RESUMO
This open-label, phase 1/1b study was conducted to evaluate the safety, tolerability, and pharmacokinetics (PK) of fruquintinib in United States (U.S.) patients to confirm the recommended phase 2 dose (RP2D) established in China. Patients with advanced solid tumors who had progressed on approved systemic therapy, were enrolled into 2 successive dose escalation cohorts, fruquintinib 3 mg (n = 7) or 5 mg (n = 7), orally, once daily (QD), 3 weeks on and 1 week off (3/1) with a 3 + 3 design followed by a dose expansion cohort at the RP2D 5 mg dose (n = 6). PK samples were collected on Days 1, 14, and 21 (Cycle 1). One of 6 dose-limiting toxicity (DLT)-evaluable patients in the 3 mg cohort had a DLT of grade 4 hypertension; there were no DLTs in the 5 mg cohort. The RP2D was confirmed to be 5 mg QD 3/1. All 20 patients experienced a treatment-emergent adverse event; grade ≥ 3 in 5 (71.4%; 3 mg dose) and 12 (92.3%; 5 mg dose) patients. Two patients had a confirmed partial response. After single and multiple doses, median peak plasma concentrations occurred at 2 h post-dose. Steady-state was achieved after 14 days of QD dosing with systemic exposure four-fold higher than that after a single dose. Fruquintinib was well tolerated, and the safety and PK profile at the 5 mg RP2D in U.S. patients with advanced solid tumors was consistent with dose-finding studies in China. Preliminary anticancer activity was observed. This study is registered at Clinicaltrials.gov NCT03251378.
Assuntos
Antineoplásicos , Benzofuranos , Neoplasias , Humanos , Antineoplásicos/efeitos adversos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Quinazolinas/efeitos adversos , Benzofuranos/efeitos adversos , Dose Máxima TolerávelRESUMO
Surufatinib, is a potent inhibitor of vascular endothelial growth factor receptors 1-3; fibroblast growth factor receptor-1; colony-stimulating factor 1 receptor. This Phase 1/1b escalation/expansion study in US patients with solid tumors evaluated 5 once daily (QD) surufatinib doses (3 + 3 design) to identify maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), and evaluate safety and efficacy at the RP2D in 4 disease-specific expansion cohorts including pancreatic neuroendocrine tumors [pNET] and extrapancreatic NETs [epNET]. MTD and RP2D were 300 mg QD (escalation [n = 35]); 5 patients (15.6%) (Dose Limiting Toxicity [DLT] Evaluable Set [n = 32]) had DLTs. Pharmacokinetics were dose proportional. Estimated progression-free survival (PFS) rates at 11 months were 57.4% (95% confidence interval [CI]: 28.7, 78.2) and 51.1% (95% CI: 12.8, 80.3) for pNET and epNET expansion cohorts, respectively. Median PFS was 15.2 (95% CI: 5.2, not evaluable) and 11.5 (95% CI: 6.5,11.5) months. Response rates were 18.8% and 6.3%. The most frequent treatment-emergent adverse events (both cohorts) were fatigue (46.9%), hypertension (43.8%), proteinuria (37.5%), diarrhea (34.4%). Pharmacokinetics, safety, and antitumor efficacy of 300 mg QD oral surufatinib in US patients with pNETs and epNETs are consistent with previously reported studies in China and may support applicability of earlier surufatinib studies in US patients. Clinical trial registration: Clinicaltrials.gov NCT02549937.
