Current Issue : October-December Volume : 2023 Issue Number : 4 Articles : 5 Articles
Drugs’ safety and effectiveness are evaluated in randomized, dose-ranging trials in most therapeutic areas. However, this is only sometimes feasible in oncology, and dose-ranging studies are mainly limited to Phase 1 clinical trials. Moreover, although new treatment modalities (e.g., small molecule targeted therapies, biologics, and antibody-drug conjugates) present different characteristics compared to cytotoxic agents (e.g., target saturation limits, wider therapeutic index, fewer off-target side effects), in most cases, the design of Phase 1 studies and the dose selection is still based on the Maximum Tolerated Dose (MTD) approach used for the development of cytotoxic agents. Therefore, the dose was not optimized in some cases and was modified post-marketing (e.g., ceritinib, dasatinib, niraparib, ponatinib, cabazitaxel, and gemtuzumab-ozogamicin). The FDA recognized the drawbacks of this approach and, in 2021, launched Project Optimus, which provides the framework and guidance for dose optimization during the clinical development stages of anticancer agents. Since dose optimization is crucial in clinical development, especially of targeted therapies, it is necessary to identify the role of pharmacological tools such as pharmacogenomics, therapeutic drug monitoring, and pharmacodynamics, which could be integrated into all phases of drug development and support dose optimization, as well as the chances of positive clinical outcomes....
What Is Known and Objective. Pyrotinib maleate, also known as pyrotinib, is an irreversible dual receptor tyrosine kinase inhibitor that primarily targets the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2). Cytochrome P450 3A4 (CYP3A4) enzyme mainly catalyzes pyrotinib, and its metabolism is influenced apparently by CYP3A4 strong inhibitor, but the effect of CYP3A4 moderate inhibitor is still unclear as a moderate inhibitor of CYP3A4 enzyme. This study evaluated the effect of fluconazole, a widespread antifungal medication, on the pharmacokinetics and safety tolerance of pyrotinib. Methods. This study was an open, single-dose, and self-controlled clinical trial. Eighteen healthy Chinese participants were enrolled in this study. All participants were administered fluconazole on days 6–18 and pyrotinib on days 1 and 9. The maximum plasma concentration (Cmax), time to Cmax (Tmax), area under the concentration–time curve from time 0 to the last measurable concentration (AUC0−t), area under the concentration–time curve from time 0 extrapolated to infinity (AUC0−∞), terminal elimination half-life (t1/2), apparent volume of distribution (Vz/F), and apparent clearance (CL/F) were calculated using WinNonlin software (version 8.1). Safety tolerance was assessed throughout the process. Results and Discussion. Compared with the single administration of pyrotinib, the exposure level was enhanced significantly after the coadministration of pyrotinib and fluconazole. The geometric mean ratios (pyrotinib + fluconazole/pyrotinib alone) of Cmax, AUC0−t, and AUC0−∞ were 2.16, 3.6, and 3.5, respectively. The parameter of t1/2 is 14.16 h and 24.03 h, and CL/F is 275.06 L/h and 78.42 L/h, for pyrotinib alone and with fluconazole. No serious adverse events were reported in this trial, and no participant withdrew from the trial because of adverse events. What Is New and Conclusion. The PK profile of pyrotinib, a CYP3A4 substrate, was significantly influenced by fluconazole, with increased exposure levels and prolonged t1/2. Dosage adjustment is suggested for the clinical application of pyrotinib when coadministered with fluconazole or other CYP3A4 inhibitors/inducers....
Zonarol, which was discovered in the brown algae Dictyopteris undulata, has antibiotic, antioxidative, anti-inflammatory, and neuroprotective hydroquinone properties. Additionally, a daily treatment of zonarol taken orally has been proven to prevent ulcerative colitis and nonalcoholic fatty liver disease in experimentally induced mice models. In this study, to elucidate the physiological behavior of zonarol in vivo, the establishment of quantitative methods for the determination of zonarol in biological samples and basic pharmacokinetics parameters after oral or intravenous administration with purified zonarol to mice were investigated. The zonarol (20–600 ng/mL) in this study was dose-dependently detected using an HPLC-FI system as a single peak on the ODS column with 80% aqueous methanol at 332 nm with an excitation of 293 nm. The pharmacokinetic parameters were derived from a non-compartment analysis of the plasma concentration of zonarol following oral or intravenous treatment in mice. The absolute bioavailability of zonarol was calculated as 25.0%. Interestingly, the maximal distribution of zonarol in the brain (2.525 ± 1.334 μg/g tissue) at 30 min was observed to be higher and slower than that in the liver and kidney at 15 min after bolus intravenous administrations to the mice (10 mg/kg BW). Based on these results, zonarol might be a candidate for a potential drug, an effective tool for drug delivery, or enhancing the treatment of cerebral disease....
Background: The effects of various dosages and treatment regimens on intravitreal aflibercept concentrations and the proportion of free vascular endothelial growth factor (VEGF) to total VEGF were evaluated using a drug and disease assessment model. The 8 mg dosage received specific attention. Methods: A time-dependent mathematical model was developed and implemented using Wolfram Mathematica software v12.0. This model was used to obtain drug concentrations after multiple doses of different aflibercept dosages (0.5 mg, 2 mg, and 8 mg) and to estimate the time-dependent intravitreal free VEGF percentage levels. A series of fixed treatment regimens were modeled and evaluated as potential clinical applications. Results: The simulation results indicate that 8 mg aflibercept administered at a range of treatment intervals (between 12 and 15 weeks) would allow for the proportion of free VEGF to remain below threshold levels. Our analysis indicates that these protocols maintain the ratio of free VEGF below 0.001%. Conclusions: Fixed q12–q15 (every 12–15 weeks) 8 mg aflibercept regimens can produce adequate intravitreal VEGF inhibition....
Given the limitations of existing antiviral drugs and vaccines, there is still an urgent need for new anti-influenza drugs. CAM106, a rupestonic acid derivative, was studied for its potent antiviral activity and showed a favorable inhibitory effect on influenza virus replication. However, many gaps exist in preclinical studies of CAM106. This study focused on the pharmacokinetic profile and metabolites of CAM106 in vivo. An efficient and fast bioanalytical method was successfully developed and validated for the quantitation of CAM106 in rat plasma. A mobile phase aqueous solution (A, containing 0.1% formic acid) and acetonitrile (B) worked within 0–3.5 min, with 60% B. The mass spectrum scanning mode was the parallel reaction monitoring (PRM) with a resolution of 17,500. The linear range of the method was 2.13–1063.83 ng/mL. The validated method was applied to a pharmacokinetic study in rats. The matrix effects ranged from 93.99% to 100.08% and the recovery ranged from 86.72% to 92.87%. The intra- and inter-day precisions were less than 10.24% and the relative error (RE) ranged from −8.92% to 7.1%. The oral bioavailability of CAM106 was 1.6%. Thereafter, its metabolites in rats were characterized using high-resolution mass spectrometry. The isomers M7-A, M7-B, M7-C, and M7-D were well separated. As a result, a total of 11 metabolites were identified in the feces, urine, and plasma of rats. The main metabolic pathways of CAM106 were oxidation, reduction, desaturation, and methylation. The assay was reliable and provided useful information for further clinical studies of CAM106....
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