An Open-label, Single-arm Study to Provide Continued Access to Study Drug to Participants Who Have Completed Pediatric Clinical Studies Involving Gilead HIV Treatments

The goal of this clinical study is to provide continued access to the study drug(s) to children and adolescents with human immunodeficiency virus type 1 (HIV-1) who completed their participation in an applicable parent study and to monitor for adverse events.
The primary objectives of this study are as follows:
* To provide continued access to the study drug received in the parent protocol or switch to bictegravir/emtricitabine/tenofovir (B/F/TAF) for participants who completed a Gilead parent study evaluating drugs for HIV treatment.
* To evaluate the safety of the study drug(s) in participants with HIV-1.

开始日期2024-08-27

申办/合作机构

Gilead Sciences, Inc.

100 项与 CYP3A5 x CYP3A4 x CYP3A7 相关的临床结果

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100 项与 CYP3A5 x CYP3A4 x CYP3A7 相关的转化医学

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0 项与 CYP3A5 x CYP3A4 x CYP3A7 相关的专利（医药）

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172

项与 CYP3A5 x CYP3A4 x CYP3A7 相关的文献（医药）

2024-10-01·Clinical Pharmacology & Therapeutics

Age‐Dependent Abundance of CYP450 Enzymes Involved in Metronidazole Metabolism: Application to Pediatric PBPK Modeling

Article

作者: Basit, Abdul ; Stancil, Stephani ; Pearce, Robin E. ; Leeder, J. Steven ; Mehrotra, Aanchal ; Parvez, Md Masud ; Thakur, Aarzoo ; Prasad, Bhagwat

The expression of cytochrome P450 (CYP) enzymes is highly variable and associated with factors, such as age, genotype, sex, and disease states. In this study, quantification of metronidazole metabolizing CYP isoforms (CYP2A6, CYP2E1, CYP3A4, CYP3A5, and CYP3A7) in human liver microsomes from 115 children and 35 adults was performed using a quantitative proteomics method. The data confirmed age‐dependent increase in CYP2A6, CYP2E1, and CYP3A4 abundance, whereas, as expected, CYP3A7 abundance showed postnatal decrease with age. In particular, the fold difference (neonatal to adulthood levels) in the protein abundance of CYP2A6, CYP2E1, and CYP3A4 was 14, 11, and 20, respectively. In contrast, protein abundance of CYP3A7 was > 125‐fold higher in the liver microsomes of neonates than of adults. The abundance of CYP2A6 and CYP3A5 was associated with genotypes, rs4803381 and rs776746, respectively. A proteomics‐informed physiologically based pharmacokinetic (PBPK) model was developed to describe the pharmacokinetics of metronidazole and its primary metabolite, 2‐hydroxymethylmetronidazole. The model revealed an increase in the metabolite‐to‐parent ratio with age and showed a strong correlation between CYP2A6 abundance and metabolite formation (r2 = 0.75). Notably, the estimated contribution of CYP3A7 was ~ 75% in metronidazole clearance in neonates. These data suggest that variability in CYP2A6 and CYP3A7 in younger children poses the risk of variable pharmacokinetics of metronidazole and its active metabolite with a potential impact on drug efficacy and safety. No sex‐dependent difference was observed in the protein abundance of the studied CYPs. The successful integration of hepatic CYP ontogeny data derived from a large liver bank into the pediatric PBPK model of metronidazole can be extended to other drugs metabolized by the studied CYPs.

2024-06-01·Food and Chemical Toxicology

Undifferentiated HepaRG cells show reduced sensitivity to the toxic effects of M8OI through a combination of CYP3A7-mediated oxidation and a reduced reliance on mitochondrial function

Article

作者: Abdelghany, Tarek M ; Budastour, Alaa A ; Charlton, Alex ; Hedya, Shireen A ; Aljehani, Fahad A ; Alanazi, Khalid ; Marin, Larissa ; Wright, Matthew C

The methylimidazolium ionic liquid M8OI (1-octyl-3-methylimidazolium chloride, also known as [C8mim]Cl) has been detected in the environment and may represent a hazard trigger for the autoimmune liver disease primary biliary cholangitis, based in part on studies using a rat liver progenitor cell. The effect of M8OI on an equivalent human liver progenitor (undifferentiated HepaRG cells; u-HepaRG) was therefore examined. u-HepaRG cells were less sensitive (>20-fold) to the toxic effects of M8OI. The relative insensitivity of u-HepaRG cells to M8OI was in part, associated with a detoxification by monooxygenation via CYP3A7 followed by further oxidation to a carboxylic acid. Expression of CYP3A7 - in contrast to the related adult hepatic CYP3A4 and CYP3A5 forms - was confirmed in u-HepaRG cells. However, blocking M8OI metabolism with ketoconazole only partly sensitized u-HepaRG cells. Despite similar proliferation rates, u-HepaRG cells consumed around 75% less oxygen than B-13 cells, reflective of reduced dependence on mitochondrial activity (Crabtree effect). Replacing glucose with galactose, resulted in an increase in u-HepaRG cell sensitivity to M8OI, near similar to that seen in B-13 cells. u-HepaRG cells therefore show reduced sensitivity to the toxic effects of M8OI through a combination of metabolic detoxification and their reduced reliance on mitochondrial function.

2024-02-01·YAKUGAKU ZASSHI

ヒト薬物代謝酵素シトクロムP450（CYP）2D6及びCYP3Aサブファミリーの代謝反応及び内在性ステロイドホルモンなどによる相互作用

Article

作者: Niwa, Toshiro

My research focused on the effects of various drugs on (1) dopamine formation from p-tyramine catalyzed by polymorphic cytochrome P450 (CYP or P450) 2D6 variants and (2) endogenous steroid hormone hydroxylation catalyzed by CYP3A subfamily members (CYP3A4, CYP3A5, CYP3A7). The activation (cooperativity) of metabolic reactions catalyzed by P450s was especially emphasized. The effects of various psychotropic agents on dopamine formation from p-tyramine, catalyzed by wild-type CYP2D6.1 and CYP2D6 variants, including CYP2D6.2 (Arg296Cys;Ser486Thr), CYP2D6.10 (Pro34Ser;Ser486Thr), and CYP2D6.39 (Ser486Thr) were compared. Michaelis (K_m) and inhibition (K_i) constants of the psychotropic agents in the presence of CYP2D6.10 were higher than those observed in the presence of other CYP2D6 variants. Fluvoxamine, fluoxetine, milnacipran, and haloperidol activated CYP2D6-catalyzed dopamine formation [decreasing the K_m and/or increasing the maximal velocity (k_cat)], and this activation was CYP2D6 variant-dependent. Regarding the CYP3A subfamily, the effects of various compounds including endogenous steroid hormones on the 6β-hydroxylation of steroid hormones, such as testosterone, progesterone, and cortisol, were determined; it was found that testosterone, dehydroepiandrosterone, and/or α-naphthoflavone activated 6β-hydroxylation of cortisol and/or progesterone, but the effects varied in the presence of different CYP3A subfamily members. Further studies are required to confirm the mechanisms and therapeutic relevance of these activation phenomena.