RESUMEN
BACKGROUND: Domperidone has long been used as a prokinetic agent in the treatment of epigastric distress symptoms. This study aimed to provide adequate evidence for registration approval of a new generic dry suspension formulation of domperidone by comparing the safety and pharmacokinetic profiles between the test and branded reference formulation in the context of fasted and fed condition. MATERIALS AND METHODS: This was designed as a randomized, open-label, single-dose, two-period, two-treatment crossover study. 32 and 28 eligible healthy subjects were enrolled in the fasted and fed study, respectively. Each subject was randomly assigned to receive either the test or reference formulation in the first period, followed by a 1-week washout period and dosing of the alternate formulation in the second period. A series of blood samples were collected at scheduled timepoints within 48 hours after administration during each treatment period. Plasma concentrations of domperidone were determined by validated HPLC-MS/MS. Pharmacokinetic parameters, including Cmax, tmax, AUC0-t, AUC0-∞, and T1/2, were acquired based on the concentration vs. time profiles by non-compartmental analysis using WinNonlin software. Then the geometric mean ratios (GMR) of Cmax, AUC0-t, and AUC0-∞ between the two formulations and corresponding 90% confidence intervals (CIs) were calculated for bioequivalence determination. Safety was assessed as routine. RESULTS: The two formulations showed similar pharmacokinetic profiles. Under fasted condition, the GMR and corresponding 90% CIs of AUC0-t, AUC0-∞, and Cmax were 101.48% (96.79 - 106.38%), 101.17% (96.66 - 105.90%), and 104.61% (96.73 - 113.14%), respectively. Under fed condition, the GMR and corresponding 90% CIs were 105.46% (99.19 - 112.12%), 104.21% (98.19 - 110.61%), and 112.78% (103.64 - 122.73%), respectively, for AUC0-t, AUC0-∞, and Cmax. All values fell within the accepted bioequivalence range of 80 - 125%. Both the test and the reference products were well tolerated without any serious or unexpected adverse reactions. CONCLUSION: Pharmacokinetic bioequivalence was established between the two dry suspension formulations of domperidone in healthy Chinese subjects. Both products were safe and well tolerated.
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Domperidona , Espectrometría de Masas en Tándem , Humanos , Área Bajo la Curva , Estudios Cruzados , Domperidona/farmacocinética , Pueblos del Este de Asia , Ayuno , Voluntarios Sanos , Comprimidos , Equivalencia TerapéuticaRESUMEN
AIMS: The aims of this study were to evaluate and compare the pharmacokinetic profiles and bioequivalence of two tablet formulations of methylprednisolone (test formulation: Zhejiang Xianju Pharmaceutical Co., Ltd., China; reference formulation: Medrol, Pfizer Italia SRL) in healthy Chinese subjects under fasting and fed conditions. MATERIALS AND METHODS: Subjects were randomly allocated to either the fasting group or the fed group and also to one of two sequences (test-reference or reference-test), according to which they received a single 16-mg dose of the test or reference methylprednisolone tablet in the study periods. Blood samples were collected pre dose and at intervals up to 16 hours after administration. Plasma methylprednisolone concentrations were determined using a validated liquid chromatography tandem mass spectrometry method. The safety of the medications was monitored throughout the study. The primary pharmacokinetic parameters measured were Cmax, AUC0-t, and AUC0-∞. RESULTS: A total of 56 subjects were enrolled, and all completed the study. The 90% confidence intervals for Cmax, AUC0-t, and AUC0-∞, measured under both fasting and fed conditions, fell within the acceptable range for bioequivalence of 80 - 125%. Analysis of variance showed that there were no signiï¬cant differences in the primary pharmacokinetic parameters (Cmax, AUC0-t, and AUC0-∞) between the test and reference formulation measured under both fasted and fed conditions. No serious or unexpected adverse drug reactions occurred during the study period. CONCLUSION: The test methylprednisolone 16 mg tablet produced in China is bioequivalent to the reference formulation (Medrol) in healthy Chinese subjects measured under both fasting and fed conditions. Both formulations were well tolerated by all study participants.