Assuntos
Neoplasias , Tumores Neuroectodérmicos Primitivos , Tumores Neuroendócrinos , Humanos , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/patologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular , Fator A de Crescimento do Endotélio Vascular , Neoplasias/patologia , Inibidores de Proteínas Quinases/efeitos adversos , Tumores Neuroectodérmicos Primitivos/induzido quimicamente , Dose Máxima TolerávelRESUMO
Fruquintinib, a novel, highly selective, small-molecule tyrosine kinase inhibitor of VEGF receptors (VEGFRs)-1, -2 and -3, is approved in China for the treatment of metastatic colorectal cancer. FRESCO-2, a global, randomized, double-blind, placebo-controlled, Phase III study, is investigating the efficacy and safety of fruquintinib in patients with refractory metastatic colorectal cancer. Key inclusion criteria include: progression on or intolerance to TAS-102 and/or regorafenib; and prior treatment with approved chemotherapy, anti-VEGF therapy, and, if RAS wild-type, anti-EGFR therapy. Approximately 687 patients will be randomized 2:1 to fruquintinib plus best supportive care or placebo plus best supportive care. Primary and key secondary end points are overall survival and progression-free survival, respectively. FRESCO-2 is enrolling in the USA, Europe, Australia and Japan.
Lay abstract Fruquintinib is a drug that slows down, reduces or prevents the growth of vessels that supply blood to certain tumors. Fruquintinib is approved in China for the treatment of cancer of the colon and rectum that has spread to these parts of the body from the primary site of cancer: metastatic colorectal cancer. The FRESCO-2 study is being conducted globally to determine how safe and effective fruquintinib is at treating patients with metastatic colorectal cancer that has grown or spread following other forms of treatment, such as chemotherapy. About 687 patients will be enrolled globally to receive either fruquintinib or a matching placebo in a 2:1 ratio, respectively. The FRESCO-2 study is enrolling patients in the USA, Europe, Australia and Japan. Clinical trial registration: NCT04322539 (ClinicalTrials.gov).
Assuntos
Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Benzofuranos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/uso terapêutico , Método Duplo-Cego , HumanosRESUMO
In this phase 1 study, the absolute bioavailability and absorption, metabolism, and excretion (AME) of apalutamide, a competitive inhibitor of the androgen receptor, were evaluated in 12 healthy men. Subjects received 240 mg of apalutamide orally plus a 15-minute intravenous infusion of 100 µg of apalutamide containing 9.25 kBq (250 nCi) of 14C-apalutamide (2 hours postdose) for absolute bioavailability assessment or plus one 400-µg capsule containing 37 kBq (1000 nCi) of 14C-apalutamide for AME assessment. Content of 14C and metabolite profiling for whole blood, plasma, urine, feces, and expired air samples were analyzed using accelerator mass spectrometry. Apalutamide absolute oral bioavailability was ≈100%. After oral administration, apalutamide, its N-desmethyl metabolite (M3), and an inactive carboxylic acid metabolite (M4) accounted for most 14C in plasma (45%, 44%, and 3%, respectively). Apalutamide elimination was slow, with a mean plasma half-life of 151-178 hours. The mean cumulative recovery of total 14C over 70 days postdose was 64.6% in urine and 24.3% in feces. The urinary excretion of apalutamide, M3, and M4 was 1.2%, 2.7%, and 31.1% of dose, respectively. Fecal excretion of apalutamide, M3, and M4 was 1.5%, 2.0%, and 2.4% of dose, respectively. Seventeen apalutamide metabolites and six main metabolic clearance pathways were identified. In vitro studies confirmed CYP2C8 and CYP3A4 roles in apalutamide metabolism.
