Prediction of the Optimal Dosing Regimen Using a Mathematical Model of Tumor Uptake for Immunocytokine-Based Cancer Immunotherapy

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.

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Determination of an Optimal Dosing Regimen for Fexinidazole, a Novel Oral Drug for the Treatment of Human African Trypanosomiasis: First-in-Human Studies

Clinical Pharmacokinetics ◽

10.1007/s40262-014-0136-3 ◽

2014 ◽

Vol 53 (6) ◽

pp. 565-580 ◽

Cited By ~ 45

Author(s):

Antoine Tarral ◽

Séverine Blesson ◽

Olaf Valverde Mordt ◽

Els Torreele ◽

Daniela Sassella ◽

...

Keyword(s):

Human African Trypanosomiasis ◽

Human Studies ◽

Oral Drug ◽

African Trypanosomiasis ◽

Dosing Regimen ◽

Optimal Dosing

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BCG-Mediated Bladder Cancer Immunotherapy: Identifying Determinants of Treatment Response Using a Calibrated Mathematical Model

PLoS ONE ◽

10.1371/journal.pone.0056327 ◽

2013 ◽

Vol 8 (2) ◽

pp. e56327 ◽

Cited By ~ 7

Author(s):

Cyrill A. Rentsch ◽

Claire Biot ◽

Joël R. Gsponer ◽

Alexander Bachmann ◽

Matthew L. Albert ◽

...

Keyword(s):

Mathematical Model ◽

Bladder Cancer ◽

Cancer Immunotherapy ◽

Treatment Response

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A Nonparametric Pharmacokinetic Approach to Determine the Optimal Dosing Regimen for 30-Minute and 3-Hour Meropenem Infusions in Critically Ill Patients

Therapeutic Drug Monitoring ◽

10.1097/ftd.0000000000000323 ◽

2016 ◽

Vol 38 (5) ◽

pp. 593-599 ◽

Cited By ~ 7

Author(s):

Sumith K. Mathew ◽

Binu S. Mathew ◽

Michael N. Neely ◽

Girish S. Naik ◽

Ratna Prabha ◽

...

Keyword(s):

Critically Ill ◽

Critically Ill Patients ◽

Dosing Regimen ◽

Optimal Dosing ◽

Pharmacokinetic Approach

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Pediatric Palliative Care Pharmacy Pearls—A Focus on Pain and Sedation

Children ◽

10.3390/children8100902 ◽

2021 ◽

Vol 8 (10) ◽

pp. 902

Author(s):

Jennifer Placencia ◽

Kevin Madden

Keyword(s):

Palliative Care ◽

Adult Patient ◽

Pediatric Patient ◽

Pediatric Patients ◽

Care Patient ◽

Pediatric Palliative Care ◽

Palliative Care Patient ◽

Dosing Regimen ◽

Developmental Pharmacology ◽

Optimal Dosing

Determining the optimal dosing regimen for pediatric patients is a challenge due to the lack of dosing guidelines and studies. In addition, many developmental pharmacology changes that occur throughout childhood that have profound impacts on the absorption, distribution, metabolism, and elimination of medications are commonly used in palliative care. Adding to that complexity, certain medications have different effects in the pediatric patient compared to the adult patient. Being aware of the pharmacokinetic changes, impact on neurodevelopment and unique medication factors that are present in pediatric patients helps clinicians treat the pediatric palliative care patient in the best and safest way possible.

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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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Aminoglycosides in the Intensive Care Unit: What's New in Population PK Modeling?

10.20944/preprints202104.0416.v1 ◽

2021 ◽

Author(s):

Alexandre Duong ◽

Chantale Simard ◽

Yi Le Wang ◽

David R. Williamson ◽

Amélie Marsot

Keyword(s):

Intensive Care ◽

External Validation ◽

Compartment Model ◽

Dosing Regimen ◽

Mixed Effect ◽

Icu Patients ◽

Optimal Dosing ◽

Pubmed Database ◽

Dosing Regimens ◽

Significant Covariates

Background Although aminoglycosides are often used as treatment for Gram-Negative infections, optimal dosing regimens remains unclear, especially in ICU patients. This is due to a large between- and within-subject variability in the aminoglycosides’ pharmacokinetics in this population. Objective The review provides comprehensive data on the pharmacokinetics of aminoglycosides in patients hospitalized in ICU by summarizing all published PopPK models in ICU patients for amikacin, gentamicin, and tobramycin. The objective was to determine the presence of a consensus on the structural model used, significant covariates included, and therapeutic targets considered during dosing regimen simulations. Methods A literature search was conducted from the Medline/PubMed database, using the terms: ‘amikacin’, ’gentamicin’, ’tobramycin’, ‘pharmacokinetic(s)’, nonlinear mixed effect’, population’, ‘intensive care’ and ‘critically ill’. Results Nineteen articles were retained where amikacin, gentamicin and tobramycin pharmacokinetics were described in six, eleven and five models, respectively. Two-compartment model best described amikacin and tobramycin pharmacokinetics, whereas one-compartment model majorly described gentamicin pharmacokinetics. The most recurrent significant covariates were renal clearance and bodyweight. Across all aminoglycosides, mean interindividual variability in clearance and volume of distribution were 41.6% and 22.0%, respectively. A common consensus for an optimal dosing regimen for each aminoglycoside was not reached. Conclusion This review showed models developed for amikacin, from 2015 until now and for gentamicin and tobramycin from the past decades. Despite growing challenges of external evaluation, the latter should be more considered during model development. Further research including new covariates, additional simulated dosing regimens and external validation should be considered to better understand aminoglycosides pharmacokinetics in ICU patients.

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