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Metilprednisolona , Equivalencia Terapéutica , Humanos , Área Bajo la Curva , Estudios Cruzados , Pueblos del Este de Asia , Ayuno , Voluntarios Sanos , Comprimidos , Metilprednisolona/farmacocinéticaRESUMEN
AIMS: This clinical study was conducted to evaluate the impact of rifampicin on the pharmacokinetics of fuzuloparib. METHODS: In this single-centre, single-arm, open-label, fixed-sequence study, healthy male subjects took a single 50 mg dose of fuzuloparib on two separate occasions: the first was on Day 1 as monotherapy, and the second was on Day 12 after oral administration of rifampicin 600 mg once daily for 8 days. Series of blood samples were obtained before and after fuzuloparib administration at different time points: pre-dose, and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours post-dose. All samples were examined using liquid chromatography with tandem mass spectrometry. PK parameters were estimated by using a non-compartmental method with Phoenix WinNonlin software. Safety was assessed by monitoring for changes in vital signs and laboratory tests, physical examinations, and incidences of adverse events (AEs). RESULTS: A total of 16 Chinese male subjects were enrolled. Of these, 16 and 15 cases were evaluable for PK analysis following administration with fuzuloparib alone and pretreatment with rifampicin, respectively. Pretreatment with rifampicin resulted in a statistically significant reduction in the systemic exposure to fuzuloparib. The treatment ratio and 90% confidence intervals (CIs) for AUC0-∞ and Cmax were 0.10 (0.095-0.115) and 0.32 (0.281-0.365), respectively. A single administration of fuzuloparib after multiple oral dosing of rifampicin was well-tolerated, without severe AEs. CONCLUSION: The exposure of fuzuloparib was dramatically decreased when pretreated with rifampicin. Strong CYP3A4 inducers should be avoided during fuzuloparib treatment.
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Inductores del Citocromo P-450 CYP3A , Rifampin , Área Bajo la Curva , China , Estudios Cruzados , Inductores del Citocromo P-450 CYP3A/efectos adversos , Interacciones Farmacológicas , Voluntarios Sanos , Humanos , Masculino , Rifampin/efectos adversosRESUMEN
Ravidasvir (RDV) is a novel oral hepatitis C virus NS5A inhibitor. This study aimed to evaluate the pharmacokinetics and safety of RDV and the drug-drug interactions between RDV and ritonavir-boosted danoprevir (DNVr) in healthy adults. In the 1st study, healthy volunteers were administered single oral doses of 100, 200, and 300 mg of RDV and 200 mg once daily for 7 days. The 2nd study was a randomized, double-blinded, and placebo-controlled sequential design (day 1 for 200 mg of RDV alone, day 7 for 100 mg/100 mg of DNVr, day 13 for 200 mg of RDV plus 100 mg/100 mg DNVr, followed by 200 mg of RDV once daily with 100 mg/100 mg of DNVr twice daily for 10 days). The results showed that RDV exposure increased in a dose-proportional manner following a single dose with no evidence of accumulation with multiple doses. Coadministration with DNVr (100 mg/100 mg, twice daily) resulted in a 2.92-fold and 1.99-fold increase in minimum plasma concentration at steady state (Cmin,ss) and area under the concentration-time curve at steady state (AUCτ) of RDV, respectively. With coadministration of RDV, maximum plasma concentration (Cmax) and area under the concentration-time curve from 0 to 12 h (AUC0-12) of DNV increased 1.71-fold and 2.33-fold, respectively. We did not observe any significant changes in ritonavir exposure. Both single and multiple doses of RDV with or without DNVr were well tolerated. The favorable pharmacokinetic and safety results support ravidasvir's continued clinical development and treatment. (The studies described in this paper have been registered at ClinicalTrials.gov under identifiers NCT03430830 and NCT03288636.).
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Lactamas , Ritonavir , Adulto , Área Bajo la Curva , Bencimidazoles , Ciclopropanos , Voluntarios Sanos , Humanos , Isoindoles , Lactamas Macrocíclicas , Prolina/análogos & derivados , Ritonavir/efectos adversos , Sulfonamidas , Valina/análogos & derivadosRESUMEN
The effects of multiple-dose administration of tenofovir disoproxil fumarate (TDF) on the pharmacokinetics of morinidazole (MOR) were compared in healthy subjects. MOR exposure was similar, with an area under the curve from 0 h to infinity (AUC0-∞) treatment ratio for MOR+TDF/MOR of 1.01 (90% confidence interval, 0.97 to 1.06). No relevant differences were observed regarding plasma exposure of metabolites. Renal clearances of MOR and its metabolites were not affected by TDF. No unexpected safety or tolerability issues were observed.
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Antivirales/farmacología , Antivirales/farmacocinética , Interacciones Farmacológicas , Nitroimidazoles/farmacocinética , Tenofovir/farmacología , China , Voluntarios Sanos , HumanosRESUMEN
Physalin B (PB) is one of the major constituents of Physalis alkekengi var. franchetii, a well-known Chinese traditional herb. In this study, we demonstrated for the first time that PB exhibits significant antiproliferative and apoptotic activity in A549 human lung cancer cells in a concentration-dependent and time-dependent manner. Flow cytometric analyses indicated that PB-induced G2/M arrest through down-regulation of cyclin B1 and cell division control protein cyclin-dependent kinase 1, and up-regulation of p21. The reduction in the level of cyclin B1/cyclin-dependent kinase 1 complex down-regulated oxidative phosphorylation multisubunit activity to reduce mitochondrial energetic homeostasis. Moreover, defects in mitochondrial ATP synthesis and mitochondrial membrane potential were found in PB-treated cell lines. These abnormalities led to an increase in intracellular superoxide and apoptosis. Thus, as an inhibitor of mitochondrial energetic homeostasis, PB demonstrates potent antitumor activities and may be developed as an alternative therapeutic agent against non-small-cell lung cancer.