Assuntos
Hepatócitos/metabolismo , Tioidantoínas/metabolismo , Idoso , Idoso de 80 Anos ou mais , Disponibilidade Biológica , Líquidos Corporais/metabolismo , Radioisótopos de Carbono/metabolismo , Citocromo P-450 CYP2C8/metabolismo , Citocromo P-450 CYP3A/metabolismo , Fezes/química , Meia-Vida , Humanos , Infusões Intravenosas/métodos , Masculino , Taxa de Depuração Metabólica/fisiologia , Pessoa de Meia-IdadeRESUMO
Abiraterone acetate, the prodrug of the cytochrome P450 C17 inhibitor abiraterone, plus prednisone is approved for treatment of metastatic castration-resistant prostate cancer. We explored whether abiraterone interacts with drugs metabolized by CYP2C8, an enzyme responsible for the metabolism of many drugs. Abiraterone acetate and abiraterone and its major metabolites, abiraterone sulfate and abiraterone sulfate N-oxide, inhibited CYP2C8 in human liver microsomes, with IC50 values near or below the peak total concentrations observed in patients with metastatic castration-resistant prostate cancer (IC50 values: 1.3-3.0 µM, 1.6-2.9 µM, 0.044-0.15 µM, and 5.4-5.9 µM, respectively). CYP2C8 inhibition was reversible and time-independent. To explore the clinical relevance of the in vitro data, an open-label, single-center study was conducted comprising 16 healthy male subjects who received a single 15-mg dose of the CYP2C8 substrate pioglitazone on day 1 and again 1 hour after the administration of abiraterone acetate 1000 mg on day 8. Plasma concentrations of pioglitazone, its active M-III (keto derivative) and M-IV (hydroxyl derivative) metabolites, and abiraterone were determined for up to 72 hours after each dose. Abiraterone acetate increased exposure to pioglitazone; the geometric mean ratio (day 8/day 1) was 125 [90% confidence interval (CI), 99.9-156] for Cmax and 146 (90% CI, 126-171) for AUClast Exposure to M-III and M-IV was reduced by 10% to 13%. Plasma abiraterone concentrations were consistent with previous studies. These results show that abiraterone only weakly inhibits CYP2C8 in vivo.
Assuntos
Acetato de Abiraterona/metabolismo , Citocromo P-450 CYP2C8/efeitos dos fármacos , Inibidores das Enzimas do Citocromo P-450/metabolismo , Humanos , Técnicas In Vitro , Microssomos Hepáticos/enzimologiaRESUMO
The worldwide prevalence of chronic hepatitis C virus (HCV) infection is estimated to be approaching 200 million people. Current therapy relies upon a combination of pegylated interferon-alpha and ribavirin, a poorly tolerated regimen typically associated with less than 50% sustained virological response rate in those infected with genotype 1 virus. The development of direct-acting antiviral agents to treat HCV has focused predominantly on inhibitors of the viral enzymes NS3 protease and the RNA-dependent RNA polymerase NS5B. Here we describe the profile of BMS-790052, a small molecule inhibitor of the HCV NS5A protein that exhibits picomolar half-maximum effective concentrations (EC(50)) towards replicons expressing a broad range of HCV genotypes and the JFH-1 genotype 2a infectious virus in cell culture. In a phase I clinical trial in patients chronically infected with HCV, administration of a single 100-mg dose of BMS-790052 was associated with a 3.3 log(10) reduction in mean viral load measured 24 h post-dose that was sustained for an additional 120 h in two patients infected with genotype 1b virus. Genotypic analysis of samples taken at baseline, 24 and 144 h post-dose revealed that the major HCV variants observed had substitutions at amino-acid positions identified using the in vitro replicon system. These results provide the first clinical validation of an inhibitor of HCV NS5A, a protein with no known enzymatic function, as an approach to the suppression of virus replication that offers potential as part of a therapeutic regimen based on combinations of HCV inhibitors.
