F qNMR based pharmacokinetics, metabolism and mass balance studies of SARS-CoV-2-3CL protease inhibitor simnotrelvir (SIM0417) in humans.

Simnotrelvir (SIM0417), an inhibitor of the 3CL protease of SARS-CoV-2, has been identified as a CYP3A sensitive substrate. This study investigated the pharmacokinetics, metabolism, and mass balance of simnotrelvir following a single oral dose of 750 mg in six healthy Chinese male subjects, co-administered with four doses of 100 mg ritonavir. Analysis using F qNMR combined with LC-MS/MS showed that the parent drug M0 constituted over 90% of the drug-related components in plasma.

Drug-drug interactions of simnotrelvir/ritonavir: an open-label, fixed-sequence, two-period clinical trial.

Objectives: Simnotrelvir is a small-molecule highly specific 3C-like protease inhibitor for anti-SARS-CoV-2 and was approved as a combination drug with ritonavir (simnotrelvir/ritonavir) in China. Simnotrelvir is a substrate of cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp), and a weak inhibitor of CYP3A. Ritonavir is a substrate and inhibitor of CYP3A and an inhibitor of P-gp.

Mechanisms Underlying the Protective Effects of Obeticholic Acid-Activated FXR in Valproic Acid-Induced Hepatotoxicity via Network Pharmacology, Molecular Docking, and Molecular Dynamics Simulations.

Background: Valproic acid (VPA)-induced hepatotoxicity is among the most common and severe adverse drug reactions, limiting its clinical application. Recent studies have suggested that activating the farnesoid X receptor (FXR) could be a promising therapeutic approach to alleviate VPA-induced hepatotoxicity; however, related research remains limited.

Objective: This study aims to comprehensively investigate the mechanisms underlying FXR activation by obeticholic acid (OCA) for the treatment of VPA-induced hepatotoxicity.

Model Informed Development of SIM0295 in Patients with Gout and Hyperuricemia and Healthy Volunteers Using a Population Pharmacokinetics/ Pharmacodynamics Approach.

Background: SIM0295, a novel inhibitor of human uric acid transporter 1 (hURAT1), is used to treat patients with gout and hyperuricemia. This study aimed to develop population pharmacokinetics and pharmacodynamics (popPK/PD) models of SIM0295 and explore potential covariates to inform clinical drug development.

Research Design And Methods: Data were obtained from four phase I studies conducted in healthy Korean and Chinese subjects and two phase II studies conducted in Korean patients with gout and hyperuricemia.

Association between the perturbation of bile acid homeostasis and valproic acid-induced hepatotoxicity.

Valproic acid (VPA), a widely prescribed antiepileptic drug, is known to induce hepatotoxicity. However, the mechanisms underlying this toxicity are not well understood. In this study, we performed a nontargeted metabolomic analysis of children with epilepsy treated with VPA (n = 23).

Lipidomic Profiling Reveals Disruption of Lipid Metabolism in Valproic Acid-Induced Hepatotoxicity.

Valproic acid (VPA) is one of the most widely prescribed antiepileptic drugs, as VPA-induced hepatotoxicity is one of the most severe adverse reaction that can lead to death. The objective of this study was to gain an understanding of dysregulated lipid metabolism in mechanism of hepatotoxicity. Nontargeted lipidomics analysis with liquid chromatography-quadrupole-time-of-flight mass spectrometry (LC-Q-TOF/MS) was performed to explore differential lipids from the patient serum and L02 cells.

Dosage Optimization Based on Population Pharmacokinetic Analysis of Tacrolimus in Chinese Patients with Nephrotic Syndrome.

Purpose: The objective of this study was to merge genetic and non-genetic factors of tacrolimus pharmacokinetics to establish a more stable population pharmacokinetic model for individualized dosage regimen in Chinese nephrotic syndrome patients.

Methods: Nephrotic syndrome patients (>16 years old) treated with tacrolimus were included in the study. The population pharmacokinetic approach was analyzed using NONMEM version 7.