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Apoptosis , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Neoplasias Pulmonares/patología , Puntos de Control de la Fase M del Ciclo Celular/efectos de los fármacos , Mitocondrias/patología , Secoesteroides/farmacología , Proliferación Celular , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Mitocondrias/efectos de los fármacos , Células Tumorales CultivadasRESUMEN
Physalins are the major steroidal constituent of Physalis plants and display a range of biological activities. For this study, a rapid and sensitive high-performance liquid chromatography with triple quadrupole mass spectrometry method was developed for the simultaneous quantification of six physalins. Specifically, it was for the quantification of physalin A, physalin B, physalin D, physalin G, 4,7-didehydroneophysalin B, and isophysalin B in rat plasma and rat intestinal bacteria. After a solid-phase extraction, analytes and internal standards (prednisolone) were separated on a Shield reverse-phase C18 column (measuring 3 mm × 150 mm with an internal diameter of 3.5 µm) and determined using multiple reactions in a monitoring mode with a positive-ion electrospray ionization source. The mobile phase was a mixture of 0.1% formic acid in water (A) and acetonitrile (B) and was used at a flow rate of 0.6 mL/min. The intra- and interday precisions were within 15% with accuracies ranging from 86.2 to 114%. The method was validated and successfully applied to pharmacokinetics and stability studies of six physalins in rat plasma and rat intestinal bacteria, respectively. The results showed that physalin B and isophysalin B could not be absorbed by rats, and rat intestinal bacteria could quickly transform physalins.
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Medios de Cultivo/química , Intestinos/química , Secoesteroides/farmacocinética , Witanólidos/farmacocinética , Animales , Cromatografía Liquida , Femenino , Intestinos/microbiología , Masculino , Espectrometría de Masas , Conformación Molecular , Ratas , Ratas Sprague-Dawley , Secoesteroides/sangre , Extracción en Fase Sólida , Witanólidos/sangreRESUMEN
Physalin D is known to show extensive bioactivities. However, no excretion study has elucidated the excretion of physalin D and its metabolites. This study investigates the excretion of physalin D and its metabolites in rats. Metabolites in rat urine and feces were separated and identified by liquid chromatography with triple quadrupole time-of-flight mass spectrometry. Furthermore, a validated high-performance liquid chromatography with tandem mass spectrometry method was developed to quantify physalin D, physalin D glucuronide, and physalin D sulfate in rat feces and urine after the intragastric administration of physalin D. The analyte showed good linearity over a wide concentration range (r > 0.995), and the lower limit of quantification was 0.0532 µg/mL and 0.226 µg/g for urine and feces, respectively. Nine metabolites, including five phase I and four phase II metabolites, were identified and clarified after dosing in vivo. Only 4.0% of the gavaged dose, including physalin D and its phase II metabolites, was excreted in urine, whereas 10.8% was found in feces in the unchanged form. The results indicate that the extensive and rapid metabolism may be the main factors leading to the short half-life of physalin D. These results can provide a basis for further studies on the structural modification and pharmacology of physalin D.
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Heces/química , Secoesteroides/farmacocinética , Secoesteroides/orina , Animales , Cromatografía Líquida de Alta Presión , Ratas , Espectrometría de Masas en TándemRESUMEN
LESSONS LEARNED: This phase I study evaluated the maximum tolerated dose, dose-limiting toxicities, safety, pharmacokinetics, and efficacy of icotinib with a starting dose of 250 mg in pretreated, advanced non-small cell lung cancer patients. We observed a maximum tolerated dose of 500 mg with a favorable pharmacokinetics profile and antitumor activity.These findings provide clinicians with evidence for application of higher-dose icotinib. BACKGROUND: Icotinib, an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has shown favorable tolerability and antitumor activity at 100-200 mg in previous studies without reaching the maximum tolerated dose (MTD). In July 2011, icotinib was approved by the China Food and Drug Administration at a dose of 125 mg three times daily for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one platinum-based chemotherapy regimen. This study investigated the MTD, tolerability, and pharmacokinetics of higher-dose icotinib in patients with advanced NSCLC. METHODS: Twenty-six patients with advanced NSCLC were treated at doses of 250-625 mg three times daily The EGFR mutation test was not mandatory in this study. RESULTS: Twenty-four (92.3%) of 26 patients experienced at least one adverse event (AE); rash (61.5%), diarrhea (23.1%), and oral ulceration (11.5%) were most frequent AEs. Dose-limiting toxicities were seen in 2 of 6 patients in the 625-mg group, and the MTD was established at 500 mg. Icotinib was rapidly absorbed and eliminated. The amount of time that the drug was present at the maximum concentration in serum (Tmax) ranged from 1 to 3 hours (1.5-4 hours) after multiple doses. The t1/2 was similar after single- and multiple-dose administration (7.11 and 6.39 hours, respectively). A nonlinear relationship was observed between dose and drug exposure. Responses were seen in 6 (23.1%) patients, and 8 (30.8%) patients had stable disease. CONCLUSION: This study demonstrated that higher-dose icotinib was well-tolerated, with a MTD of 500 mg. Favorable antitumor activity and pharmacokinetic profile were observed in patients with heavily pretreated, advanced NSCLC.