Assuntos
Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Imidazóis/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Adolescente , Adulto , Animais , Antivirais/sangue , Antivirais/química , Antivirais/uso terapêutico , Carbamatos , Linhagem Celular , Chlorocebus aethiops , Farmacorresistência Viral , Feminino , Genótipo , Células HeLa , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Humanos , Imidazóis/sangue , Imidazóis/química , Concentração Inibidora 50 , Masculino , Pessoa de Meia-Idade , Pirrolidinas , Fatores de Tempo , Valina/análogos & derivados , Células Vero , Carga Viral/efeitos dos fármacos , Adulto JovemRESUMO
BACKGROUND: BMS-663068 is a prodrug of the small-molecule inhibitor BMS-626529, which inhibits human immunodeficiency virus type 1 (HIV-1) infection by binding to gp120 and interfering with the attachment of virus to CD4+ T-cells. METHODS: Fifty HIV-1-infected subjects were randomized to 1 of 5 regimen groups (600 mg BMS-663068 plus 100 mg ritonavir every 12 hours [Q12H], 1200 mg BMS-663068 plus 100 mg ritonavir every bedtime, 1200 mg BMS-663068 plus 100 mg ritonavir Q12H, 1200 mg BMS-663068 Q12H plus 100 mg ritonavir every morning, or 1200 mg BMS-663068 Q12H) for 8 days in this open-label, multiple-dose, parallel study. The study assessed the pharmacodynamics, pharmacokinetics, and safety of BMS-663068. RESULTS: The maximum median decrease in plasma HIV-1 RNA load from baseline ranged from 1.21 to 1.73 log(10) copies/mL. Plasma concentrations of BMS-626529 were not associated with an antiviral response, while low baseline inhibitory concentrations and the minimum and average steady-state BMS-626529 plasma concentrations, when adjusted by the baseline protein binding-adjusted 90% inhibitory concentration (inhibitory quotient), were linked with antiviral response. BMS-663068 was generally well tolerated. CONCLUSIONS: Administration of BMS-663068 for 8 days with or without ritonavir resulted in substantial declines in plasma HIV-1 RNA levels and was generally well tolerated. Longer-term clinical trials of BMS-663068 as part of combination antiretroviral therapy are warranted. Clinical Trials Registration.NCT01009814.
Assuntos
Inibidores da Fusão de HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Organofosfatos/uso terapêutico , Piperazinas/uso terapêutico , Adulto , Idoso , Área Sob a Curva , Quimioterapia Combinada , Feminino , Inibidores da Fusão de HIV/efeitos adversos , Inibidores da Fusão de HIV/farmacocinética , Infecções por HIV/sangue , Infecções por HIV/virologia , Inibidores da Protease de HIV/uso terapêutico , HIV-1/genética , Humanos , Concentração Inibidora 50 , Masculino , Pessoa de Meia-Idade , Organofosfatos/efeitos adversos , Organofosfatos/farmacocinética , Piperazinas/efeitos adversos , Piperazinas/farmacocinética , RNA Viral/sangue , Ritonavir/uso terapêutico , Resultado do Tratamento , Carga Viral/efeitos dos fármacos , Adulto JovemRESUMO
PURPOSE: Apalutamide plus androgen-deprivation therapy (ADT) has been approved for treatment of patients with metastatic castration-sensitive prostate cancer (mCSPC) based on data from phase 3 TITAN study. This analysis was conducted to describe pharmacokinetics of apalutamide and N-desmethyl-apalutamide and explore relationships between apalutamide exposure and selected clinical efficacy and safety observations. METHODS: 1052 patients were randomized to apalutamide + ADT (n = 525) or placebo + ADT (n = 527). A previously developed population pharmacokinetic model was applied. Cox regression analysis investigated the relationships between apalutamide exposure and overall survival (OS; n = 1004) and radiographic progression-free survival (rPFS; n = 1003). Logistic regression analysis assessed the relationships between apalutamide exposure and selected clinically relevant adverse events (n = 1051). RESULTS: Apalutamide + ADT treatment was efficacious in extending rPFS and OS versus placebo + ADT. Within a relatively narrow apalutamide exposure range (coefficient of variation: 22%), no statistical association was detected between rPFS, OS and apalutamide exposure quartiles. Incidence of skin rash and pruritus increased significantly with increasing apalutamide exposure. CONCLUSIONS: Differences in apalutamide exposure were not associated with clinically relevant differences in rPFS or OS in patients with mCSPC. Patients with increased apalutamide exposure are more likely to develop skin rash and pruritus. Dose reductions may improve these adverse events, based on an individual risk-benefit approach.
