Publications by authors named "Lichuan Liu"

Purpose: Omadacycline (PTK-0796) is a first-in-class aminomethylcycline for adult patients with community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible pathogens. We investigated the pharmacokinetic (PK) and pharmacodynamic (PD) profile of omadacycline, considering the impact of covariates, particularly ethnicity, on PK and determined the PK/PD cutoff values for dosing regimens.

Methods: Utilizing nonlinear mixed-effects modeling, we pooled data from 11 clinical trials for PopPK analysis.

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Purpose: We describe the clinical pharmacology characterization of giredestrant in a first-in-human study.

Experimental Design: This phase Ia/Ib dose-escalation/-expansion study (NCT03332797) evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of giredestrant in estrogen receptor-positive HER2-negative locally advanced/metastatic breast cancer. The single-agent dose-escalation stage evaluated giredestrant 10, 30, 90, or 250 mg once daily.

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GDC-0810 is a small molecule therapeutic agent having potential to treat breast cancer. In plasma of the first-in-human study, metabolite M2, accounting for 20.7% of total drug-related materials, was identified as a discrete diglucuronide that was absent in rats.

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Omadacycline is a new type of aminomethylcycline antibiotic, having a broad antibacterial spectrum. But the pharmacokinetic characteristics and safety profile of the Chinese population remain unknown. It is also unclear whether the US-approved treatment regimen is applicable for the Chinese population.

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The tremendous success of stereogenic carbon compounds has never ceased to inspire researchers to explore the potentials of stereogenic silicon compounds. Intermolecular C-H silylation thus represents the most versatile and straightforward strategy to construct C-Si bonds, however, its enantioselective variant has been scarcely reported to date. Herein we report a protocol that allows for the enantioselective intermolecular C-H bond silylation, leading to the construction of a wide array of acyclic stereogenic Si-H compounds under simple and mild reaction conditions.

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The signature reactivity of silacyclobutane (SCB) is their cycloaddition reactions with various π bonds. Recently, the first cases were disclosed where SCBs reacted with both C -H and C -H σ bonds in an intramolecular fashion. Herein, it is reported that SCB is also an efficient reagent for C -H bond silylation.

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The preparation of chiral monohydrosilanes remains a rarely achieved goal. To this end a Rh-catalyzed desymmetrization of dihydrosilanes by way of intramolecular C(sp )-H functionalization under simple and mild conditions has now been developed. This method provides easy access to a broad range of chiral monohydrosilanes in good yields with excellent enantioselectivities (up to >99 % ee).

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Bruton's tyrosine kinase (Btk) is thought to play a pathogenic role in chronic immune diseases such as rheumatoid arthritis and lupus. While covalent, irreversible Btk inhibitors are approved for treatment of hematologic malignancies, they are not approved for autoimmune indications. In efforts to develop additional series of reversible Btk inhibitors for chronic immune diseases, we sought to differentiate from our clinical stage inhibitor fenebrutinib using cyclopropyl amide isosteres of the 2-aminopyridyl group to occupy the flat, lipophilic H2 pocket.

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Catalytic, enantioselective synthesis of stereogenic silicon compounds remains a challenge. Herein, we report a rhodium-catalyzed regio- and enantio-selective intermolecular hydrosilylation of alkene with prochiral dihydrosilane. This new method features a simple catalytic system, mild reaction conditions and a wide functional group tolerance.

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Purpose: ERK1/2 signaling can be dysregulated in cancer. GDC-0994 is an oral inhibitor of ERK1/2. A first-in-human, phase I dose escalation study of GDC-0994 was conducted in patients with locally advanced or metastatic solid tumors.

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GDC-0810 (Cheeti et al., 2018) is an orally bioavailable, selective estrogen receptor (ER) degrader developed to treat ER-positive breast cancer. A first-in-human (FIH) dose escalation phase I study ( = 41) was conducted to characterize the pharmacokinetics (PK) of GDC-0810 and its two major metabolites.

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Regulatory agencies currently recommend itraconazole (ITZ) as a strong cytochrome P450 3A (CYP3A) inhibitor for clinical drug-drug interaction (DDI) studies. This work by an International Consortium for Innovation and Quality in Pharmaceutical Development working group (WG) is to develop and verify a mechanistic ITZ physiologically-based pharmacokinetic model and provide recommendations for optimal DDI study design based on model simulations. To support model development and verification, in vitro and clinical PK data for ITZ and its metabolites were collected from WG member companies.

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The ability of rodent immune-mediated arthritis models to quantitatively predict therapeutic activity of antiarthritis agents is poorly understood. Two commonly used preclinical models of arthritis are adjuvant-induced arthritis (AIA) and collagen-induced arthritis (CIA) in rats. The objective of the current study is to investigate the relationship between efficacy in AIA and CIA in rats, and clinical efficacy in rheumatoid arthritis patients using translational pharmacokinetic-pharmacodynamic (PK-PD) analysis.