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Antineoplásicos/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Éteres Corona/efectos adversos , Receptores ErbB/antagonistas & inhibidores , Neoplasias Pulmonares/tratamiento farmacológico , Quinazolinas/efectos adversos , Adulto , Anciano , Éteres Corona/farmacocinética , Receptores ErbB/genética , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Mutación , Quinazolinas/farmacocinéticaRESUMEN
OBJECTIVE: Recently a formulation of intravenous (IV) ibuprofen was developed in China for management of mild to moderate pain in patients who could not take oral medications or where intravenous administration was preferable. The aim of this study was to evaluate the pharmacokinetic properties and tolerability of single and multiple doses of ibuprofen injection in healthy Chinese volunteers. METHODS: This open-label, single- and multiple-dose study was conducted in healthy Chinese volunteers. In the single-dose phase, subjects were randomized to receive a single dose of ibuprofen injection 0.2, 0.4, or 0.8 g administered as a 30-minute IV infusion with a 1-week washout between periods. Blood samples were collected at regular intervals from 0 to 12.5 hours after drug administration and were analyzed using a validated LC-MS/MS method. In the multiple-dose phase, subjects received 0.4 g ibuprofen every 6 hours for 9 doses. Blood samples were obtained before the 7th, 8th, and 9th administration to determine the Cmin at steady state; on the 9th intravenous administration, blood samples were also collected for 12.5 hours after drug administration. Pharmacokinetic parameters were estimated using a noncompartmental model. Tolerability was determined using clinical evaluation and monitoring of adverse events (AEs). RESULTS: A total of 12 healthy male (n = 6) and female (n = 6) Chinese volunteers were enrolled and completed the trial. After IV administration of single dose, the mean (SD) Cmax value increased from 35.77 (6.98) to 117.12 (19.78) µg/mL, and the mean (SD) AUC0-t value increased from 67.63 (10.30) to 230.50 (33.55) µg×h/mL in the range of 0.2-g to 0.8-g dose. The terminal half-life in plasma was ~ 2.0 hours. After IV administration of 9 doses of ibuprofen 400 mg every 6 hours, the mean (SD) Cmax was 66.49 (8.49) µg/mL, the AUC0-t was 135.65 (26.91) µg×h/mL, the t1/2 was 2.14 (0.34) hours, the Cl/F was 3.34 (0.68) L/h, and the Vz/F was 10.32 (2.69) L, which were comparable with those after single dosing. The accumulation index was 1.17 (0.06), and the fluctuation was 304.0 (57.7) %. Results of the t-tests of Cmax and AUC found no significant differences between the male and female groups. No serious AEs were reported, and there were no discontinuations due to AEs. CONCLUSION: The pharmacokinetics of ibuprofen exhibited dose-related kinetics from the 0.2- to the 0.8-g dose. After multiple doses, the pharmacokinetic parameters of ibuprofen were consistent with those after single doses. There was no accumulation in ibuprofen exposure in healthy Chinese between multiple doses and single dose. At the doses studied, ibuprofen appeared to be well tolerated in these healthy volunteers.â©.
