Population Pharmacokinetic/Pharmacodynamic Models for P2Y12 Inhibitors: A Systematic Review and Clinical Appraisal Using Exposure Simulation.

BACKGROUND AND OBJECTIVE: Recent research indicates a correlation between plasma concentration of P2Y12 inhibitors and clinical events, particularly bleeding, which significantly impeded their clinical therapeutic performance. It is therefore vital to delve into the factors that might affect the plasma concentration. The study aims to summarize population pharmacokinetics/pharmacodynamics (PopPKPD) models for commonly prescribed P2Y12 inhibitors (clopidogrel, prasugrel, and ticagrelor) and assess bleeding risk in specific individual groups. METHODS: The PopPKPD models of P2Y12 inhibitors were collected and summarized based on predetermined inclusion and exclusion criteria. The collected models were replicated in simulations, which were used to assess factors affecting plasma concentrations of P2Y12 inhibitors. Simulation results for special populations were compared to therapeutic window based on reported exposure-effect relationships (PK/PD-related bleeding and thrombotic clinical outcomes) to predict bleeding risk in special populations with different dosing regimens and cumulative covariates. RESULT: Finally, 12 studies were included for PK simulation, 7 of which that also included PD data were subjected to further analysis, with the majority being based on Phase I or II trials. Simulations showed that several covariates such as female gender, weight, elderly can significantly impact on exposure, with special populations reaching up to 179% of the general population. However, after dose adjustment, blood concentrations for special populations can reach approximately ±20% of general population exposure. Therefore, lowering the maintenance dose of ticagrelor from 90 to 60 mg bid was first recommended to reduce bleeding risk without significantly increasing ischemic risk, particularly in elderly, small-weight Asian females. CONCLUSION: Lowering the maintenance dose of ticagrelor from 90 to 60 mg bid effectively reduces bleeding risk without increasing thrombotic infarction risk in elderly, small-weight Asian females.

Optimization of the dosage regimen of zoledronic acid with a kinetic-pharmacodynamic model and exposure-response analysis.

Purpose: In order to support the dose optimization of zoledronic acid, the kinetic-pharmacodynamic model and exposure-response analysis were used to describe the changes in bone mineral density in different doses of zoledronic acid and establish the relationship between dose and acute phase reaction. Methods: Data were extracted from literature in accessible public databases. The kinetic-pharmacodynamic model was developed based on the above data using the NONMEM package to estimate parameters describing the relationship between the dose of zoledronic acid and bone mineral density. Exposure-response analysis was developed to establish the relationship between dose and acute phase reaction. Model evaluation was performed using goodness-of-fit, coefficient of variation (CV%). And sensitivity analyses were performed to assess the necessity of related parameters. Then the established model was used to simulate the changes of bone mineral density under different administration regimens, and the literature data was verified. Results: The kinetic-pharmacodynamic model successfully described zoledronic acid dose and change of bone mineral density in osteoporosis patients, with coefficient of variation of most less than 71.5%. The exposure-response analysis showed the incidence of acute phase reaction is dose-dependent. The bone mineral density was simulated based on the developed kinetic-pharmacodynamic model. And the simulated change of bone mineral density and the incidence of acute phase reaction could be helpful to propose a dosage regimen. Conclusion: Overall, the kinetic-pharmacodynamic model described changes of bone mineral density in different doses of zoledronic acid in vivo. And, the model and the exposure-response analysis also showed to provide the assessment of dose-response relationship for zoledronic acid.

Turn-on fluorescence ferrous ions detection based on MnO2 nanosheets modified upconverion nanoparticles.

A turn on upconversion fluorescence probe based on the combination of ~32 nm NaYF4: Yb/Tm nanoparticles and MnO2 nanosheets has been established for rapid, sensitive detection of Fe2+ ions levels in aqueous solutions and serum. X-ray diffraction (XRD), transmission electron microscopy (TEM), absorption and emission spectra have been used to characterize the crystal structure, morphology and optical properties of the samples. MnO2 nanosheets on the surface of UCNPs act as a fluorescence quencher, resulting in the quenching of the blue fluorescence (with excitation/emission maximum of 980/476 nm) via fluorescence resonance energy transfer from upconversion nanoparticles to MnO2 nanosheets. With the adding of Fe2+, upconversion fluorescence of the nanocomposites recovers due to the reduction of MnO2 to Mn2+. Because of the low background of the probe offered by upconversion fluorescence, this probe can be used for detecting Fe2+ in aqueous solutions in the range of 0.1-22 µM with detection limit of 0.113 µM. The developed method has also been applied to detect 10 µM Fe2+ ions in serum with recoveries ranging from 97.6 to 105.3% for the five serum samples. Significantly, the probe shows fast response and stable signal, which is beneficial for long-time dynamic sensing. Thus, the proposed strategy holds great potential for disease diagnosis and treatment.