Assuntos
Exantema , Neoplasias de Próstata Resistentes à Castração , Antagonistas de Androgênios/efeitos adversos , Castração , Exantema/induzido quimicamente , Humanos , Masculino , Prurido/induzido quimicamente , TioidantoínasRESUMO
BACKGROUND AND OBJECTIVES: Two phase I studies assessed the drug-drug interaction potential of apalutamide as a substrate and perpetrator. METHODS: Study A randomized 45 healthy men to single-dose apalutamide 240 mg alone or with strong inhibitors of cytochrome P450 (CYP)3A4 (itraconazole) or CYP2C8 (gemfibrozil). In study B, 23 patients with castration-resistant prostate cancer received probes for CYP3A4 (midazolam), CYP2C9 (warfarin), CYP2C19 (omeprazole), and CYP2C8 (pioglitazone), and transporter substrates for P-glycoprotein (P-gp) (fexofenadine) and breast cancer resistance protein (BCRP)/organic anion transporting polypeptide (OATP) 1B1 (rosuvastatin) at baseline and after repeat once-daily administration of apalutamide 240 mg to steady state. RESULTS: Systemic exposure (area under the plasma concentration-time curve) to single-dose apalutamide increased 68% with gemfibrozil but was relatively unchanged with itraconazole (study A). Apalutamide reduced systemic exposure to midazolam ↓92%, omeprazole ↓85%, S-warfarin ↓46%, fexofenadine ↓30%, rosuvastatin ↓41%, and pioglitazone ↓18% (study B). After a single dose, apalutamide is predominantly metabolized by CYP2C8, and less by CYP3A4. CONCLUSIONS: Co-administration of apalutamide with CYP3A4, CYP2C19, CYP2C9, P-gp, BCRP or OATP1B1 substrates may cause loss of activity for these medications. Therefore, appropriate mitigation strategies are recommended.
Assuntos
Inibidores das Enzimas do Citocromo P-450/farmacocinética , Neoplasias de Próstata Resistentes à Castração , Tioidantoínas/farmacocinética , Interações Medicamentosas , Humanos , Masculino , Proteínas de Neoplasias , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológicoRESUMO
BACKGROUND: Apalutamide is predominantly metabolized via cytochrome P450 (CYP) 2C8 and CYP3A4, whose contributions change due to autoinduction with repeated dosing. OBJECTIVES: We aimed to predict CYP3A4 and CYP2C8 inhibitor/inducer effects on the steady-state pharmacokinetics of apalutamide and total potency-adjusted pharmacologically active moieties, and simulated drug-drug interaction (DDI) between single-dose and repeated-dose apalutamide coadministered with known inhibitors/inducers. METHODS: We applied physiologically based pharmacokinetic modeling for our predictions, and simulated DDI between single-dose and repeated-dose apalutamide 240 mg coadministered with ketoconazole, gemfibrozil, or rifampicin. RESULTS: The estimated contribution of CYP2C8 and CYP3A4 to apalutamide metabolism is 58% and 13%, respectively, after single dosing, and 40% and 37%, respectively, at steady-state. Apalutamide exposure is predicted to increase with ketoconazole (maximum observed concentration at steady-state [Cmax,ss] 38%, area under the plasma concentration-time curve at steady-state [AUCss] 51% [pharmacologically active moieties, Cmax,ss 23%, AUCss 28%]) and gemfibrozil (Cmax,ss 32%, AUCss 44% [pharmacologically active moieties, Cmax,ss 19%, AUCss 23%]). Rifampicin exposure is predicted to decrease apalutamide (Cmax,ss 25%, AUCss 34% [pharmacologically active moieties, Cmax,ss 15%, AUCss 19%]). CONCLUSIONS: Based on our simulations, no major changes in the pharmacokinetics of apalutamide or pharmacologically active moieties are expected with strong CYP3A4/CYP2C8 inhibitors/inducers. This observation supports the existing recommendations that no dose adjustments are needed during coadministration of apalutamide and the known inhibitors or inducers of CYP2C8 or CYP3A4.
