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Background: Vupanorsen is a GalNAc 3 -conjugated antisense oligonucleotide targeting angiopoietin-like 3 (ANGPTL3) mRNA shown to reduce atherogenic lipoproteins in individuals with dyslipidemia., Objectives: The aim of this study was to satisfy Chinese regulatory requirements and support ethnic sensitivity assessment by evaluating pharmacokinetics (PK), pharmacodynamics (PD), and safety of vupanorsen in healthy Chinese adults with elevated triglycerides (TG)., Methods: In this phase I, parallel-cohort, open-label study, 18 Chinese adults with elevated fasting TG (≥ 90 mg/dL) were randomized 1:1 to receive a single subcutaneous dose of vupanorsen 80 mg or 160 mg. PK parameters, PD markers (including ANGPTL3, TG, non-high-density lipoprotein cholesterol [non-HDL-C]), and safety were assessed., Results: Absorption of vupanorsen was rapid (median time to maximum concentration [T max ]: 2.0 h for both doses), followed by a multiphasic decline (mean terminal half-life 475.9 [80 mg] and 465.2 h [160 mg]). Exposure (area under curve [AUC] and maximum plasma concentration [C max ]) generally increased in a greater than dose-proportional manner from 80 mg to 160 mg. Time-dependent reductions in ANGPTL3 and lipid parameters were observed. Mean percentage change from baseline for the 80-mg and 160-mg doses, respectively, were - 59.7% and - 69.5% for ANGPTL3, - 41.9% and - 52.5% for TG, and - 23.2% and - 25.4% for non-HDL-C. No serious or severe adverse events (AEs), deaths, or discontinuations due to AEs were reported. Three participants experienced treatment-related AEs; all were mild and resolved by end of study., Conclusions: This study provided the first clinical vupanorsen data in China. In Chinese participants with elevated TG, PK and PD parameters were consistent with those reported previously in non-Chinese participants, including in Japanese individuals. No safety concerns were noted., Trial Registration: ClinicalTrials.gov identifier: NCT04916795., (© 2024. The Author(s).)

Ritlecitinib, an inhibitor of Janus kinase 3 and hepatocellular carcinoma family kinases, is in development as potential treatment for several inflammatory diseases. In vitro studies presented ritlecitinib as an inhibitor of hepatic organic cation transporter (OCT) 1, renal transporters OCT2 and multidrug and toxin extrusion (MATE) proteins 1/2K using multiple substrates, and ritlecitinib's major inactive metabolite M2, as an inhibitor of OCT1. A clinical interaction study with an OCT1 drug probe (sumatriptan) and relevant probe biomarkers for OCT/MATE was conducted to assess the effect of ritlecitinib on these transporters in healthy adult participants. The selectivity of sumatriptan for OCT1 was confirmed through a series of in vitro uptake assays. A simple static model was used to help contextualize the observed changes in sumatriptan area under the plasma concentration-time curve (AUC). Coadministration of a single 400-mg dose of ritlecitinib increased sumatriptan AUC from time 0 to infinity (AUC inf ) by ≈30% relative to a single 25-mg sumatriptan administration alone. When administered 8 hours after a ritlecitinib dose, sumatriptan AUC inf increased by ≈50% relative to sumatriptan given alone. Consistent with OCT1 inhibition, the AUC from time 0 to 24 hours of isobutyryl-L-carnitine decreased by ≈15% after ritlecitinib. Based on the evaluation of the renal clearance of N 1 -methylnicotinamide, ritlecitinib does not exert clinically meaningful inhibition on renal OCT2 or MATE1/2K. This study confirmed that ritlecitinib and M2 are inhibitors of OCT1 but not OCT2 or MATE1/2K in healthy adults., (© 2023 Pfizer Inc. