RESUMEN
Fuzuloparib is a novel orally bioactive poly-ADP-ribose polymerase inhibitor (PARPi), which was approved by the Chinese Regulatory Agency (CRA) in 2020 for the treatment of platinum-sensitive recurrent ovarian, fallopian tube, and primary peritoneal cancers. This study firstly presents a rapid and accurate ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for analyzing the levels of fuzuloparib and its major metabolite (SHR165202), and to investigate drug-drug interaction between fuzuloparib and curcumin in vitro and in vivo studies. After protein precipitation with acetonitrile, mobile phase consisted of acetonitrile and 0.1â¯% formic acid with a gradient elution was used to successfully separate fuzuloparib, SHR165202 and talazoparib (internal standard, IS). The results indicated that fuzuloparib and SHR165202 had good linearity over the calibration range of 2-50â¯ng/mL and 1-20â¯ng/mL, respectively. The precision, accuracy, stability, matrix effect, and extraction recovery required for methodological validation all complied with the requirements of the Bioanalytical Method Validation Guidelines. In vitro microsome incubation experiments, curcumin exhibited inhibitory effect on fuzuloparib in both rat liver microsomes (RLM) and human liver microsomes (HLM) with half-maximal inhibitory concentration (IC50) value of 10.54⯵M and 47.64⯵M, respectively, and the corresponding mechanism was non-competitive. Furthermore, the inhibitory mechanism of curcumin on fuzuloparib was validated through molecular docking. In pharmacokinetic experiments in rats, curcumin significantly altered the plasma exposure of fuzuloparib, resulting in significant increases in AUC(0-t) and Cmax of fuzuloparib and a significant decrease in CLz/F. Moreover, the metabolite SHR165202 showed significant increases in AUC(0-t), AUC(0-∞), Tmax and Cmax and a significant decrease in CLz/F. This further supports the notion that curcumin could inhibit the metabolism of fuzuloparib. Therefore, when co-administering fuzuloparib and curcumin in clinic, it is recommended to monitor plasma levels of fuzuloparib and pay close attention to adverse effects. If necessary, the dose of fuzuloparib needs to be reduced.
Asunto(s)
Curcumina , Cromatografía Líquida con Espectrometría de Masas , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Animales , Ratas , Administración Oral , Cromatografía Líquida de Alta Presión/métodos , Curcumina/administración & dosificación , Curcumina/farmacocinética , Interacciones Farmacológicas/fisiología , Cromatografía Líquida con Espectrometría de Masas/métodos , Microsomas Hepáticos/metabolismo , Simulación del Acoplamiento Molecular , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacocinética , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Espectrometría de Masas en Tándem/métodosRESUMEN
BACKGROUND: Pamiparib is a potent, selective, poly (ADP-ribose) polymerase 1/2 inhibitor that demonstrates synthetic lethality in cells with breast cancer susceptibility gene mutations or other homologous recombination deficiency. This two-stage phase 1b study (NCT03150810) assessed pamiparib in combination with temozolomide (TMZ) in adult patients with histologically confirmed locally advanced and metastatic solid tumors. METHODS: Oral pamiparib 60 mg was administered twice daily. During the dose-escalation stage, increasing doses of TMZ (40-120 mg once daily pulsed or 20-40 mg once daily continuous) were administered to determine the recommended dose to be administered in the dose-expansion stage. The primary objectives were to determine safety and tolerability, maximum tolerated/administered dose, recommended phase 2 dose and schedule, and antitumor activity of pamiparib in combination with TMZ. Pharmacokinetics of pamiparib and TMZ and biomarkers were also assessed. RESULTS: Across stages, 139 patients were treated (dose escalation, n = 66; dose expansion, n = 73). The maximum tolerated dose of TMZ, which was administered during dose expansion, was 7-day pulsed 60 mg once daily. The most common treatment-emergent adverse events (TEAEs) were anemia (dose escalation, 56.1%; dose expansion, 63.0%), nausea (dose escalation, 54.5%; dose expansion, 49.3%), and fatigue (dose escalation, 48.5%; dose expansion, 47.9%). In the dose-escalation stage, four patients experienced dose-limiting toxicities (three neutropenia and one neutrophil count decreased). No TEAEs considered to be related to study drug treatment resulted in death. Antitumor activity was modest, indicated by confirmed overall response rate (dose escalation, 13.8%; dose expansion, 11.6%), median progression-free survival (3.7 and 2.8 months), and median overall survival (10.5 and 9.2 months). Administration of combination therapy did not notably impact pamiparib or TMZ pharmacokinetics. CONCLUSIONS: Pamiparib in combination with TMZ had a manageable safety profile. Further investigation of the efficacy of this combination in tumor types with specific DNA damage repair deficiencies is warranted.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Bencimidazoles , Dosis Máxima Tolerada , Neoplasias , Temozolomida , Humanos , Temozolomida/administración & dosificación , Temozolomida/farmacocinética , Temozolomida/efectos adversos , Temozolomida/uso terapéutico , Femenino , Persona de Mediana Edad , Masculino , Anciano , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bencimidazoles/administración & dosificación , Bencimidazoles/farmacocinética , Bencimidazoles/efectos adversos , Bencimidazoles/uso terapéutico , Anciano de 80 o más Años , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacocinética , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Esquema de Medicación , FluorenosRESUMEN
Poly ADP-ribose polymerase (PARP) plays an important role in the DNA repair process and has become an attractive target for cancer therapy in recent years. Given that niraparib has good clinical efficacy as a PARP inhibitor, this study aimed to develop radiolabeled niraparib derivatives for tumor imaging to detect PARP expression and improve the accuracy of stratified patient therapy. The niraparib isonitrile derivative (CNPN) was designed, synthesized, and radiolabeled to obtain the [99mTc]Tc-CNPN complex with high radiochemical purity (>95%). It was lipophilic and stable in vitro. In HeLa cell experiments, the uptake of [99mTc]Tc-CNPN was effectively inhibited by the ligand CNPN, indicating the binding affinity for PARP. According to the biodistribution studies of HeLa tumor-bearing mice, [99mTc]Tc-CNPN has moderate tumor uptake and can be effectively inhibited, demonstrating its specificity for targeting PARP. The SPECT imaging results showed that [99mTc]Tc-CNPN had tumor uptake at 2 h postinjection. All of the results of this study indicated that [99mTc]Tc-CNPN is a promising tumor imaging agent that targets PARP.