Assuntos
Antagonistas de Receptores de Andrógenos/farmacocinética , Indutores do Citocromo P-450 CYP2C8 , Inibidores do Citocromo P-450 CYP3A , Tioidantoínas/farmacocinética , Área Sob a Curva , Citocromo P-450 CYP3A/metabolismo , Interações Medicamentosas , HumanosRESUMO
BACKGROUND: Apalutamide is a next-generation androgen receptor inhibitor approved for treatment of subjects with high-risk, non-metastatic, castration-resistant prostate cancer (NM-CRPC). OBJECTIVE: The objective of this study was to characterize the population pharmacokinetics of apalutamide and its metabolite N-desmethyl-apalutamide in healthy male and castration-resistant prostate cancer subjects. METHODS: Plasma concentration data for apalutamide and N-desmethyl-apalutamide from 1092 subjects (seven clinical studies) receiving oral apalutamide (30-480 mg) once daily were pooled for a population pharmacokinetic analysis using a non-linear mixed-effect modelling approach. The impact of clinically relevant covariates was also assessed. RESULTS: Apalutamide absorption was rapid, and the apparent steady-state volume of distribution was large (276 L), reflecting a wide body distribution. Apalutamide was eliminated slowly, with its apparent clearance increasing from 1.31 L/h after the first dose to 2.04 L/h at steady state. No evidence of time-dependent disposition was observed for N-desmethyl-apalutamide, which was also widely distributed and slowly cleared (1.5 L/h). After 4 weeks of treatment, more than 95% of steady-state exposure of apalutamide and N-desmethyl-apalutamide was reached. At a dose of apalutamide 240 mg/day, apalutamide and N-desmethyl-apalutamide exposure exhibited 5.3- and 85.2-fold accumulation in plasma, respectively. Inter-individual variability in apalutamide apparent clearance is low (< 20%). Among the covariates evaluated, apalutamide and N-desmethyl-apalutamide exposure were statistically associated only with health status, body weight, and albumin concentration, and the effect was low (< 25%). CONCLUSIONS: A population pharmacokinetic modelling approach was successfully applied to describe the pharmacokinetics of apalutamide and N-desmethyl-apalutamide. No clinically relevant covariates were identified as predictors of apalutamide and N-desmethyl-apalutamide pharmacokinetics.
Assuntos
Albuminas/análise , Antagonistas de Receptores de Andrógenos/farmacocinética , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Tioidantoínas/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antagonistas de Receptores de Andrógenos/administração & dosagem , Antagonistas de Receptores de Andrógenos/metabolismo , Antagonistas de Receptores de Andrógenos/uso terapêutico , Variação Biológica da População/efeitos dos fármacos , Peso Corporal , Estudos de Casos e Controles , Nível de Saúde , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Valor Preditivo dos Testes , Neoplasias de Próstata Resistentes à Castração/etnologia , Neoplasias de Próstata Resistentes à Castração/metabolismo , Tioidantoínas/administração & dosagem , Tioidantoínas/metabolismo , Tioidantoínas/uso terapêuticoRESUMO
PURPOSE: Apalutamide is a next-generation androgen receptor (AR) inhibitor approved for patients with nonmetastatic castration-resistant prostate cancer (CRPC) and metastatic castration-sensitive prostate cancer. We evaluated the pharmacokinetics, safety, and antitumor activity of apalutamide combined with abiraterone acetate plus prednisone (AA-P) in patients with metastatic CRPC (mCRPC). PATIENTS AND METHODS: Multicenter, open-label, phase Ib drug-drug interaction study conducted in 57 patients with mCRPC treated with 1,000 mg abiraterone acetate plus 10 mg prednisone daily beginning on cycle 1 day 1 (C1D1) and 240 mg apalutamide daily starting on C1D8 in 28-day cycles. Serial blood samples for pharmacokinetic analysis were collected on C1D7 and C2D8. RESULTS: Systemic exposure to abiraterone, prednisone, and prednisolone decreased 14%, 61%, and 42%, respectively, when apalutamide was coadministered with AA-P. No increase in mineralocorticoid excess-related adverse events was observed. Patients without prior exposure to AR signaling inhibitors had longer median treatment duration and greater mean decrease in prostate-specific antigen (PSA) from baseline compared with those who had received prior therapy. Confirmed PSA reductions of ≥50% from baseline at any time were observed in 80% (12/15) of AR signaling inhibitor-naïve patients and 14% (6/42) of AR signaling inhibitor-treated patients. CONCLUSIONS: Treatment with apalutamide plus AA-P was well tolerated and showed evidence of antitumor activity in patients with mCRPC, including those with disease progression on AR signaling inhibitors. No clinically significant pharmacokinetic interaction was observed between abiraterone and apalutamide; however, apalutamide decreased exposure to prednisone. These data support development of 1,000 mg abiraterone acetate plus 10 mg prednisone daily with 240 mg apalutamide daily in patients with mCRPC.