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Vupanorsen (PF-07285557) is a second-generation tri-N-acetyl galactosamine (GalNAc 3 )-antisense oligonucleotide targeted to angiopoietin-like 3 (ANGPTL3) mRNA, shown to reduce lipids and apolipoproteins in subjects with dyslipidemia. To aid bringing innovative drugs to global patients efficiently, a multi-purpose Japanese phase I study was conducted, with integrated development approaches agreed by the Pharmaceuticals and Medical Devices Agency (PMDA). This randomized, double-blind, placebo-controlled, single-ascending dose (SAD) study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of vupanorsen administered subcutaneously to Japanese adults (20-65 years) with elevated triglycerides (TG). Participants were randomized (1:1:1) to vupanorsen (80:160 mg) or placebo (N = 4 each). Vupanorsen 160 mg was a first-in-human (FIH) dose level. Vupanorsen was well-tolerated with no treatment-related adverse events reported for either dose. Absorption into the systemic circulation was rapid with median time to maximum concentration (T max ) of 3.5 and 2.0 h, for vupanorsen 80 and 160 mg, respectively. Following maximum concentration (C max ), vupanorsen underwent multiphasic decline characterized by a relatively fast initial distribution phase followed by slower terminal elimination phase, with elimination half-life (t 1/2 ) of 397 and 499 h (80, 160 mg), respectively. Area under the concentration-time curve (AUC) and C max increased in a greater than dose-proportional manner. Pharmacodynamic markers (ANGPTL3, TG, and other key lipids) were reduced with vupanorsen versus placebo. Vupanorsen was safe and well-tolerated in healthy Japanese participants with elevated TG. This study provided FIH data for vupanorsen 160 mg. Moreover, the SAD study in Japanese participants fulfilled PMDA bridging requirements, and with the totality of global vupanorsen data, supported the PMDA waiver for a local phase II dose-finding study. ClinicalTrials.gov: NCT04459767., (© 2023 Pfizer Inc and The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Turmeric is one of the most used herbal supplements among cancer patients. It reportedly modulates the function of CYP450 enzymes and drug transporters. This study investigates the effect of turmeric on the pharmacokinetics of paclitaxel in breast cancer patients. This is a prospective longitudinal study with 60 breast cancer patients on treatment with single-agent paclitaxel and turmeric. The patients were followed up for two consecutive chemotherapy cycles, and their blood samples were collected, first without turmeric (first cycle) and the next after a 21-day concomitant administration of 2 g/day turmeric (second cycle). Plasma samples were quantified for paclitaxel concentration using High Performance Liquid Chromatograph with UV detector (HPLC-UV) method. The sparse concentration-time data of paclitaxel were subjected to population pharmacokinetic modeling, and then noncompartmental analysis (NCA) was performed on the simulated data to estimate the pharmacokinetic parameters of paclitaxel, before and after turmeric supplementation, for comparisons. The population pharmacokinetic parameters of paclitaxel differed from before to after turmeric supplementation. NCA of simulated concentration-time profiles showed a statistically significant reduction of 7.7% and 12.1% in AUC inf and Cmax, respectively. Given the small magnitude of the changes in pharmacokinetic parameters, the observed changes are not clinically relevant. Thereby, turmeric at the recommended dose can be combined safely with paclitaxel., (© 2022 John Wiley & Sons Ltd.)

Background: and purpose: Phytochemicals are proven to be effective in targeting numerous signaling pathways in cancer. Utilizing plant-based support in combination with currently approved chemotherapeutic strategies might prove a feasible method to improve therapeutic outcomes in cancer patients. The present study aimed to estimate the effect of turmeric supplementation on quality of life (QoL) and hematological parameters in breast cancer patients on Paclitaxel chemotherapy., Materials and Methods: The present study is a prospective consecutive case series with 60 participants. QoL was assessed using a standard questionnaire and hematological parameters were recorded from the patients' hospital records., Results: Turmeric supplementation for 21 days resulted in clinically relevant and statistically significant improvement in global health status, symptom scores (fatigue, nausea, vomiting, pain, appetite loss, insomnia), and hematological parameters., Conclusion: The study findings show that turmeric supplementation improved QoL, brought about symptom palliation and increased hematological parameters in breast cancer patients., (Copyright © 2020 Elsevier Ltd. All rights reserved.)