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Antiinflamatorios no Esteroideos/efectos adversos , Antiinflamatorios no Esteroideos/farmacocinética , Ibuprofeno/efectos adversos , Ibuprofeno/farmacocinética , Adolescente , Adulto , Antiinflamatorios no Esteroideos/administración & dosificación , Área Bajo la Curva , Pueblo Asiatico , Relación Dosis-Respuesta a Droga , Femenino , Semivida , Voluntarios Sanos , Humanos , Ibuprofeno/administración & dosificación , Infusiones Intravenosas , Inyecciones Intravenosas , Masculino , Adulto JovenRESUMEN
OBJECTIVE: Febuxostat is a novel non-purine selective inhibitor of xanthine oxidase indicated for the chronic management of hyperuricemia in patients with gout. The aim of the present study was to evaluate the pharmacokinetic properties and tolerability of single and multiple oral administrations of febuxostat capsules in healthy Chinese volunteers. METHODS: This openlabel, single- and multiple-dose three-way crossover study was conducted in healthy Chinese volunteers. Subjects were randomized to receive a single dose of febuxostat 40, 80, or 120 mg in separate trial periods, with a 1-week washout between periods. Those allocated to the 40 mg and 80 mg dose continued into the multiple-dose phase, in which they received 40 mg or 80 mg once daily for 6 consecutive days. During the course of the study, blood samples were collected and the concentrations of febuxostat were determined using LC-MS/MS. Pharmacokinetic parameters were estimated using a noncompartmental model. Tolerability was determined using clinical evaluation and monitoring of adverse events (AEs). RESULTS: 12 healthy Chinese volunteers were enrolled and completed 3 treatment periods. After oral administration of single doses of 40, 80, and 120 mg of febuxostat, the mean (SD) Cmax was 2,835.43 (1,136.41), 5,356.75 (1,711.33), and 7,718.21 (2,446.34) ng/mL, respectively; the AUC0-48h was 8,821.10 (3,018.35), 17,854.46 (5,113.28), and 30,832.05 (10,992.20) ng×h/ mL; the AUC0-∞ was 8,990.33 (3,046.14), 18,193.58 (5,160.80), and 31,466.93 (1,1074.74) ng×h/mL; the t1/2 was 5.95 (2.71), 9.41 (7.47), and 12.34 (10.34) hours; the Cl/F was 4.81 (1.18), 4.70 (1.21), and 4.18(1.19) L/h; and the Vz/F was 39.66 (16.69), 62.72 (51.41), and 73.41 (64.84) L. After administration of multiple doses of 40 and 80 mg febuxostat, the mean (SD) Cmax,ss was 2,762.38 (1,331.96) and 5,047.27 (1,456.57) ng/mL; the Cmin,ss was 124.10 (6.32) and 46.93 (15.86) ng/mL; the AUCss,0-τ was 8,525.49 (2,160.64) and 16,757.12 (4,223.17) ng×h /mL; the steadystate plasma concentration (Css) was 355.23 (90.03) and 698.21 (175.97) ng/mL; the t1/2 was 7.68 (3.30) and 11.33 (6.94) hours; the Cl/F was 4.99 (1.30) and 5.05 (1.22) L/h; and the Vz/F was 54.10 (24.10) and 85.51 (65.99) L. No serious AEs were reported, and there were no discontinuations due to AEs. CONCLUSION: The PK of febuxostat exhibited dose proportional kinetics from 40 to 120 mg dose. After multiple doses, the pharmacokinetic parameters of febuxostat were consistent with those after single doses. There was no accumulation in febuxostat exposure in healthy Chinese between multiple doses and single dose. At the doses studied, febuxostat appeared to be well tolerated in these healthy volunteers.
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Febuxostat/farmacocinética , Administración Oral , Adolescente , Adulto , Estudios Cruzados , Febuxostat/administración & dosificación , Febuxostat/efectos adversos , Femenino , Humanos , MasculinoRESUMEN
OBJECTIVES: The aim of the present study was to compare the pharmacokinetic profiles between a new generic and a branded reference formulation of irbesartan/ hydrochlorothiazide FDC tablets, and to assess the bioequivalence of the two products in healthy Chinese male volunteers. MATERIALS AND METHODS: 24 male healthy volunteers participated in the open-label, single-dose, randomized-sequence, 2-way crossover study. Eligible subjects were randomly assigned (1:1) to receive a single 300/12.5-mg dose of either the test or reference formulation followed by a 1-week washout. Blood samples were obtained before (0 hours) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 36, 48, and 72 hours after dosing. Plasma concentrations of irbesartan and hydrochlorothiazide were analyzed by two separate validated liquid chromatography/tandem mass spectrometric (LC-MS/MS) methods. RESULTS: For irbesartan, the 90% confidence intervals (CIs) of AUC0-t, AUC0-∞, and Cmax were 103.27-116.71%, 105.01-121.47%, and 84.15-96.88%, respectively. For hydrochlorothiazide, the 90% CIs of AUC0-t, AUC0-∞, and Cmax were 96.11-109.02%, 95.15-107.35%, and 91.66-101.40%, respectively. A total of 3 mild AEs were reported in 3 subjects (12.5%). CONCLUSION: In this study, a single dose (300/12.5-mg) of the test formulation of irbesartan and hydrochlorothiazide FDC tablet in fasting healthy Chinese male volunteers met WHO's and China's FDA regulatory criteria for assumption of bioequivalence to the reference formulation based on AUC and Cmax. Both formulations were well tolerated.
