RESUMO
A novel dual PI3K α/δ inhibitor, TQ-B3525, has been developed for the targeted treatment of lymphoma and solid tumors. TQ-B3525 is primarily metabolized by CYP3A4 and FOM3, while also serving as a substrate for the P-glycoprotein transporter. The aim of this study was to anticipate the drug-drug interaction (DDI) of TQ-B3525 and its two metabolites with CYP3A4 enzyme potent inducer (rifampicin) and CYP3A4/P-gp inhibitor (itraconazole) utilizing a physiologically based pharmacokinetic (PBPK) modeling approach. Clinical data from healthy and cancer patient adults were employed to construct and evaluate the PBPK model for TQ-B3525, M3, and M8-3. Models involving rifampicin combined with midazolam, itraconazole combined with midazolam or digoxin were utilized to showcase the robustness of evaluating DDI effects. The simulated drug exposure of TQ-B3525, M3, and M8-3 in healthy and patient adults were consistent with clinical data, and the mean fold error values were within the acceptable ranges. The simulated results of positive substrates correspond to those reported in the literature. Co-administration with rifampicin reduces Cmax and AUC of TQ-B3525 to 76.1% and 46.0%, while increasing the levels of M3 and M8-3. With itraconazole, Cmax and AUC of TQ-B3525 rise to 131% and 204%, but decrease substantially for M3 and M8-3. PBPK model simulation results showed that the systemic exposure of TQ-B3525 was significantly affected when co-administered with CYP3A4/P-gp inducers and inhibitors. This indicates that the combination with strong inducers and inhibitors should be carefully avoided or adjust the dosage of TQ-B3525 in clinic.
RESUMO
OBJECTIVE: TQB3602 is a novel orally bioavailable proteasome inhibitor. This study is the first-in-human phase I clinical trial to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of TQB3602 in relapsed/refractory multiple myeloma (RRMM). METHODS: This is a multicenter phase I clinical trial consisting of the 3+3 dose-escalation phase and dose expansion phase. Patients with MM who have received ≥2 prior antimyeloma therapies were enrolled. TQB3602 is administered at a dose of 0.5~7mg on days 1, 8, 15 in 28-day cycle. RESULTS: Twenty-five RRMM patients who relapsed or failed ≥2 lines of therapies were enrolled in the dose escalation phase. Two patients in the 7.0 mg dose group developed dose-limiting toxicity events (one with grade 2 peripheral neuropathy [PN] complicated by pain and one with diarrhea and abdominal pain), leading to a maximum tolerated dose of 6.0 mg. Any-grade adverse events (AEs) occurred in 24 (96.0%) patients, while grade ≥3 AEs occurred in 13 (52.0%). The most common grade ≥3 AEs was anemia (6, 24.0%). The incidence rate of PN was 16% with no grade ≥3 PN occurred. TQB3602 was rapidly absorbed, resulting in a time-to-plasma peak concentration of 0.8-1.5 h. The mean half-life was approximately 82 h. The AUClast and Cmax were approximately 1.9 times higher on day 15 than on day 1. Among 22 response-evaluable patients, 63.7% achieved stable disease or better. CONCLUSIONS: TQB3602 is well tolerated, with a favorable neurotoxicity profile, and has shown preliminary efficacy in patients with RRMM. The anticipated therapeutic dose was 6 mg and was adopted for an ongoing dose-expansion phase.
Assuntos
Mieloma Múltiplo , Inibidores de Proteassoma , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Masculino , Pessoa de Meia-Idade , Feminino , Idoso , Inibidores de Proteassoma/uso terapêutico , Inibidores de Proteassoma/farmacocinética , Inibidores de Proteassoma/efeitos adversos , Inibidores de Proteassoma/administração & dosagem , Administração Oral , Dose Máxima Tolerável , Resultado do Tratamento , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Relação Dose-Resposta a Droga , Resistencia a Medicamentos AntineoplásicosRESUMO
Depression is a common psychiatric disorder. Due to the disadvantages of current clinical drugs, including poor efficacy and unnecessary side effects, research has shifted to novel natural products with minimal or no adverse effects as therapeutic alternatives. The ocean is a vast ecological home, with a wide variety of organisms that can produce a large number of natural products with unique structures, some of which have neuroprotective effects and are a valuable source for the development of new drugs for depression. In this review, we analyzed preclinical and clinical studies of natural products derived from marine organisms with antidepressant potential, including the effects on the pathophysiology of depression, and the underlying mechanisms of these effects. It is expected to provide a reference for the development of new antidepressant drugs.
Assuntos
Antidepressivos , Organismos Aquáticos , Produtos Biológicos , Depressão , Produtos Biológicos/uso terapêutico , Produtos Biológicos/farmacologia , Humanos , Antidepressivos/uso terapêutico , Antidepressivos/farmacologia , Depressão/tratamento farmacológico , AnimaisRESUMO
PURPOSE: Envonalkib (TQ-B3139) is a novel, potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor used to treat ALK-positive non-small cell lung cancer. This phase I mass balance study investigated the pharmacokinetics, metabolism, and excretion of 14C-radiolabeled envonalkib in healthy Chinese male subjects. METHODS: A single oral dose of 600 mg (150 µCi) [14C]envonalkib was administered to healthy male subjects under fasted state. Samples of blood, urine and feces were collected for quantitative determination of total radioactivity and unchanged envonalkib, and the metabolites identification. RESULTS: After dosing, the median Tmax of radioactivity was 4 h and the mean t1/2 was 65.2 h in plasma. The exposure of total radioactivity was much higher than that of unchanged envonalkib in plasma. The mean total recovery of the radiolabeled dose was 93.93% over 504 h post-dose, with 15.23% in urine and 78.71% in feces. Envonalkib underwent extensive metabolism and a total of 15 metabolites were identified in plasma, urine, and feces. Unchanged envonalkib and its major metabolite M315 were the main components in plasma, accounting for 20.37% and 33.33% of total plasma radioactivity. In urine, O-dealkylation metabolite M315 was the major component accounted for 7.98% of dose. In feces, 16.01% of dose was excreted as cysteine conjugate M434-1. Envonalkib was well tolerated and there were no serious adverse events observed in the study. CONCLUSION: Envonalkib was extensively metabolized prior to excretion and eliminated primarily as metabolites via feces.