Cucurbitacin B suppresses proliferation of pancreatic cancer cells by ceRNA: Effect of miR-146b-5p and lncRNA-AFAP1-AS1.

Cucurbitacin B (CuB) is a natural tetracyclic triterpene product that displays antitumor activity against a wide variety of cancers. In this study, we explored the antipancreatic cancer activity of CuB via the inhibition of expression of the cancer-related long noncoding RNA, actin filament-associated protein 1-antisense RNA 1 (AFAP1-AS1). CuB arrested pancreatic cancer (PC) cells in the G2/M cell cycle phase by suppressing the expression of AFAP1-AS1.

A Population Pharmacokinetic-Pharmacogenetic Model of Lamotrigine in Chinese Children With Epilepsy.

Background: The pharmacokinetics of lamotrigine (LTG) is complex and varies significantly among individuals, especially among children. Therefore, this study aimed to establish a population pharmacokinetic (PPK) model of LTG in Chinese children with epilepsy and to comprehensively evaluate the effects of genetic variations in drug-metabolizing enzymes, transporters, and a transcriptional regulator on LTG pharmacokinetics.

Methods: Three hundred eighty-five steady-state plasma concentrations were obtained from 179 children (age 10.

Population pharmacokinetics of valproic acid in epileptic children: Effects of clinical and genetic factors.

Valproic acid (VPA) is a first-line anti-epileptic drug that is used in the treatment of generalized and partial seizures. Gene variants had been proved to influence the pharmacokinetics (PK) of VPA and contribute to its inter-individual variability (IIV). The aim of this study was to systematically investigate the effects of candidate gene variants (CYPs, UGTs, ABC transporters, and nuclear receptors) on VPA PK in Chinese children with epilepsy.

Population pharmacokinetics of lamotrigine co-administered with valproic acid in Chinese epileptic children using nonlinear mixed effects modeling.

Purpose: The aims of this study were to develop a population pharmacokinetic (PPK) model of lamotrigine (LTG) in Chinese epileptic children by using nonlinear mixed effects modeling (NONMEM) and to investigate the effects of valproic acid (VPA) and genetic polymorphisms of the major metabolizing enzymes (UGT1A4, UGT2B7) on the pharmacokinetics of LTG.

Methods: A total of 182 epileptic children who were treated with LTG as monotherapy or as part of combination therapy were included in this study as the model group, and 61 patients were included as the validation group. The steady-state serum trough concentrations of LTG and VPA were determined using a high-performance liquid chromatography method and fluorescence polarization immunoassay, respectively.

Development of a Simple and Rapid Method to Measure Free Fraction of Valproic Acid in Plasma Using Ultrafiltration and Ultra High Performance Liquid Chromatography-Mass Spectroscopy: Application to Therapeutic Drug Monitoring.

Background: Valproic acid (VPA) is widely used as an antiepileptic drug in children, and it is usually coadministered with other antiepileptic drugs. Because of its narrow therapeutic range and large variations in pharmacokinetic/pharmacodynamic behavior in different individuals, therapeutic drug monitoring of the trough total VPA concentration is commonly used to guide dosing. However, as only the free fraction of VPA that exerts pharmacological and toxic effects, it may be more meaningful to determine the unbound VPA concentration in plasma.

Effects of Polymorphisms in NR1H4, NR1I2, SLCO1B1, and ABCG2 on the Pharmacokinetics of Rosuvastatin in Healthy Chinese Volunteers.

The nuclear receptors (NR)-farnesoid X receptor (FXR, NR1H4) and pregnane X receptor (PXR, NR1I2)-have important effects on the expression of genes related to the pharmacokinetics (PKs) of rosuvastatin. This study was designed to investigate whether the genetic variants in drug disposition genes (SLCO1B1 and ABCG2) combined with their upstream regulators (NR1H4 and NR1I2) would affect the PKs of rosuvastatin in a Chinese population. Sixty-one healthy male volunteers were enrolled and the plasma concentrations of rosuvastatin were measured using the liquid chromatographic-tandem mass spectrometry/MS method.