assay for the measurement of FVIII activity (FVIII:C, IU/mL) was used for population PK modelling. The software, Monolix version 2019R1, was used for non-linear mixed-effects modelling. A linear two-compartment model best described FVIII:C. The estimated PK parameters (between-subject variability) were: 2640 mL (23.2%) for volume of central compartment (V1), 339 mL (46.8%) for volume of peripheral compartment (V2), 135 mL/h for Q (fixed random effect), and 204 mL/h (34.9%) for clearance (Cl). Weight, age, and categorical covariate EHL were found to influence Cl and only weight for V1. This model can be used for all of the FVIII cited in the study. Moreover, we demonstrated, in accordance with previous studies, that Elocta had longer half-life (EHL) than SHL (mean ratio: 1.48) as compared to Advate, Factane, Kogenate, Novoeight, and Refacto.

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Nemonoxacin Dosage Adjustment in Patients with Severe Renal Impairment Based on Population Pharmacokinetic and Pharmacodynamic Analysis

10.22541/au.161167889.97008719/v1 ◽

2021 ◽

Author(s):

Yi Li ◽

Jianda Lu ◽

Yue Kang ◽

Xiaoyong Xu ◽

Xin Li ◽

...

Keyword(s):

Renal Impairment ◽

Severe Renal Impairment ◽

Compartment Model ◽

Central Compartment ◽

Peripheral Compartment ◽

Population Pharmacokinetic ◽

Healthy Controls ◽

Dosing Regimen ◽

Open Label ◽

Optimal Dosing

Aims: To optimize the dosing regimen in patients with severe renal impairment based on population pharmacokinetic/pharmacodynamic (PPK/PD) analysis. Methods: The pharmacokinetics and safety of nemonoxacin was evaluated in a single-dose, open-label, nonrandomized, parallel-group study after single oral dose of 0.5 g nemonoxacin capsule in 10 patients with severe renal impairment and 10 healthy controls. Both blood and urine samples were collected within 48 hours after admission and determined the concentrations. A PPK model was built using nonlinear mixed effects modelling. The probability of target attainment (PTA) and the cumulative fraction of response (CFR) against S. Pneumoniae and S. aureus was calculated by Monte Carlo simulation. Results: The data best fitted to a two-compartment model, from which the PPK parameters were estimated, including clearance (8.55 L/h), central compartment volume (80.8 L), and peripheral compartment volume (50.6 L). The accumulative urinary excretion was 23.4±6.5% in severe renal impairment patients and 66.1±16.8% in healthy controls. PPK/PD modeling and simulation of 4 dosage regimens found that nemonoxacin 0.5 g q48h was the optimal dosing regimen in severe renal impairment patients, evidenced by higher PTA (92.7%) and CFR (>99%) at nemonoxacin MIC ≤ 1 mg/L against S. pneumoniae and S. aureus. The alternative regimens (0.25 g q24h; loading dose 0.5 g on Day 1 followed by 0.25 g q24h) were insufficient to cover the pathogens even if MIC ≤ 0.5 mg/L. Conclusion: An extended dosing interval (0.5 g q48h) may be appropriate for optimal efficacy of nemonoxacin in case of severe renal impairment.

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Bioconcentration and Elimination Kinetics of Copper with Different Tissues of the Ascidian Styela Clava

Advanced Materials Research ◽

10.4028/www.scientific.net/amr.343-344.583 ◽

2011 ◽

Vol 343-344 ◽

pp. 583-589

Author(s):

Ai Li Jiang ◽

Zhen Yu ◽

Chang Hai Wang

Keyword(s):

Rate Constant ◽

Accumulation Rate ◽

Elimination Rate ◽

Equilibrium Concentration ◽

Compartment Model ◽

High Rate ◽

Elimination Kinetics ◽

Styela Clava ◽

Marine System ◽

Different Tissues

Based on the semi-static two compartment model, the bioconcentration and elimination of copper with tissues of Styela clava were investigated. The kinetic parameters (accumulation rate constant k1, elimination rate constant k2, bioconcentration factor BCF, biological half life t1/2 and maximum equilibrium concentration CAmax) were obtained by non-linear regression. The results showed S. clava could accumulate copper from the aquatic environment and that BCF decreased with increasing metal concentration in water. When the accumulation achieved balance, CAmax showed positive correlation to metal concentrations in water. Concentrations of copper in different tissues of S. clava were in the order of gonad > digestive gland ≈ other part >tunic, and t1/2 of copper was 12.57 to 38.18 days in elimination phase. The high rate to accumulate and eliminate copper from its body exhibited a useful potential biomonitor of short-term copper fluctuations status in marine system.