Assuntos
Acetato de Abiraterona/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Prednisona/farmacocinética , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Tioidantoínas/farmacocinética , Acetato de Abiraterona/administração & dosagem , Acetato de Abiraterona/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Estudos Cross-Over , Esquema de Medicação , Interações Medicamentosas , Humanos , Calicreínas/sangue , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Tioidantoínas/administração & dosagem , Tioidantoínas/efeitos adversos , Resultado do TratamentoRESUMO
PURPOSE: To evaluate the relationship between exposure of apalutamide and its active metabolite, N-desmethyl-apalutamide, and selected clinical efficacy and safety parameters in men with high-risk nonmetastatic castration-resistant prostate cancer. PATIENTS AND METHODS: An exploratory exposure-response analysis was undertaken using data from the 1,207 patients (806 apalutamide and 401 placebo) enrolled in the SPARTAN study, including those who had undergone dose reductions and dose interruptions. Univariate and multivariate Cox regression models evaluated the relationships between apalutamide and N-desmethyl-apalutamide exposure, expressed as area under the concentration-time curve at steady state, and metastasis-free survival (MFS). Univariate and multivariate logistic regression models assessed the relationship between apalutamide and N-desmethyl-apalutamide exposure and common treatment-emergent adverse events including fatigue, fall, skin rash, weight loss, and arthralgia. RESULTS: A total of 21% of patients in the apalutamide arm experienced dose reductions diminishing the average daily dose to 209 mg instead of 240 mg. Within the relatively narrow exposure range, no statistically significant relationship was found between MFS and apalutamide and N-desmethyl-apalutamide exposure. Within apalutamide-treated subjects, skin rash and weight loss had a statistically significant association with higher apalutamide exposure. CONCLUSIONS: The use of apalutamide at the recommended dose of 240 mg once daily provided a similar delay in metastases across the SPARTAN patient population, regardless of exposure. The exploratory exposure-safety analysis supports dose reductions in patients experiencing adverse events.