Asunto(s)
Indazoles , Piperidinas , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Animales , Humanos , Ratones , Piperidinas/química , Piperidinas/farmacocinética , Indazoles/química , Indazoles/farmacocinética , Células HeLa , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacocinética , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/química , Distribución Tisular , Tomografía Computarizada de Emisión de Fotón Único/métodos , Radiofármacos/farmacocinética , Radiofármacos/química , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Femenino , Tecnecio/química , Nitrilos/química , Nitrilos/farmacocinética , Ratones Desnudos , Ratones Endogámicos BALB CRESUMEN
Compounds 8a-j were designed to adjust the mode of interaction and lipophilicity of FTT by scaffold hopping and changing the length of the alkoxy groups. Compounds 8a, 8d, 8g, and BIBD-300 were screened for high-affinity PARP-1 through enzyme inhibition assays and are worthy of further evaluation. PET imaging of MCF-7 subcutaneous tumors with moderate expression of PARP-1 showed that compared to [18F]FTT, [18F]8a, [18F]8d, and [18F]8g exhibited greater nonspecific uptake, a lower target-to-nontarget ratio, and severe defluorination, while [18F]BIBD-300 exhibited lower nonspecific uptake and a greater target-to-nontarget ratio. PET imaging of 22Rv1 subcutaneous tumors, which highly express PARP-1, confirmed that the uptake of [18F]BIBD-300 in normal organs, such as the liver, muscle, and bone, was lower than that of [18F]FTT, and the ratio of tumor-to-muscle and tumor-to-liver [18F]BIBD-300 was greater than that of [18F]FTT. The biodistribution results in mice with MCF-7 and 22Rv1 subcutaneous tumors further validated the results of PET imaging. Unlike [18F]FTT, which mainly relies on hepatobiliary clearance, [18F]BIBD-300, which has lower lipophilicity, undergoes a partial shift from hepatobiliary to renal clearance, providing the possibility for [18F]BIBD-300 to indicate liver cancer. The difference in the PET imaging results for [18F]FTT, [18F]BIBD-300, and [18F]8j in 22Rv1 mice and the corresponding molecular docking results further confirmed that subtle structural modifications in lipophilicity greatly optimize the properties of the tracer. Cell uptake experiments also demonstrated that [18F]BIBD-300 has a high affinity for PARP-1. Metabolized and unmetabolized [18F]FTT and [18F]BIBD-300 were detected in the brain, indicating that they could not accurately quantify the amount of PARP-1 in the brain. However, PET imaging of glioma showed that both [18F]FTT and [18F]BIBD-300 could accurately localize both in situ to C6 and U87MG tumors. Based on its potential advantages in the diagnosis of breast cancer, prostate cancer, and glioma, as well as liver cancer, [18F]BIBD-300 is a new option for an excellent PARP-1 tracer.