A quantitative systems pharmacology approach to predict the safe-equivalent dose of doxorubicin in patients with cardiovascular comorbidity.

Patients with cardiovascular comorbidity are less tolerant to cardiotoxic drugs and should be treated with reduced doses to prevent cardiotoxicity. However, the safe-equivalent dose of antitumor drugs in patients with cardiovascular disease/risk is difficult to predict because they are usually excluded from clinical trials as a result of ethical considerations. In this study, a translational quantitative system pharmacology-pharmacokinetic-pharmacodynamic (QSP-PK-PD) model was developed based on preclinical study to predict the safe-equivalence dose of doxorubicin in patients with or without cardiovascular disease. Virtual clinical trials were conducted to validate the translational QSP-PK-PD model. The model replicated several experimental and clinical observations: the left ventricular ejection fraction (LVEF) was reduced and the left ventricular end-diastolic volume (LVEDV) was elevated in systolic dysfunction rats, the LVEF was preserved and LVEDV reduced in diastolic dysfunction rats, and patients with preexisting cardiovascular disease were more vulnerable to doxorubicin-induced cardiac dysfunction than cardiovascular healthy patients. A parameter sensitivity analysis showed that doxorubicin-induced cardiovascular dysfunction was mainly determined by the sensitivity of cardiomyocytes to cardiotoxic drugs and the baseline value of LVEDV, reflected in LVEF change percentage from the baseline. Blood pressure was the least sensitive factor affecting doxorubicin-induced cardiotoxicity.

The Combination of Cell Cultured Technology and In Silico Model to Inform the Drug Development.

Human-derived in vitro models can provide high-throughput efficacy and toxicity data without a species gap in drug development. Challenges are still encountered regarding the full utilisation of massive data in clinical settings. The lack of translated methods hinders the reliable prediction of clinical outcomes. Therefore, in this study, in silico models were proposed to tackle these obstacles from in vitro to in vivo translation, and the current major cell culture methods were introduced, such as human-induced pluripotent stem cells (hiPSCs), 3D cells, organoids, and microphysiological systems (MPS). Furthermore, the role and applications of several in silico models were summarised, including the physiologically based pharmacokinetic model (PBPK), pharmacokinetic/pharmacodynamic model (PK/PD), quantitative systems pharmacology model (QSP), and virtual clinical trials. These credible translation cases will provide templates for subsequent in vitro to in vivo translation. We believe that synergising high-quality in vitro data with existing models can better guide drug development and clinical use.

Multiple logic operations based on chemically triggered upconversion fluorescence switching.

The development of upconversion nanoparticles based logic systems, especially integrated logic systems is still a challenge until now. In this work, an upconversion nanocomposite system is developed and studied for the sensing abilities toward hydrion, hydroxyl ions, metal ions and anions (S2-, I-) by taking the advantages of turn-on and turn-off upconversion fluorescence switching response. Triggering by different kinds of ions, the upconversion system can act as a fluorescence switch due to the specific recognition abilities of Rhodamine 6G functionalized PEI for specific ions and the energy transfer process from upconversion nanoparticles to recognition molecules. Based on these results, multiple molecular logic gates, including single-input logic operation (YES, NOT), double-inputs logic operation (OR, AND, NOR, INHIBIT) and multiple-input integrative logic operation (INHIBIT+OR) are developed by employing hydrion, hydroxyl ions, metal ions and anions as inputs and the changes in the upconversion fluorescence intensity as output. The multiple logic operations are of great significance for the applications in biomedicine and molecular calculation.

Iminium Ion and N-Hydroxyimide as the Surrogate Components in DEAD-Promoted Oxidative Ugi Variant.

A practical metal-free oxidative Ugi-type three-component assembly has been achieved efficiently, employing a tertiary-amine-derived iminium ion as an imine surrogate, N-hydroxyimide as an acid surrogate, and DEAD as an oxidant. This dual-surrogate Ugi variant proceeded with a broad substrate scope and desired functional group tolerance, leading to a wide range of N-alkyl- N-acyl aminophthalimide and N-alkyl- N-acylaminosuccinimide derivatives in good isolated yields.