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Compartmental Pharmacokinetic Analysis of Oral Amprenavir with Secondary Peaks

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00570-06 ◽

2007 ◽

Vol 51 (5) ◽

pp. 1822-1826 ◽

Cited By ~ 16

Author(s):

Olanrewaju Okusanya ◽

Alan Forrest ◽

Robin DiFrancesco ◽

Sanela Bilic ◽

Susan Rosenkranz ◽

...

Keyword(s):

Plasma Concentrations ◽

Compartment Model ◽

Central Compartment ◽

Volume Of Distribution ◽

Information Criteria ◽

Secondary Peak ◽

Pharmacokinetic Analysis ◽

Therapeutic Drug ◽

Healthy Human ◽

Two Compartment Model

ABSTRACT Amprenavir is a protease inhibitor that has been shown to have secondary peaks postulated to be due to enterohepatic recycling. We propose a model to describe the pharmacokinetics of amprenavir which accommodates the secondary peak(s). A total of 82 healthy human immunodeficiency virus (HIV)-seronegative subjects were administered a single 600-mg dose of amprenavir as part of adult AIDS Clinical Trials Group protocol A5043. Serial blood samples were obtained over 24 h. Samples were analyzed for amprenavir and fit to a compartmental model using ADAPT II software, with all relevant parameters conditional with respect to bioavailability. The model accommodated secondary peaks by incorporating clearance out of the central compartment with delayed instantaneous release back into the gut compartment. The data were weighted by the inverse of the estimated measurement error variance; model discrimination was determined using Akaike's Information Criteria. A total of 76 subjects were evaluable in the study analysis. The data were best fit by a two-compartment model, with 98.7% of the subjects demonstrating a secondary peak. Amprenavir had a mean total clearance of 1.163 liters/h/kg of body weight (0.7), a central volume of distribution of 1.208 liters/kg (0.8), a peripheral volume of distribution of 8.2 liters/kg (0.81), and distributional clearance of 0.04 liters/h/kg (0.81). The time to the secondary peak was 7.86 h (0.17), and clearance into a recycling compartment was 0.111 liters/kg/h (0.74). Amprenavir pharmacokinetics has been well described using a two-compartment model with clearance to a recycling compartment and release back into the gut. The nature of the secondary peaks may be an important consideration for the interpretation of amprenavir plasma concentrations during therapeutic drug monitoring.

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Pharmacokinetic-Pharmacodynamic Modeling of the Electroencephalogram Effect of Imipenem in Healthy Rats

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.45.6.1682-1687.2001 ◽

2001 ◽

Vol 45 (6) ◽

pp. 1682-1687 ◽

Cited By ~ 13

Author(s):

Antoine Dupuis ◽

William Couet ◽

Joël Paquereau ◽

Stanley Debarre ◽

Agnès Portron ◽

...

Keyword(s):

Spline Function ◽

Elimination Rate ◽

Compartment Model ◽

Central Compartment ◽

Pharmacodynamic Modeling ◽

Effect Compartment ◽

Partial Seizures ◽

Effect Compartment Model ◽

The Relationship ◽

Electroencephalogram Eeg

ABSTRACT A pharmacokinetic-pharmacodynamic (PK-PD) modeling approach was developed to investigate the epileptogenic activity of imipenem in rats. Initially, animals received an intravenous infusion of imipenem at a rate of 2.65 mg min−1 for 30 min. Blood samples were collected for drug assay, and an electroencephalogram (EEG) was recorded during infusion and postinfusion. A dramatic delay was observed between concentrations of imipenem in serum and the EEG effect; this effect was accompanied by tremors and partial seizures. Indirect-effect models failed to describe these data, which were successfully fitted using an effect compartment model. The relationship between effect and concentration at the effect site was best described by a spline function. The elimination rate constant from the effect compartment was severalfold lower than that from the central compartment. The robustness of the model was then confirmed after administering the imipenem dose over 60 and 90 min. In conclusion, the successful PK-PD modeling of the imipenem EEG effect in rats constitutes a major improvement for better prediction of the epileptogenic risk associated with this antibiotic.

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Application of Pharmacometrics in Pharmacotherapy: Open-Source Software for Vancomycin Therapeutic Drug Management

Pharmaceutics ◽

10.3390/pharmaceutics11050224 ◽

2019 ◽

Vol 11 (5) ◽

pp. 224 ◽

Cited By ~ 1

Author(s):

Soo Hyeon Bae ◽

Dong-Seok Yim ◽

Hyemi Lee ◽

Ae-Ryoung Park ◽

Ji-Eun Kwon ◽

...