Asunto(s)
Radioisótopos de Flúor , Poli(ADP-Ribosa) Polimerasa-1 , Tomografía de Emisión de Positrones , Animales , Humanos , Tomografía de Emisión de Positrones/métodos , Ratones , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Femenino , Distribución Tisular , Radiofármacos/farmacocinética , Línea Celular Tumoral , Ratones Desnudos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacocinética , Diseño de Fármacos , Ratones Endogámicos BALB C , Células MCF-7RESUMEN
Niraparib is a potent and orally bioavailable inhibitor of poly (ADP-ribose) polymerase (PARP) with high specificity for isoforms 1 and 2. It has been approved by the U.S. Food and Drug Administration for ovarian cancer maintenance therapy and is currently under development for various cancers, including glioblastoma. To assess central nervous system (CNS) penetration of niraparib in glioblastoma patients, a novel bioanalytical method was developed to measure total and unbound niraparib levels in human brain tumor tissue and cerebrospinal fluid (CSF). The method was validated using plasma as a surrogate matrix over the concentration range of 1-10,000â¯nM on an LC-MS/MS system. The MS/MS detection was conducted in positive electrospray ionization mode, while chromatography was performed using a Kinetex™ PS C18 column with a total 3.5-minute gradient elution run time. The maximum coefficient of variation for both intra- and inter-day precision was 10.6%, with accuracy ranging from 92.8% - 118.5% across all matrices. Niraparib was stable in human brain homogenate for at least 6â¯hours at room temperature (RT) and 32 days at -20°C, as well as in stock and working solutions for at least 21â¯hours (RT) and 278 days (4°C). Equilibrium dialysis experiments revealed the fractions unbound of 0.05 and 0.16 for niraparib in human brain and plasma, respectively. The validated method is currently employed to assess niraparib levels in human glioblastoma tissue, CSF, and plasma in an ongoing trial on newly diagnosed glioblastoma and recurrent IDH1/2(+) ATRX mutant glioma patients (NCT05076513). Initial results of calculated total (Kp) and unbound (Kp,uu) tumor-to-plasma partition coefficients indicate significant brain penetration ability of niraparib in glioblastoma patients.
Asunto(s)
Neoplasias Encefálicas , Indazoles , Piperidinas , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Espectrometría de Masas en Tándem , Humanos , Piperidinas/farmacocinética , Piperidinas/sangre , Piperidinas/administración & dosificación , Piperidinas/uso terapéutico , Indazoles/farmacocinética , Indazoles/administración & dosificación , Indazoles/uso terapéutico , Espectrometría de Masas en Tándem/métodos , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacocinética , Cromatografía Liquida/métodos , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Reproducibilidad de los Resultados , Encéfalo/metabolismo , Sulfonamidas/farmacocinética , Sulfonamidas/análisis , Sulfonamidas/administración & dosificación , Cromatografía Líquida con Espectrometría de MasasRESUMEN
Talazoparib, a poly(ADP-ribose) polymerase inhibitor, has demonstrated efficacy in the treatment of advanced breast and prostate cancers in Western populations. This open-label, phase 1 study investigated the pharmacokinetics, safety, and antitumor activity of talazoparib monotherapy in Chinese patients with advanced solid tumors. Molecularly unselected patients (≥18 years) with advanced solid tumors resistant to standard therapy received talazoparib (oral, 1 mg once daily). Primary endpoint was characterization of single-dose and steady-state pharmacokinetics. Secondary endpoints evaluated safety, unconfirmed objective response rate (ORR), and duration of response. The safety population comprised 15 Chinese patients (median [range] age 53.0 [31.0-72.0] years). Single-dose median time to first occurrence of maximum observed concentration was 1.9 h; concentrations then declined with a mean terminal half-life (t1/2) of 67 h. Following multiple dosing, median Tmax was approximately 1.85 h with steady state generally achieved by Day 21. Treatment-related treatment-emergent adverse events (TEAEs) occurred in 86.7% (13/15) of patients (grade 3, 20.0%; grade 4, 13.3%). Two patients (13.3%) experienced serious treatment-related TEAEs. ORR (investigator-assessed) was 6.7% (95% CI: 0.2-31.9); one patient (6.7%) had a partial response. In patients with measurable disease at baseline, the ORR was 9.1% (1/11; 95% CI: 0.2-41.3; duration of response: 114 days); stable disease was achieved by 36.4% (4/11) of patients, and 54.5% (6/11) progressed by data cut-off. In Chinese patients with advanced solid tumors, the pharmacokinetic profile of talazoparib monotherapy (1 mg/day) was consistent with other patient populations. TEAEs were generally manageable with no unexpected safety findings. (ClinicalTrials.gov: NCT04635631 [prospectively registered November 19, 2020]).
Asunto(s)
Antineoplásicos , Neoplasias , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Humanos , Masculino , Persona de Mediana Edad , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Pueblos del Este de Asia , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Ftalazinas/efectos adversos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacocinética , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Administración Oral , Adulto , Anciano , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiologíaRESUMEN
PURPOSE: To develop a population pharmacokinetics (PPK) model for rucaparib, an oral poly(ADP-ribose) polymerase inhibitor. METHODS: The PPK analysis used PK data from patients in Study 1014 (NCT01009190, n = 35), Study 10 (NCT01482715, n = 123), and ARIEL2 (NCT01891344, n = 300), including intensive intravenous data (12-40 mg), intensive and sparse oral data (12-360 mg single-dose, 40-500 mg once daily, and 240-840 mg twice daily [BID]), and intensive single-dose oral data under fasted conditions and after a high-fat meal (40, 300, and 600 mg). RESULTS: Rucaparib PK was well described by a two-compartment model with sequential zero-order release and first-order absorption and first-order elimination. A high-fat meal slightly increased bioavailability at 600 mg but not at lower doses; this is not considered clinically significant, and rucaparib can be taken with or without food. Covariate effects of baseline creatinine clearance and albumin on rucaparib clearance were identified. Despite numerical increases in exposure with renal impairment, no dose adjustment is recommended for patients with mild or moderate renal impairment. No statistically significant relationships were detected for demographics, hepatic function (normal versus mild impairment), CYP1A2 and CYP2D6 phenotypes, or strong CYP1A2 or CYP2D6 inhibitors. Concomitant proton pump inhibitors showed no clinically significant effect on absorption. External validation of the model with data from ARIEL3 (NCT01968213) and TRITON2 (NCT02952534) studies showed no clinically meaningful PK differences across indications or sex. CONCLUSION: The PPK model adequately described rucaparib PK, and none of the covariates evaluated had a clinically relevant effect. CLINICALTRIALS: GOV: Study 1014 (NCT01009190), Study 10 (NCT01482715), ARIEL2 (NCT01891344), ARIEL3 (NCT01968213), and TRITON2 (NCT02952534).