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Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacocinética , Antihipertensivos/farmacocinética , Compuestos de Bifenilo/farmacocinética , Diuréticos/farmacocinética , Medicamentos Genéricos/farmacocinética , Hidroclorotiazida/farmacocinética , Tetrazoles/farmacocinética , Administración Oral , Adulto , Bloqueadores del Receptor Tipo 1 de Angiotensina II/administración & dosificación , Bloqueadores del Receptor Tipo 1 de Angiotensina II/efectos adversos , Bloqueadores del Receptor Tipo 1 de Angiotensina II/sangre , Antihipertensivos/administración & dosificación , Antihipertensivos/efectos adversos , Antihipertensivos/sangre , Área Bajo la Curva , Pueblo Asiatico , Compuestos de Bifenilo/administración & dosificación , Compuestos de Bifenilo/efectos adversos , Compuestos de Bifenilo/sangre , China , Cromatografía Líquida de Alta Presión , Estudios Cruzados , Diuréticos/administración & dosificación , Diuréticos/efectos adversos , Diuréticos/sangre , Combinación de Medicamentos , Medicamentos Genéricos/administración & dosificación , Medicamentos Genéricos/efectos adversos , Voluntarios Sanos , Humanos , Hidroclorotiazida/administración & dosificación , Hidroclorotiazida/efectos adversos , Hidroclorotiazida/sangre , Irbesartán , Masculino , Tasa de Depuración Metabólica , Comprimidos , Espectrometría de Masas en Tándem , Tetrazoles/administración & dosificación , Tetrazoles/efectos adversos , Tetrazoles/sangre , Equivalencia Terapéutica , Adulto JovenRESUMEN
Copen is a derivative obtained from the structural modification of osthole, which inhibits tumoral proliferation in many tumor cell lines. A rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was established for the quantification of copen in rat plasma. After a simple sample preparation procedure by one-step protein precipitation with methanol, copen and bicalutamide (internal standard, IS) were chromatographed on a Zorbax SB-C18 (4.6×100 mm, 1.8 µm) column with a mobile phase consisting of methanol-5 mm ammonium formate water with 0.1% formic acid (80:20, v/v). MS detection was performed on a triple quadrupole tandem mass spectrometer in the multiple reaction monitoring mode with a positive eletrospray ionization source. The assay was validated in the concentration range of 51.58-20,630 ng/mL, with a limit of quantitation (LOQ) of 51.58 ng/mL. The intra- and inter-day precisions (relative standard deviation) were ≤3.21 and ≤11.3%, respectively, with accuracy (%) in the range of 94.66-102.1%. The method was fully validated in a study of the pharmacokinetics of copen (25 mg/kg) after intragastric administration in rats.
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Antineoplásicos/sangre , Cromatografía Liquida/métodos , Cumarinas/sangre , Espectrometría de Masas en Tándem/métodos , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Cumarinas/química , Cumarinas/farmacocinética , Modelos Lineales , Masculino , Ratas , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
OBJECTIVE: Sitafloxacin is a new fluoroquinolone with a broad spectrum of antibacterial activity, including grampositive and gram-negative bacteria. This study was to evaluate the pharmacokinetic characteristics of a single dose of sitafloxacin in healthy Chinese volunteers. METHODS: This was a single-center, open-label, randomized-sequence study conducted in 12 subjects. Subjects were randomly assigned to receive single doses of 50, 100, and 200 mg of sitafloxacin in a 3-way crossover design with a 7-day washout period between administrations. Quantification was carried out using a validated high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method. Pharmacokinetic parameters were calculated and analyzed statistically. Safety assessments were conducted throughout the study. RESULTS: After administration of single doses of 50, 100, and 200 mg, geometric mean estimate for sitafloxacin Cmax were 0.72, 1.62, and 2.73 µg/mL and the mean of AUClast were 3.97, 8.71, and 18.03 µg x h/mL, respectively. Sitafloxacin was rapidly absorbed, reaching Cmax ranged from 0.85 to 1.21 hours. The terminal half-life ranged from 5.19 to 6.28 hours. The Cmax and AUC last were proportional to the doses. The mean clearance, the half-life, and the volume of distribution were constant, irrespective of the dose. CONCLUSION: In healthy Chinese subjects, single dosing of sitafloxacin resulted in linear plasma pharmacokinetics.
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Antibacterianos/farmacocinética , Fluoroquinolonas/farmacocinética , Administración Oral , Adulto , Área Bajo la Curva , Estudios Cruzados , Femenino , Fluoroquinolonas/efectos adversos , Voluntarios Sanos , Humanos , MasculinoRESUMEN
Purpose: Estradiol valerate (Progynova®) is used as hormone therapy to supplement estrogen deficiency. This study aimed to assess the bioequivalence of an estradiol valerate tablet and its generic form, under fasting and fed conditions. Methods: A randomized, open-label, single-dose, 2-period crossover study was conducted on healthy postmenopausal Chinese female volunteers under fasting and fed conditions. For each period, the subjects received either a 1 mg tablet of estradiol valerate or its generic. Blood samples were collected before dosing and up to 72 hours after administration. Plasma levels of total estrone, estradiol, and unconjugated estrone were quantified using a validated liquid chromatography-tandem mass spectrometry method. Results: A total of 54 volunteers were enrolled in this study. The primary pharmacokinetic parameters, including Cmax, AUC0-t, and AUC0-∞, were similar for the two drugs under both fasting and fed conditions, with 90% confidence intervals for the geometric mean ratios of these parameters, all meeting the bioequivalence criterion of 80-125%. A total of 48 adverse events (AEs) were reported in the fed study compared with 24 AEs in the fasting study. Conclusion: Estradiol valerate and its generic form were bioequivalent and well tolerated under both fasting and fed conditions.