Keyword(s):

Open Source ◽

Open Source Software ◽

Compartment Model ◽

Therapeutic Drug ◽

Peripheral Compartment ◽

Population Pharmacokinetic ◽

Drug Management ◽

Korean Patients ◽

Population Pk ◽

R Shiny

The population pharmacokinetic (PK) parameters that are implemented in therapeutic drug management (TDM) software were generally obtained from a Western population and might not be adequate for PK prediction with a Korean population. This study aimed to develop a population PK model for vancomycin using Korean data to improve the quality of TDM for Korean patients. A total of 220 patients (1020 observations) who received vancomycin TDM services were included in the dataset. A population PK analysis was performed using non-linear mixed effects modeling, and a covariate evaluation was conducted. A two-compartment model with first-order elimination best explained the vancomycin PK, with estimates of 2.82 L/h, 31.8 L, 11.7 L/h, and 75.4 L for CL, V1, Q, and V2, respectively. In the covariate analysis, weight correlated with the volume of the peripheral compartment, and creatinine clearance, hemodialysis, and continuous renal replacement therapy treatments contributed to the clearance of vancomycin. The results show the clear need to optimize the PK parameters used for TDM in Korean patients. Specifically, V1 should be smaller for Korean patients, and renal replacement therapies should be considered in TDM practice. This final model was successfully applied in R shiny as open-source software for Koreans.

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1300. ACOG Committee Opinion #797 and the Dose of Intrapartum Vancomycin: a Potential Danger to Mother and Newborn Alike

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1483 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S664-S665

Author(s):

Andras Farkas ◽

Kristina M Feldman ◽

Krystina L Woods ◽

Arsheena Yassin

Keyword(s):

Cord Blood ◽

Significant Risk ◽

Compartment Model ◽

Therapeutic Drug ◽

Published Data ◽

Time Data ◽

Blood Concentrations ◽

Dosing Regimens ◽

Neonatal Group ◽

Group B

Abstract Background Intra-partum (IP) IV vancomycin (VAN) 20 mg/kg every 8 hours is proposed by #797 for the prevention of early onset neonatal group B streptococcal disease (GBS), a recommendation for which the basis of scientific merit is poor. The goal of our study was to analyze the sparsely sampled published data and raise awareness about the underlying risk of VAN toxicity with this dosing approach. Methods Plasma and cord-blood concentration-time data of IV VAN given to mothers in the IP period was analyzed. 5000 Monte Carlo runs were conducted to simulate maternal/fetal exposure (AUC0-24; 24-48) for doses of 1500, 1750 and 2000 mgs q8h and for possible birth times at two-hour intervals. Neonatal VAN clearance was not possible to determine; hence, we used a validated PK model to calculate exposure for the first 24h of life for gestational ages (GA) of 33 to 40 weeks. The AUC range of 400 – 600, and > 600 mg*h/L were considered for indices of efficacy and toxicity, respectively. Results Estimates from 30 pairs of serum and cord-blood concentrations analyzed with a 2-compartment model are shown in Table 1. Maternal VAN exposures seem acceptable up to 2 IP doses given with mean (SD) AUC0-24 of 394 (140), 474 (167), and 540 (193) mg*h/L for the 1500, 1750 and 2000 mg regimens. Most mothers (up to 83%) who receive three or more doses will be subjected to nephrotoxic exposures (Figure 1.). Neonatal evaluations indicate similarly low PTAs for the three dosing regimens when the efficacy target is considered (Figure 2. A). On the other hand, the PTAs for potentially nephrotoxic exposure is expected to reach undesirable levels when three or more doses were to be administered. The risk is profoundly high in GA of 33 to 35 weeks and birth times beyond 20 hours after the initiation of intra-partum prophylaxis (Figure 2. B). Figure 1. Figure 2.A Figure 2.B Conclusion Current recommendations by #797 for dosing of vancomycin pose significant risk to mother and newborn alike, especially in cases with lengthy duration of labor. Based on our results, maternal therapeutic drug monitoring for all cases requiring more than two doses should be considered. With the proposed dosing regimen going un-adjusted, 1 out of 4 newborns and 4 out of 5 mothers may be subjected to nephrotoxic exposures in prolonged labor. Table 1. Disclosures All Authors: No reported disclosures

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Population Pharmacokinetics of Propofol