Asunto(s)
Antineoplásicos , Neoplasias Ováricas , Antineoplásicos/uso terapéutico , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Estudios Clínicos como Asunto , Citocromo P-450 CYP1A2 , Femenino , Humanos , Indoles , Neoplasias Ováricas/patología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacocinéticaRESUMEN
BACKGROUND: Pamiparib, a PARP1/2 inhibitor, demonstrated antitumor activity in preclinical models. METHODS: This Phase 1A/1B dose-escalation/dose-expansion study enrolled adults (≥18 years) with advanced/metastatic cancer. The dose-escalation phase evaluated the recommended Phase 2 dose (RP2D), maximum tolerated dose (MTD), and pharmacokinetics; the dose-expansion phase evaluated the antitumor activity and food effects. RESULTS: Patients (N = 101) were enrolled in dose-escalation (n = 64) and dose-expansion (n = 37). During BID dose-escalation, dose-limiting toxicities were Grade 2 nausea (n = 1, 40 mg; n = 1, 80 mg); Grade 2 nausea and Grade 2 anorexia (n = 1, 120 mg), Grade 2 nausea, Grade 3 fatigue and Grade 3 paraesthesia (n = 1, 120 mg); MTD was 80 mg BID and RP2D was 60 mg BID. Common adverse events (AEs) were nausea (69.3%), fatigue (48.5%) and anaemia (35.6%); the most common Grade ≥3 AE was anaemia (24.8%). There was a dose-proportional increase in pamiparib exposure; no food effects on pharmacokinetics were observed. In the efficacy-evaluable population (n = 77), objective response rate (ORR) was 27.3% (95% CI, 17.7-38.6%). Median duration of response was 14.9 months (95% CI, 8.7-26.3). In the epithelial ovarian cancer (EOC)-evaluable population (n = 51), ORR was 41.2% (95% CI, 27.6-55.8%). CONCLUSIONS: Pamiparib was tolerated with manageable AEs, and antitumor activity was observed in patients with EOC. CLINICALTRIALS. GOV IDENTIFIER: NCT02361723.
Asunto(s)
Fluorenos/administración & dosificación , Neoplasias/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Fluorenos/efectos adversos , Fluorenos/farmacocinética , Alimentos , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacocinética , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
PURPOSE: Fuzuloparib (AiRuiYiTM, formerly fluzoparib, SHR3162) is a new orally active poly adenosine diphosphate ribose polymerase (PARP) inhibitor. It has multiple pharmacological activities in breast, ovarian, and prostatic cancer. Fuzuloparib is mainly metabolized through the enzyme CYP3A4 may slow fuzuloparib metabolism and increase its concentrations in blood. We evaluated the pharmacokinetics and tolerability of fuzuloparib by fluconazole, which is a broad antifungal agent and a moderate inhibitor of CYP3A4. METHODS: In this study, the effects of CYP3A4 inhibition on the pharmacokinetics of fuzuloparib were assessed in a total of 20 healthy Chinese male subjects in an open-label, two-period, single-sequence, crossover study. RESULTS: Pharmacokinetic parameters, including the maximal plasma concentration (Cmax), the plasma concentration-time curve from time 0 to last measurable area under concentration (AUC0-t), and from time 0 to infinity (AUC0-∞), were increased by 32.4%, 104.5%, and 109.6%, with corresponding 90% confidence intervals of (23-43%), (93-116%), and (98-122%), respectively, when fluconazole was combined with fuzuloparib compared to fuzuloparib alone. There was also a slight increase in the incidence of treatment emergent adverse events, including hyperlipidemia and elevated aspartate transaminase. CONCLUSION: The fuzuloparib is 150 mg b.i.d in clinics use. Our results suggest that fuzuloparib could well be tolerated when administered as a single 20 mg oral dose alone or co-administered with 400 mg fluconazole in healthy male subjects. It is recommended to avoid using moderate CYP3A4 inhibitors together with fuzuloparib or instead of 50 mg when necessary.
