Drug‐Drug Interaction Studies to Evaluate the Effect of Inhibition of UGT1A1 and CYP3A4 and Induction of CYP3A4 on the Pharmacokinetics of Tropifexor in Healthy Subjects

Chen, Jin; Stringer, Rowan; Shah, Bharti; Gu, Jessie; Zhang, Yiming; Hackling, Melissa; Prince, William; Woessner, Ralph

doi:10.1002/cpdd.1140

Cited by 4 publications

(4 citation statements)

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“…A clinical study in healthy individuals revealed that the inhibitory effect of itraconazole on CYP3A4 resulted in the increased systemic exposure of tropifexor (Chen et al. 2022 ). The inhibition of CYP3A4 by physcion was also observed in this study, which was non-competitive.…”

Section: Discussionmentioning

confidence: 99%

Physcion inhibition of CYP2C9, 2D6 and 3A4 in human liver microsomes

Liu,

Sun,

2024

Pharmaceutical Biology

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Context The effect of the active ingredients in traditional Chinese medicines on the activity of cytochrome P450 enzymes (CYP450s) is a critical factor that should be considered in TCM prescriptions. Physcion, the major active ingredient of Rheum spp. (Polygonaceae), possesses wide pharmacological activities. Objectives The effect of physcion on CYP450 activity was investigated to provide a theoretical basis for use. Materials and methods The experiments were conducted in pooled human liver microsomes (HLMs). The activity of CYP450 isoforms was evaluated with corresponding substrates and probe reactions. Blank HLMs were set as negative controls, and typical inhibitors were employed as positive controls. The inhibition model was fitted with Lineweaver Burk plots. The concentration (0, 2.5, 5, 10, 25, 50 and 100 μM physcion) and time-dependent (0, 5, 10, 15 and 30 min) effects of physcion were also assessed. Results Physcion suppressed CYP2C9, 2D6 and 3A4 in a concentration-dependent manner with IC 50 values of 7.44, 17.84 and 13.50 μM, respectively. The inhibition of CYP2C9 and 2D6 was competitive with the K i values of 3.69 and 8.66 μM, respectively. The inhibition of CYP3A4 was non-competitive with a K i value of 6.70 μM. Additionally, only the inhibition of CYP3A4 was time-dependent with the K I and K inact parameters of 3.10 μM −1 and 0.049 min −1 , respectively. Conclusions The inhibition of CYP450s by physcion should be considered in its clinical prescription, and the study design can be employed to evaluate the interaction of CYP450s with other herbs.

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Section: Discussionmentioning

confidence: 99%

Physcion inhibition of CYP2C9, 2D6 and 3A4 in human liver microsomes

Liu,

Sun,

2024

Pharmaceutical Biology

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“…Due to the elimination of this drug in the form of glucuronides, incompatibilities of lumateperone with substances that are inhibitors of UGT enzymes are also important. The drugs and food components with which lumateperone interacts and their description are shown in Table 1 (Intra-Cellular Therapies, 2019; Hussar, 2021; Chen et al, 2022).…”

Section: { Lumateperone -Interactions With Other Drugsmentioning

confidence: 99%

“…Interakcje lumateperonu z lekami i składnikami pożywienia (Intra-Cellular Therapies, 2019; Hussar, 2021;Chen et al, 2022) …”

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Lumateperone in the treatment of psychiatric disorders – a review of the literature