Anesthesiology ◽

10.1097/00000542-200003000-00017 ◽

2000 ◽

Vol 92 (3) ◽

pp. 727-738 ◽

Cited By ~ 295

Author(s):

Jürgen Schüttler ◽

Harald Ihmsen

Keyword(s):

San Francisco ◽

Sampling Site ◽

Compartment Model ◽

Central Compartment ◽

Peripheral Compartment ◽

Population Pharmacokinetic ◽

Power Functions ◽

Target Controlled Infusion ◽

Three Compartment Model ◽

Elimination Clearance

Background Target-controlled infusion is an increasingly common type of administration for propofol. This method requires accurate knowledge of pharmacokinetics, including the effects of age and weight. The authors performed a multicenter population analysis to quantitate the effects of covariates. Methods The authors analyzed 4,112 samples of 270 individuals (150 men, 120 women, aged 2-88 yr, weighing 12-100 kg). Population pharmacokinetic modeling was performed using NONMEM (NONMEM Project Group, University of California, San Francisco, CA). Inter- and intraindividual variability was estimated for clearances and volumes. The effects of age, weight, type of administration and sampling site were investigated. Results The pharmacokinetics of propofol were best described by a three-compartment model. Weight was found to be a significant covariate for elimination clearance, the two intercompartmental clearances, and the volumes of the central compartment, the shallow peripheral compartment, and the deep peripheral compartment; power functions with exponents smaller than 1 yielded the best results. The estimates of these parameters for a 70-kg adult were 1.44 l/min, 2.25 l/min, 0.92 l/min, 9.3 l, 44.2 l, and 266 l, respectively. For patients older than 60 yr the elimination clearance decreased linearly. The volume of the central compartment decreased with age. For children, all parameters were increased when normalized to body weight. Venous data showed a decreased elimination clearance; bolus data were characterized by increases in the volumes of the central and shallow peripheral compartments and in the rapid distribution clearance (Cl2) and a decrease in the slow distribution clearance (Cl3). Conclusions Pharmacokinetics of propofol can be well described by a three-compartment model. Inclusion of age and weight as covariates significantly improved the model. Adjusting pharmacokinetics to the individual patient should improve the precision of target-controlled infusion and may help to broaden the field of application for target-controlled infusion systems.

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Optimised Dosing of Vancomycin in Critically Ill Indigenous Australian Patients with Severe Sepsis

Anaesthesia and Intensive Care ◽

10.1177/0310057x1804600405 ◽

2018 ◽

Vol 46 (4) ◽

pp. 374-380 ◽

Cited By ~ 4

Author(s):

D. Tsai ◽

P. C. Stewart ◽

S. Hewagama ◽

S. Krishnaswamy ◽

S. C. Wallis ◽

...

Keyword(s):

Severe Sepsis ◽

Severe Renal Impairment ◽

Compartment Model ◽

Central Compartment ◽

Volume Of Distribution ◽

Published Data ◽

Time Data ◽

Indigenous Australian ◽

Final Population ◽

Population Pk

Vancomycin is a commonly used antibiotic due to the high burden of methicillin-resistant Staphylococcus aureus infections. This study aimed to describe the pharmacokinetics (PK) of vancomycin in Australian Indigenous patients with severe sepsis, and advise an optimal dosing strategy. A population PK study was conducted in a remote Australian intensive care unit (ICU). Serial plasma samples were collected over one to two dosing intervals and assayed by validated chromatography. Concentration–time data collected were analysed using Pmetrics® software. The final population PK model was then used for Monte Carlo dosing simulations to determine optimal loading and intermittent maintenance doses. Fifteen Indigenous subjects were included for analysis with a median (interquartile range, IQR) age, weight and creatinine clearance (CrCL) of 43 (34–46) years, 73 (66–104) kg and 99 (56–139) ml/minute respectively. A two-compartment model described the data adequately. Vancomycin clearance (CL) and volume of distribution of the central compartment (Vc) were described by CrCL and patient weight respectively. Median (IQR) CL, Vc, distribution rate constants from central to peripheral, and from peripheral to central compartments were 4.6 (3.8–5.6) litres per hour, 25.4 (16.1–31.3) litres, 0.46 (0.28–0.52)/hour and 0.25 (0.12–0.37)/hour respectively. No significant interethnic PK differences were observed in comparison to published data. Therapeutic loading doses were significantly dependent on both weight and CrCL, whereas maintenance doses were dependent on CrCL. In the absence of severe renal impairment, initiation of maintenance dose eight hours post–loading dose achieved higher probability of target attainment at 24 hours. This is the first report of vancomycin PK in this patient group.

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