Asunto(s)
Fluconazol , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Adulto , Humanos , Masculino , Persona de Mediana Edad , Estudios Cruzados , Inhibidores del Citocromo P-450 CYP3A/efectos adversos , Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Fluconazol/efectos adversos , Fluconazol/farmacocinética , Voluntarios Sanos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacocinéticaRESUMEN
Poly (ADPribose) polymerase (PARP) inhibitors, including olaparib, niraparib, rucaparib, talazoparib and veliparib, have emerged as one of the most exciting new treatments for solid tumors, particularly in patients with breastrelated cancer antigen 1/2 mutations. Oral administration is convenient and shows favorable compliance with the majority of patients, but it may be affected by numerous factors, including food, metabolic enzymes and transporters. These interactions may be associated with serious adverse drug reactions or may reduce the treatment efficacy of PARP inhibitors. In fact, numerous pharmacokinetic (PK)based drugdrug interactions (DDIs) involve the metabolism of PARP inhibitors, particularly those metabolized via cytochrome P450 enzymes. The present review aims to characterize and summarize the metabolismrelated PKbased DDIs of PARP inhibitors, and to provide specific recommendations for reducing the risk of clinically significant DDIs.
Asunto(s)
Interacciones Farmacológicas , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacocinética , HumanosRESUMEN
PURPOSE: Veliparib (V), an oral poly(ADP-ribose) polymerase (PARP) inhibitor, potentiates effects of alkylating agents and topoisomerase inhibitors in preclinical tumor models. We conducted a phase I trial of V with iv cyclophosphamide (C) and V plus iv doxorubicin (A) and C. METHODS: Objectives were to establish the maximum tolerated dose (MTD) of the combinations, characterize V pharmacokinetics (PK) in the presence and absence of C, measure PAR in peripheral blood mononuclear cells (PBMCs) and γH2AX in circulating tumor cells (CTCs). In Group 1, dose escalations of V from 10 to 50 mg every 12 h Days 1-4 plus C 450 to 750 mg/m2 Day 3 in 21-day cycles were evaluated. In Group 2, V doses ranged from 50 to 150 mg every 12 h Days 1-4 with AC (60/600 mg/m2) Day 3 in 21-day cycles. In Group 3, patients received AC Day 1 plus V Days 1-7, and in Group 4, AC Day 1 plus V Days 1-14 was given in 21-day cycles to evaluate effects on γH2AX foci. RESULTS: Eighty patients were enrolled. MTD was not reached for V and C. MTD for V and AC was V 100 mg every 12 h Days 1-4 with AC (60/600 mg/m2) Day 3 every 21 days. V PK appears to be dose-dependent and has no effect on the PK of C. Overall, neutropenia and anemia were the most common adverse events. Objective response in V and AC treated groups was 22% (11/49). Overall clinical benefit rate was 31% (25/80). PAR decreased in PBMCs. Percentage of γH2AX-positive CTCs increased after treatment with V and AC. CONCLUSION: V and AC can be safely combined. Activity was observed in patients with metastatic breast cancer.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bencimidazoles/farmacocinética , Ciclofosfamida/farmacocinética , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bencimidazoles/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Ciclofosfamida/administración & dosificación , Ciclofosfamida/sangre , Doxorrubicina/administración & dosificación , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/patología , Poli Adenosina Difosfato Ribosa/sangre , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacocinética , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéuticoRESUMEN
Niraparib (Zejula), a selective oral PARP1/2 inhibitor registered for ovarian, fallopian tube, and primary peritoneal cancer treatment, is under investigation for other malignancies, including brain tumors. We explored the impact of the ABCB1 and ABCG2 multidrug efflux transporters, the OATP1A/1B uptake transporters, and the CYP3A drug-metabolizing complex on oral niraparib pharmacokinetics, using wild-type and genetically modified mouse and cell line models. In vitro, human ABCB1 and mouse Abcg2 transported niraparib moderately. Compared to wild-type mice, niraparib brain-to-plasma ratios were 6- to 7-fold increased in Abcb1a/1b-/- and Abcb1a/1b;Abcg2-/- but not in single Abcg2-/- mice, while niraparib plasma exposure at later time points was â¼2-fold increased. Niraparib recovery in the small intestinal content was markedly reduced in the Abcb1a/1b-deficient strains. Pretreatment of wild-type mice with oral elacridar, an ABCB1/ABCG2 inhibitor, increased niraparib brain concentration and reduced small intestinal content recovery to levels observed in Abcb1a/1b;Abcg2-/- mice. Oatp1a/1b deletion did not significantly affect niraparib oral bioavailability or liver distribution but decreased metabolite M1 liver uptake. No significant effects of mouse Cyp3a ablation were observed, but overexpression of transgenic human CYP3A4 unexpectedly increased niraparib plasma exposure. Thus, Abcb1 deficiency markedly increased niraparib brain distribution and reduced its small intestinal content recovery, presumably through reduced biliary excretion and/or decreased direct intestinal excretion. Elacridar pretreatment inhibited both processes completely. Clinically, the negligible role of OATP1 and CYP3A could be advantageous for niraparib, diminishing drug-drug interaction or interindividual variation risks involving these proteins. These findings may support the further clinical development and application of niraparib.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/fisiología , Encéfalo/metabolismo , Indazoles/farmacocinética , Intestinos/metabolismo , Piperidinas/farmacocinética , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacocinética , Acridinas/farmacología , Animales , Transporte Biológico , Citocromo P-450 CYP3A/fisiología , Perros , Células de Riñón Canino Madin Darby , Ratones , Tetrahidroisoquinolinas/farmacología , Distribución TisularRESUMEN
