Dataset Information

Population Pharmacokinetic/Pharmacodynamic Model-Guided Dosing Optimization of a Novel Sedative HR7056 in Chinese Healthy Subjects.

ABSTRACT: HR7056 is a new benzodiazepine, showing more faster acting onset and recovery than currently available short-acting sedatives. To avoid inadequate anesthesia and predict return of cognition, allowing for immediate neurological evaluation, HR7056 pharmacokinetics and pharmacodynamics were characterized in Chinese healthy subjects. We report on modeling of the data and simulations of dosage regimens for future study. Up to 63 subjects were evaluated, using Bispectral Index (BIS) and Modified Observer's Assessment of Alertness/Sedation (MOAA/S) as pharmacodynamics endpoints. A three-compartment model best described HR7056 pharmacokinetics. Total clearance was 1.49 L min-1, central volume was 2.1 L, inter-compartmental clearances were 0.96 and 0.27 L min-1, respectively. The population mean pharmacodynamic parameters were as follows: BIS, E0: 95.3; IC50: 503 ng mL-1; ?: 1.5; ke0: 0.0855 min-1; Imax: 47.9 and MOAA/S, IC50: 436 ng mL-1; ?: 1.5; ke0: 0.05 min-1; Imax: 27.9. The model simulation will enable maintenance doses to be given more accurately for future study. Clinical Trial Registration: identifier: NCT01970072.

SUBMITTER: Zhou Y

PROVIDER: S-EPMC6252322 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Population Pharmacokinetic/Pharmacodynamic Model-Guided Dosing Optimization of a Novel Sedative HR7056 in Chinese Healthy Subjects.

Zhou Ying Y Hu Pei P Huang Yuguang Y Nuoer Sang S Song Kaicheng K Wang Hongyun H Wen Jinhua J Jiang Ji J Chen Xia X

Frontiers in pharmacology 20181119

HR7056 is a new benzodiazepine, showing more faster acting onset and recovery than currently available short-acting sedatives. To avoid inadequate anesthesia and predict return of cognition, allowing for immediate neurological evaluation, HR7056 pharmacokinetics and pharmacodynamics were characterized in Chinese healthy subjects. We report on modeling of the data and simulations of dosage regimens for future study. Up to 63 subjects were evaluated, using Bispectral Index (BIS) and Modified Obser ...[more]

PMID: 30510509

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Project description:Primary membranous nephropathy (PMN) is the most common cause for adult nephrotic syndrome. Rituximab has demonstrated promising clinical efficacy by random controlled trials and the off-label use is widely adopted in PMN. However, the standard dosage is borrowed from B cell lymphoma treatment with far more antigens and is oversaturated for PMN treatment, accompanied with additional safety risk and unnecessary medical cost. More than 15% serious adverse events were observed under standard dosage and low dose therapies were explored recently. Dose optimization by clinical trials is extremely time- and cost-consuming and can be significantly accelerated with the aid of model-informed drug development. Here, we aim to establish the first population pharmacokinetic and pharmacodynamic (PPK/PD) model for rituximab in PMN to guide its dosage optimization. Rituximab pharmacokinetic and pharmacodynamic data from 41 PMN patients in a retrospective study under a newly proposed monthly mini-dose were used to construct quantitative dose-exposure-response relationship via mechanistic target-mediated drug disposition (TMDD) model followed by regression between the reduction of anti-PLA2R titer and time after the treatment. The final model, validated by goodness-of-fit plots, visual predictive checks and bootstrap, was used to recommend the optimized dosing regimen by simulations. The model was well validated for PK/PD prediction. The systemic clearance and half-life are 0.54 L/h and 14.7 days, respectively. Simulation of a novel regimen (6 monthly doses of 100 mg) indicated the comparable ability and superior duration time of CD20+ B cell depletion compared with standard dosage, while the cumulative dosage and safety risk was significantly decreased. We established the first PPK/PD model and provide evidence to support the dosage optimization based on monthly mini-dose. Our study can also efficiently accelerate dosage optimization of novel anti-CD20 antibodies in PMN and other indications.

Dataset Information

Population Pharmacokinetic/Pharmacodynamic Model-Guided Dosing Optimization of a Novel Sedative HR7056 in Chinese Healthy Subjects.

Publications

Population Pharmacokinetic/Pharmacodynamic Model-Guided Dosing Optimization of a Novel Sedative HR7056 in Chinese Healthy Subjects.

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