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Estudios Cruzados , Medicamentos Genéricos , Estradiol , Posmenopausia , Comprimidos , Equivalencia Terapéutica , Femenino , Humanos , Persona de Mediana Edad , Administración Oral , Pueblo Asiatico , China , Medicamentos Genéricos/farmacocinética , Medicamentos Genéricos/administración & dosificación , Medicamentos Genéricos/efectos adversos , Pueblos del Este de Asia , Estradiol/farmacocinética , Estradiol/administración & dosificación , Estradiol/sangre , Estradiol/análogos & derivados , Voluntarios SanosRESUMEN
The purpose of this study was to design a simple, sensitive and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for a febuxostat bioequivalence study in healthy Chinese male volunteers. In this method, febuxostat and etodolac (internal standard) were isolated from plasma samples by protein precipitation with acetonitrile. The supernatant was chromatographed on a Zorbax SB-C18 (150 x 3.0 mm, 3.5-microm particle size, Agilent) column with a SecurityGuard Inertsil Symmetry C18 column (12.5 x 4.6 mm, 5-microm particle size, Waters). The lower limit of quantification for febuxostat in 0.2 mL of human plasma was 13.40 ng x mL(-1), and the linearity was achieved over a concentration range from 13.40 to 21440 ng x mL(-1). Febuxostat tablets from Hengrui Medicine Co., Ltd (test, Jiangsu, China) and from Takeda pharmaceuticals america, Inc. (reference, Deerfield, IL) were evaluated following a single 80 mg oral dose to 18 healthy volunteers. Bioequivalence was determined by calculating 90% confidence intervals (90% CI) for the ratio of C(max), AUC(0-t), and AUC(0-infinity) values for the test and reference products, using logarithmic transformed data. The calculated 90% CIs for the ratio of C(max) (88.7-131.2%), AUC(0-t) (99.2-122.7%) and AUC(0-infinity) (99.5-123.1%) values for the test and reference products were all located within the bioequivalence criteria range (80-125% for AUC, and 70-143% for Ca(mzax)), proposed by State of Food and Drug Administration [SFDA, 2005. China]. It was concluded that the two febuxostat formulations (test and reference) analyzed were bioequivalent in terms of rate and extent of absorption and the method met the principle of quick and easy clinical analysis.
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Tiazoles/sangre , Tiazoles/farmacocinética , Xantina Oxidasa/antagonistas & inhibidores , Adulto , Área Bajo la Curva , Calibración , Cromatografía Líquida de Alta Presión , Febuxostat , Semivida , Humanos , Masculino , Espectrometría de Masas , Estándares de Referencia , Reproducibilidad de los Resultados , Espectrometría de Masas en Tándem , Equivalencia Terapéutica , Tiazoles/efectos adversosRESUMEN
A single-dose, open-label, randomized, two-period crossover-design study was conducted to evaluate the bioequivalence of the reference and test formulations of mifepristone tablets. Each subject was randomized at the beginning to receive a 25-mg tablet of the test or the reference mifepristone under fasting conditions during the first period, then received the alternate formulation during the second period following a 2-week washout period. A validated high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was used to determine the plasma concentrations of mifepristone and its two metabolites (RU42633 and RU42698). Fifty-two healthy subjects were enrolled in this trial, 50 of whom completed the study. The 90% confidence intervals for the log-transformed Cmax , AUC0-t , and AUC0-∞ fell within the accepted 80%-125% range. Throughout the study period, a total of 58 treatment-emergent adverse events were reported. No serious adverse event was observed. In conclusion, the test and reference mifepristone were bioequivalent and well tolerated under fasting conditions.