Poly (ADP-ribose) polymerase-1 (PARP-1) is a potential target for the discovery of chemosensitizers and anticancer drugs. Amentoflavone (AMF) is reported to be a selective PARP-1 inhibitor. Here, structural modifications and trimming of AMF have led to a series of AMF derivatives (9a-h) and apigenin-piperazine/piperidine hybrids (14a-p, 15a-p, 17a-h, and 19a-f), respectively. Among these compounds, 15l exhibited a potent PARP-1 inhibitory effect (IC50 = 14.7 nM) and possessed high selectivity to PARP-1 over PARP-2 (61.2-fold). Molecular dynamics simulation and the cellular thermal shift assay revealed that 15l directly bound to the PARP-1 structure. In in vitro and in vivo studies, 15l showed a potent chemotherapy sensitizing effect against A549 cells and a selective cytotoxic effect toward SK-OV-3 cells through PARP-1 inhibition. 15l·2HCl also displayed good ADME characteristics, pharmacokinetic parameters, and a desirable safety margin. These findings demonstrated that 15l·2HCl may serve as a lead compound for chemosensitizers and the (BRCA-1)-deficient cancer therapy.
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Antineoplásicos/uso terapéutico , Flavonas/uso terapéutico , Neoplasias/tratamiento farmacológico , Piperazinas/uso terapéutico , Poli(ADP-Ribosa) Polimerasa-1/antagonistas & inhibidores , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Descubrimiento de Drogas , Femenino , Flavonas/síntesis química , Flavonas/metabolismo , Flavonas/farmacocinética , Humanos , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Estructura Molecular , Piperazinas/síntesis química , Piperazinas/metabolismo , Piperazinas/farmacocinética , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Inhibidores de Poli(ADP-Ribosa) Polimerasas/síntesis química , Inhibidores de Poli(ADP-Ribosa) Polimerasas/metabolismo , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacocinética , Unión Proteica , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Pamiparib (PARTRUVIX™; BeiGene Ltd.) is a selective poly (ADP-ribose) polymerase 1 and 2 (PARP1 and PARP2) inhibitor being developed for the treatment of various cancers. Based on the results from the pivotal phase II portion of a phase I/II trial (NCT03333915) pamiparib was recently approved in China for the treatment of germline BRCA mutation-associated recurrent advanced ovarian, fallopian tube or primary peritoneal cancer previously treated with two or more lines of chemotherapy. This article summarizes the milestones in the development of pamiparib leading to this first approval.
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Fluorenos/farmacología , Fluorenos/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Peritoneales/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Área Bajo la Curva , China , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Aprobación de Drogas , Femenino , Fluorenos/efectos adversos , Fluorenos/farmacocinética , Semivida , Humanos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacocinéticaRESUMEN
BACKGROUND: Talazoparib is a poly(ADP-ribose) polymerase enzyme inhibitor. This open-label, non-randomized, phase 1 study of talazoparib investigated the safety, pharmacokinetics, and preliminary antitumor activity in Japanese patients with locally advanced or metastatic solid tumors, regardless of mutations in DNA damage repair-related genes, who are resistant to/ineligible for standard therapies. METHODS: Patients received talazoparib dosed orally at 0.75 or 1 mg once daily using a modified 3 + 3 dose-escalation scheme. Primary endpoint was dose-limiting toxicities during the first cycle of talazoparib. RESULTS: Nine patients (median age 62.0 years) were included: 3 and 6 patients at the 0.75 and 1.0 mg once-daily dose levels, respectively. No dose-limiting toxicities were reported. The most commonly reported treatment-emergent adverse events (≥2 patients) were anemia, stomatitis, maculopapular rash, platelet count decreased, neutrophil count decreased, and alanine aminotransferase increased. Three patients had grade ≥ 3 treatment-emergent adverse events (anemia, brain metastases [1 patient each], and neutrophil and white blood cell count decreased [same patient]). Two patients temporarily discontinued treatment due to a treatment-emergent adverse event, and 1 patient required a dose reduction for neutrophil count decreased (all at 1 mg once daily). Talazoparib exposure (Cmax and AUC) after single and multiple dosing was slightly higher proportionally with talazoparib 1 mg than talazoparib 0.75 mg. The overall disease control rate was 44.4%, including 2 patients with stable disease. The recommended phase 2 dose of talazoparib was established as 1 mg once daily. CONCLUSIONS: Single-agent talazoparib was well tolerated and had preliminary antitumor activity in Japanese patients with advanced solid tumors. ClinicalTrials.gov identifier: NCT03343054 (November 17, 2017).