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The Publisher regrets the typesetting mistake of retaining incorrect text in the Figure 1 caption. The correct text for the caption is "Molecular Structure of GDC-0810 NMG Salt". The original article has been corrected.

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The World Health Organization has promoted age-friendly city (AFC) projects in response to the aging population. Taiwan has also promoted AFC policies. This study was conducted in Taitung County, where 15.

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GDC-0810 was under development as an oral anti-cancer drug for the treatment of estrogen receptor-positive breast cancer as a single agent or in combination. In vitro data indicated that GDC-0810 is a potent inhibitor of OATP1B1/1B3. To assess clinical risk, a PBPK model was developed to predict the transporter drug-drug interaction (tDDI) between GDC-0810 and pravastatin in human.

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A copper-catalyzed trifunctionalization of alkynes that provides rapid access to oxindoles bearing a geminal diboronate side chain, highlighted by the simultaneous formation of one C-C bond and two C-B bonds, is reported. This new reaction features simple reaction conditions (ligand-free catalysis), a general substrate scope, and excellent chemoselectivity. Mechanistic study revealed a reaction sequence constituted by, in the order, borylation, intramolecular cross-coupling, hydroboration, which has been rarely documented.

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Purpose: GDC-0810, administered orally, was used in Phase I and II clinical studies to treat estrogen receptor positive breast cancers. It contains N-methyl-D-glucamine (NMG) salt of GDC-0810 with 10% sodium lauryl sulfate (SLS) as a surfactant and 15% sodium bicarbonate (NaHCO) as an alkalizing agent to aid dissolution. To improve the processability of the formulation and reduce potential mucosal irritation in future Phase III clinical studies, the salt form and the amount of excipient required further optimization.

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The clinical success of ibrutinib validates Bruton tyrosine kinase (BTK) inhibition as an effective strategy for treating hematologic malignancies, including chronic lymphocytic leukemia (CLL). Despite ibrutinib's ability to produce durable remissions in patients, acquired resistance can develop, mostly commonly by mutation of C481 of BTK in the ibrutinib binding site. Here, we characterize a novel BTK inhibitor, GDC-0853, to evaluate its preclinical efficacy in ibrutinib-naive and ibrutinib-resistant CLL.

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Disilylation of alkynes could provide rapid entry to synthetically useful 1,2-bissilyl-alkenes, but is currently limited to activated disilanes reacting in an intramolecular fashion. Reported herein is an efficient rhodium(I)-catalyzed intermolecular disilylation of a wide array of alkynones with unactivated disilanes. Importantly, this reaction produces exclusively trans-disilylation products, selectivity that has been rarely reported.

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Developed as an oral anticancer drug to treat estrogen receptor-positive breast cancer, GDC-0810 was shown to be a potent inhibitor of organic anion-transporting polypeptide 1B1 and 1B3 (OATP1B1/1B3) from an in vitro assay. A clinical study was conducted to assess the drug-drug interaction potential between GDC-0810 and pravastatin, which is a relatively selective and sensitive OATP1B1/1B3 substrate. Fifteen healthy female subjects of non-childbearing potential were enrolled in the study.

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GDC-0853 is a selective, reversible, and non-covalent inhibitor of Bruton's tyrosine kinase (BTK) that does not require interaction with the Cys481 residue for activity. In this first-in-human phase 1 study we evaluated safety, tolerability, pharmacokinetics, and activity of GDC-0853 in patients with relapsed or refractory non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL). Twenty-four patients, enrolled into 3 cohorts, including 6 patients who were positive for the C481S mutation, received GDC-0853 at 100, 200, or 400 mg once daily, orally.

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The pH labile metabolite, hydrophobicity, high oral dose and systematic exposure of GDC-0810 posed tremendous challenges to develop a LC-MS method for a stable isotope labeled aBA study. In this study, we explored practical solutions to balance stability and sensitivity and to cope with the impact of high C to C ratio on the labeling selection and assay dynamic range. A [C] GDC-0810 was synthesized to minimize the isotopic interference between PO dose, internal standard and I.

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Article Synopsis
  • Bruton's tyrosine kinase (Btk) is important for activating B-cells and myeloid cells and may play a role in treating autoimmune diseases like rheumatoid arthritis and lupus.
  • A new drug, GDC-0853, has been developed as a potent, selective, and noncovalent Btk inhibitor that shows promise in preclinical tests.
  • Early studies suggest that GDC-0853 is effective in reducing disease symptoms in rats and shows good safety and effectiveness in ongoing human trials for rheumatoid arthritis, lupus, and chronic spontaneous urticaria.
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