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Mifepristona , Espectrometría de Masas en Tándem , Humanos , Pueblos del Este de Asia , Ayuno , Voluntarios Sanos , Mifepristona/efectos adversos , Mifepristona/farmacología , Comprimidos , Espectrometría de Masas en Tándem/métodos , Equivalencia TerapéuticaRESUMEN
BACKGROUND: SCT510 is a recombinant humanized monoclonal antibody targeting vascular endothelial growth factor (VEGF), which is intended as a candidate biosimilar of bevacizumab that is approved for various metastatic cancers.Please confirm change in wording to match definition for VEGF belowYes. OBJECTIVE: This study aimed to compare the pharmacokinetics profiles, safety, and immunogenicity of SCT510 to bevacizumab (Avastin®) in healthy Chinese males. METHODS: This was a single-center, double-blind, parallel-group phase I study. A total of 84 participants were randomly assigned (1:1) to receive a single 3 mg/kg infusion of either SCT510 or bevacizumab and followed up for 99 days. Primary endpoints were area under the serum concentration-time curve from time 0 extrapolated to infinity (AUC0-∞), area under the serum concentration-time curve from time 0 to last quantifiable concentration (AUC0-t), and the maximum observed concentration (Cmax). Secondary endpoints included safety and immunogenicity.Kindly check and confirm the edit made in the article title.Yes. RESULTS: A total of 82 subjects completed the study. Geometric means ratios (GMR) for AUC0-∞, AUC0-t, and Cmax were 0.88, 0.89, and 0.97, respectively, for SCT510 versus bevacizumab (USA). The 90% confidence intervals for GMRs of AUC0-∞, AUC0-t, and Cmax were all within the prespecified criteria (80-125%). No adverse events (AEs) led to study termination, and no serious adverse events (SAEs) were reported. None of the anti-drug antibodies (ADAs) identified were found to be neutralizing antibodies (NAbs), and only one subject from the SCT510 group tested positive for the ADA at the day 99 visit. CONCLUSION: This study demonstrated that the pharmacokinetics, safety, and immunogenicity of SCT510 were equivalent to bevacizumab (Avastin®). As a proposed biosimilar drug to bevacizumab, SCT510 was well tolerated in healthy Chinese males. CLINICAL TRIALS REGISTRATION: NCT05113511.
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Bevacizumab , Biosimilares Farmacéuticos , Humanos , Masculino , Área Bajo la Curva , Bevacizumab/farmacocinética , Método Doble Ciego , Pueblos del Este de Asia , Voluntarios Sanos , Equivalencia TerapéuticaRESUMEN
Purpose: Suramin is a multifunctional molecule with a wide range of potential applications, including parasitic and viral diseases, as well as cancer. Methods: A double-blinded, randomized, placebo-controlled single ascending dose study was conducted to investigate the safety, tolerability, and pharmacokinetics of suramin in healthy Chinese volunteers. A total of 36 healthy subjects were enrolled. All doses of suramin sodium and placebo were administered as a 30-minute infusion. Blood and urine samples were collected at the designated time points for pharmacokinetic analysis. Safety was assessed by clinical examinations and adverse events. Results: After a single dose, suramin maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to the time of the last measurable concentration (AUClast) increased in a dose-proportional manner. The plasma half-life (t1/2) was dose-independent, average 48 days (range 28-105 days). The cumulative percentages of the dose excreted in urine over 7 days were less than 4%. Suramin can be detected in urine samples for longer periods (more than 140 days following infusion). Suramin was generally well tolerated. Treatment-emergent adverse events (TEAEs) were generally mild in severity. Conclusion: The PK and safety profiles of suramin in Chinese subjects indicated that 10 mg/kg or 15 mg/kg could be an appropriate dose in a future multiple-dose study.
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Pueblos del Este de Asia , Suramina , Humanos , Área Bajo la Curva , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Semivida , Voluntarios Sanos , Suramina/administración & dosificación , Suramina/efectos adversos , Suramina/sangre , Suramina/farmacocinética , Suramina/orinaRESUMEN
SHR-1222, a novel humanized monoclonal antibody targeting sclerostin, has been shown to induce bone formation and decrease bone resorption at a single dose ranging 50-400 mg in our previous phase 1 trial. This study was a randomized, double-blind, placebo-controlled, dose-escalation phase 1 trial, which further investigated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of multiple ascending doses of SHR-1222 in women with postmenopausal osteoporosis (POP). A total of 105 women with POP were enrolled and randomly assigned. Twenty-one received placebo and eighty-four received SHR-1222 sequentially (100 mg QM, n=4; 200 or 300 mg QM, n=20; and 400 or 600 mg Q2M, n=20). The most common adverse events included increased blood parathyroid hormone, increased low-density lipoprotein, increased blood alkaline phosphatase, increased blood cholesterol, back pain, and arthralgia, the majority of which were mild in severity without noticeable safety concerns. Serum SHR-1222 exposure (Cmax,ss and AUC0-tau,ss) increased in a greater than dose-proportional manner. Following multiple doses of SHR-1222, the bone formation markers (terminal propeptide of type I procollagen, bone-specific alkaline phosphatase, and osteocalcin) increased in a dose-dependent manner, whereas the bone resorption marker (ß-C-telopeptide) was downregulated. Accordingly, BMD gains in the lumbar spine, total hip, and femoral neck were observed. The maximum BMD increase from baseline at the lumbar spine was detected in the 300 mg QM cohort (14.6% vs. 0.6% in the placebo group on day 169). Six (6/83; 7.2%) subjects developed anti-SHR-1222 antibodies with no discernible effects on PKs, PDs, and safety. Thus, multiple doses of SHR-1222 showed an acceptable safety profile and dose-dependent plasma exposure in women with POP, and could improve their BMD rapidly and prominently by promoting bone formation and inhibiting bone resorption. These findings further support SHR-1222 as a potential alternative agent for the treatment of POP.