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Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Ftalazinas/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Pueblo Asiatico , Relación Dosis-Respuesta a Droga , Humanos , Japón , Dosis Máxima Tolerada , Persona de Mediana Edad , Clasificación del Tumor , Metástasis de la Neoplasia , Neoplasias/patología , Ftalazinas/administración & dosificación , Ftalazinas/efectos adversos , Ftalazinas/farmacocinética , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacocinéticaRESUMEN
In this work, two series of cyclic amine-containing benzimidazole carboxamide derivatives were designed and synthesized as potent anticancer agents. PARP1/2 inhibitory activity assays indicated that most of the compounds showed significant activity. The in vitro antiproliferative activity of these compounds was investigated against four human cancer cell lines (MDA-MB-436, MDA-MB-231, MCF-7 and CAPAN-1), and several compounds exhibited strong cytotoxicity to tumor cells. Among them, 2-(1-(4,4-difluorocyclohexyl)piperidin-4-yl)-1H-benzo[d]imidazole-4-carboxamide (17d) was found to be effective PARP1/2 inhibitors (IC50 = 4.30 and 1.58 nM, respectively). In addition, 17d possessed obvious selective antineoplastic activity and noteworthy microsomal metabolic stability. What's more, further studies revealed that 17d was endowed with an excellent ADME profile. These combined results indicated that 17d could be a promising candidate for the treatment of cancer.
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Antineoplásicos/farmacología , Bencimidazoles/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Bencimidazoles/síntesis química , Bencimidazoles/metabolismo , Bencimidazoles/farmacocinética , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Masculino , Microsomas Hepáticos/metabolismo , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Inhibidores de Poli(ADP-Ribosa) Polimerasas/síntesis química , Inhibidores de Poli(ADP-Ribosa) Polimerasas/metabolismo , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacocinética , Poli(ADP-Ribosa) Polimerasas/metabolismo , Ratas Sprague-DawleyRESUMEN
PURPOSE: The poly(ADP-ribose) polymerase inhibitor rucaparib is approved for the treatment of patients with recurrent ovarian and metastatic castration-resistant prostate cancer; however, limited data are available on its use in patients with hepatic dysfunction. This study investigated whether hepatic impairment affects the pharmacokinetics, safety, and tolerability of rucaparib in patients with advanced solid tumors. METHODS: Patients with normal hepatic function or moderate hepatic impairment according to the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria were enrolled and received a single oral dose of rucaparib 600 mg. Concentrations of rucaparib and its metabolite M324 in plasma and urine were measured. Pharmacokinetic parameters were compared between hepatic function groups, and safety and tolerability were assessed. RESULTS: Sixteen patients were enrolled (n = 8 per group). Rucaparib maximum concentration (Cmax) was similar, while the area under the concentration-time curve from time 0 to infinity (AUC0-inf) was mildly higher in the moderate hepatic impairment group than in the normal control group (geometric mean ratio, 1.446 [90% CI 0.668-3.131]); similar trends were observed for M324. Eight (50%) patients experienced ≥ 1 treatment-emergent adverse event (TEAE); 2 had normal hepatic function and 6 had moderate hepatic impairment. CONCLUSION: Patients with moderate hepatic impairment showed mildly increased AUC0-inf for rucaparib compared to patients with normal hepatic function. Although more patients with moderate hepatic impairment experienced TEAEs, only 2 TEAEs were considered treatment related. These results suggest no starting dose adjustment is necessary for patients with moderate hepatic impairment; however, close safety monitoring is warranted.
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Indoles/farmacocinética , Indoles/uso terapéutico , Hepatopatías/etiología , Neoplasias/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacocinética , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Adulto , Anciano , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Área Bajo la Curva , Femenino , Humanos , Hígado/efectos de los fármacos , Pruebas de Función Hepática/métodos , Masculino , Persona de Mediana Edad , Neoplasias/metabolismoRESUMEN
Veliparib (ABT-888) is a poly(ADP-ribose) polymerase inhibitor in development for the treatment of high-grade ovarian cancer or BRCA-mutated breast cancer in combination with carboplatin and paclitaxel. The population pharmacokinetics of veliparib were characterized using combined data from 1470 adult subjects with ovarian cancer, breast cancer, or other solid tumors enrolled in 6 phase 1 studies, 1 phase 2 study, and 2 phase 3 studies of veliparib oral doses of 10 to 400 mg twice daily as monotherapy or in combination with chemotherapy. A 1-compartment model with linear clearance and first-order absorption best characterized veliparib pharmacokinetics. The predicted apparent oral clearance (CL/F) and volume of distribution (Vc /F) were 479 L/day and 152 L, respectively. The significant covariates in the final model included albumin, creatinine clearance, strong inhibitors of cytochrome P450 (CYP) 2D6, and sex on CL/F and albumin, body weight, and sex on Vc /F. Mild and moderate renal impairment increased veliparib median (95%CI) steady-state AUC (AUCss ) by 27.3% (23.7%-30.9%) and 65.4% (56.0%-75.5%), respectively, compared with normal renal function. Male subjects had 16.5% (7.53%-23.9%) lower AUCss compared with female subjects and coadministration with strong CYP2D6 inhibitors increased AUCss by 13.0% (6.11%-20.8%). Race, age, region, cancer type, or enzyme (CYP3A4, CYP2C19) or transporter (P-glycoprotein, multidrug and toxin extrusion protein 1/2, organic cation transporter 2) inhibiting/inducing comedications were not found to significantly impact veliparib pharmacokinetics. Other than baseline creatinine clearance and hence renal impairment effect on veliparib clearance, no other covariates had a clinically meaningful effect on veliparib exposure warranting dose adjustment.