Kaczmarek,

Szymajda,

Dettlaff

2023

fpn

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Drug Administration) for the treatment of patients with schizophrenia and depressive episodes associated with bipolar disorder in 2019. Literature review. The review includes up-to-date publications concerning the efficacy of lumateperone in the treatment of psychiatric disorders -schizophrenia, bipolar disorder, but also insomnia, and dementia. The pharmacokinetic and pharmacodynamic characteristics of lumateperone and its precise mechanism of action were presented. The adverse reactions and possible drug interactions were likewise discussed. Conclusions. Lumateperone is a medication with an interesting mechanism of action, which is unique compared to other antipsychotic drugs. The analysis of clinical trials suggests that lumateperone is an effective and safe medication for the treatment of schizophrenia, as well as bipolar affective disorder. There are high hopes for the use of lumateperone in the treatment of insomnia and dementia. StreSzczenieCel. Terapia schorzeń psychiatrycznych, w tym schizofrenii i choroby afektywnej dwubiegunowej, ciągle się zmienia. Pojawiają się nowe substancje, które sprawiają, że leczenie wiąże się z mniejszą liczbą działań niepożądanych i wykorzystuje nowe mechanizmy działania. Celem artykułu jest przedstawienie właściwości, mechanizmu działania, zastosowania, ale i bezpieczeństwa lumateperonu -leku zaliczanego do substancji o działaniu AbStrActObjectives. The treatment of psychiatric disorders, including schizophrenia and bipolar disorder, is constantly changing. There are new medications that reduce treatment-related side effects and present new mechanisms of action. This article aims to describe characteristics, mechanism of action, and medical use, but also the safety of lumateperone -a drug classified as antipsychotic medication, which was approved by the FDA (Food and Review article / Artykuł poglądowyLumateperone in the treatment of psychiatric disorders -a review of the literature Lumateperon w leczeniu schorzeń psychiatrycznych -przegląd literatury

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“… 1 , 10 According to recently published research, pre‐dosing of rifampin at 600 mg QD varied from 7 to 14 days in NME DDI studies. 7 , 12 , 13 To provide further evidence for standardizing the design of clinical DDI studies and reducing variability, we conducted this real‐world clinical trial to compare the two most widely used rifampin dosing regimens (600 mg QD for 7 days vs. 600 mg QD for 14 days) in DDI studies.…”

Section: Introductionmentioning

confidence: 99%

An open‐label study to explore the optimal design of CYP3A drug–drug interaction clinical trials in healthy Chinese people

Chen,

Li,

et al. 2024

Pharmacology Res & Perspec

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A drug–drug interaction (DDI) trial of cytochrome P450 3A (CYP3A) is a necessary part of early‐phase trials of drugs mainly metabolized by this enzyme, but CYP3A DDI clinical trials do not have a standard design, especially for Chinese people. We aimed to offer specific recommendations for CYP3A DDI clinical trial design. This was an open, three‐cycle, self‐controlled study. Healthy subjects were given different administration strategies of CYP3A4 perpetrators. In each cycle, blood samples were collected before and within 24 h after the administration of midazolam, the CYP3A indicator substrate. The plasma concentrations of midazolam and 1‐hydroxymidazolam was obtained using liquid chromatography tandem mass spectrometry assay. For CYP3A inhibition, itraconazole exposure with a loading dose could increase the exposure of midazolam by 3.21‐fold based on maximum plasma concentration (Cmax), 8.37‐fold based on area under the curve Pharmacology Research & Perspectives for review only from zero to the time point (AUC0–t), and 11.22‐fold based on area under the curve from zero to infinity (AUC0–∞). The data were similar for itraconazole pretreatment without a loading dose. For CYP3A induction, the exposure of rifampin for 7 days decreased the plasma concentration of midazolam ~0.27‐fold based on Cmax, ~0.18‐fold based on AUC0–t, and ~0.18‐fold based on AUC0–∞. Midazolam exposure did not significantly change when the pretreatment of rifampin increased to 14 days. This study showed that itraconazole pretreatment for 3 days without a loading dose was enough for CYP3A inhibition, and pretreatment with rifampin for 7 days could induce near‐maximal CYP3A levels.

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Drug‐Drug Interaction Studies to Evaluate the Effect of Inhibition of UGT1A1 and CYP3A4 and Induction of CYP3A4 on the Pharmacokinetics of Tropifexor in Healthy Subjects

Cited by 4 publications

References 25 publications

Physcion inhibition of CYP2C9, 2D6 and 3A4 in human liver microsomes

Physcion inhibition of CYP2C9, 2D6 and 3A4 in human liver microsomes

Lumateperone in the treatment of psychiatric disorders – a review of the literature

An open‐label study to explore the optimal design of CYP3A drug–drug interaction clinical trials in healthy Chinese people

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