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Bencimidazoles/farmacocinética , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica , Área Bajo la Curva , Bencimidazoles/uso terapéutico , Peso Corporal , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Creatinina/sangre , Inhibidores del Citocromo P-450 CYP2D6/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Proteínas de Transporte de Membrana/agonistas , Tasa de Depuración Metabólica , Modelos Biológicos , Neoplasias/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Albúmina Sérica/análisis , Factores SexualesRESUMEN
Pamiparib, a selective poly (ADP-ribose) polymerase 1/2 inhibitor, demonstrated tolerability and antitumor activity in patients with solid tumors at 60 mg orally twice daily. This phase 1 open-label study (NCT03991494; BGB-290-106) investigated the absorption, metabolism, and excretion (AME) of 60 mg [14 C]-pamiparib in 4 patients with solid tumors. The mass balance in excreta, blood, and plasma radioactivity and plasma pamiparib concentration were determined along with metabolite profiles in plasma, urine, and feces. Unchanged pamiparib accounted for the most plasma radioactivity (67.2% ± 10.2%). Pamiparib was rapidly absorbed with a median time to maximum plasma concentration (Cmax ) of 2.00 hours (range, 1.00-3.05 hours). After reaching Cmax , pamiparib declined in a biphasic manner, with a geometric mean terminal half-life (t1/2 ) of 28.7 hours. Mean cumulative [14 C]-pamiparib excretion was 84.7% ± 3.5%. Pamiparib was mainly cleared through metabolism, primarily via N-oxidation and oxidation of the pyrrolidine ring. A dehydrogenated oxidative product (M3) was the most abundant metabolite in biosamples. A mean of 2.11% and 1.11% of [14 C]-pamiparib was excreted as unchanged pamiparib in feces and urine, respectively, indicating near-complete absorption and low renal clearance of parent drug. Cytochrome P450 (CYP) phenotyping demonstrated CYP2C8 and CYP3A involvement in pamiparib metabolism. These findings provide an understanding of pamiparib AME mechanisms and potential drug-drug interaction liability.
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Fluorenos/farmacocinética , Neoplasias/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacocinética , Citocromo P-450 CYP2C8/metabolismo , Citocromo P-450 CYP3A/metabolismo , Femenino , Fluorenos/administración & dosificación , Semivida , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificaciónRESUMEN
PURPOSE: Pamiparib is an investigational, selective, oral poly(ADP-ribose) polymerase 1/2 (PARP1/2) inhibitor that has demonstrated PARP-DNA complex trapping and CNS penetration in preclinical models, as well as preliminary anti-tumor activity in early-phase clinical studies. We investigated whether the single-dose pharmacokinetic (PK) profile of pamiparib is altered by coadministration of a strong CYP3A inducer (rifampin) or a strong CYP3A inhibitor (itraconazole) in patients with solid tumors. METHODS: In this open-label, phase 1 study, adults with advanced solid tumors received either oral pamiparib 60 mg (days 1 and 10) and once-daily oral rifampin 600 mg (days 3-11) or oral pamiparib 20 mg (days 1 and 7) and once-daily oral itraconazole 200 mg (days 3-8). Primary endpoints included pamiparib maximum observed concentration (Cmax), and area under the plasma concentration-time curve from zero to last quantifiable concentration (AUC0-tlast) and infinity (AUC0-inf). Secondary endpoints included safety and tolerability. RESULTS: Rifampin coadministration did not affect pamiparib Cmax (geometric least-squares [GLS] mean ratio 0.94; 90% confidence interval 0.83-1.06), but reduced its AUC0-tlast (0.62 [0.54-0.70]) and AUC0-inf (0.57 [0.48-0.69]). Itraconazole coadministration did not affect pamiparib Cmax (1.05 [0.95-1.15]), AUC0-tlast (0.99 [0.91-1.09]), or AUC0-inf (0.99 [0.90-1.09]). There were no serious treatment-related adverse events. CONCLUSIONS: Pamiparib plasma exposure was reduced 38-43% with rifampin coadministration but was unaffected by itraconazole coadministration. Pamiparib dose modifications are not considered necessary when coadministered with CYP3A inhibitors. Clinical safety and efficacy data will be used with these results to recommend dose modifications when pamiparib is coadministered with CYP3A inducers.