Assuntos
Antagonistas de Receptores de Andrógenos/administração & dosagem , Toxidermias/epidemiologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Tioidantoínas/administração & dosagem , Redução de Peso/efeitos dos fármacos , Adulto , Antagonistas de Receptores de Andrógenos/efeitos adversos , Antagonistas de Receptores de Andrógenos/farmacocinética , Área Sob a Curva , Relação Dose-Resposta a Droga , Toxidermias/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/patologia , Tioidantoínas/efeitos adversos , Tioidantoínas/farmacocinéticaRESUMO
PURPOSE: Phase Ib study evaluating the effect of apalutamide, at therapeutic exposure, on ventricular repolarization by applying time-matched pharmacokinetics and electrocardiography (ECG) in patients with castration-resistant prostate cancer. Safety of daily apalutamide was also assessed. METHODS: Patients received 240 mg oral apalutamide daily. Time-matched ECGs were collected via continuous 12-lead Holter recording before apalutamide (Day - 1) and on Days 1 and 57 (Cycle 3 Day 1). Pharmacokinetics of apalutamide were assessed on Days 1 and 57 at matched time points of ECG collection. QT interval was corrected for heart rate using Fridericia correction (QTcF). The primary endpoint was the maximum mean change in QTcF (ΔQTcF) from baseline to Cycle 3 Day 1 (steady state). Secondary endpoints were the effect of apalutamide on other ECG parameters, pharmacokinetics of apalutamide and its active metabolite, relationship between plasma concentrations of apalutamide and QTcF, and safety. RESULTS: Forty-five men were enrolled; 82% received treatment for ≥ 3 months. At steady state, the maximum ΔQTcF was 12.4 ms and the upper bound of its associated 90% CI was 16.0 ms. No clinically meaningful effects of apalutamide were reported for heart rate or other ECG parameters. A concentration-dependent increase in QTcF was observed for apalutamide. Most adverse events (AEs) (73%) were grade 1-2 in severity. No patients discontinued due to QTc prolongation or AEs. CONCLUSION: The effect of apalutamide on QTc prolongation was modest and does not produce a clinically meaningful effect on ventricular repolarization. The AE profile was consistent with other studies of apalutamide.
Assuntos
Eletrocardiografia Ambulatorial/efeitos dos fármacos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/fisiopatologia , Tioidantoínas/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Antagonistas de Receptores de Andrógenos/administração & dosagem , Antagonistas de Receptores de Andrógenos/efeitos adversos , Antagonistas de Receptores de Andrógenos/farmacocinética , Frequência Cardíaca/efeitos dos fármacos , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias de Próstata Resistentes à Castração/metabolismo , Tioidantoínas/efeitos adversos , Tioidantoínas/farmacocinéticaRESUMO
BACKGROUND: A common germline variant in HSD3B1(1245A>C) encodes for a hyperactive 3ß-hydroxysteroid dehydrogenase 1 (3ßHSD1) missense that increases metabolic flux from extragonadal precursor steroids to DHT synthesis in prostate cancer. Enabling of extragonadal DHT synthesis by HSD3B1(1245C) predicts for more rapid clinical resistance to castration and sensitivity to extragonadal androgen synthesis inhibition. HSD3B1(1245C) thus appears to define a subgroup of patients who benefit from blocking extragonadal androgens. However, abiraterone, which is administered to block extragonadal androgens, is a steroidal drug that is metabolized by 3ßHSD1 to multiple steroidal metabolites, including 3-keto-5α-abiraterone, which stimulates the androgen receptor. Our objective was to determine if HSD3B1(1245C) inheritance is associated with increased 3-keto-5α-abiraterone synthesis in patients. METHODS: First, we characterized the pharmacokinetics of 7 steroidal abiraterone metabolites in 15 healthy volunteers. Second, we determined the association between serum 3-keto-5α-abiraterone levels and HSD3B1 genotype in 30 patients treated with abiraterone acetate (AA) after correcting for the determined pharmacokinetics. RESULTS: Patients who inherit 0, 1, and 2 copies of HSD3B1(1245C) have a stepwise increase in normalized 3-keto-5α-abiraterone (0.04 ng/ml, 2.60 ng/ml, and 2.70 ng/ml, respectively; P = 0.002). CONCLUSION: Increased generation of 3-keto-5α-abiraterone in patients with HSD3B1(1245C) might partially negate abiraterone benefits in these patients who are otherwise more likely to benefit from CYP17A1 inhibition. FUNDING: Prostate Cancer Foundation Challenge Award, National Cancer Institute.
Assuntos
Androstenos , Genótipo , Complexos Multienzimáticos/metabolismo , Mutação de Sentido Incorreto , Proteínas de Neoplasias/metabolismo , Progesterona Redutase/metabolismo , Neoplasias da Próstata/enzimologia , Esteroide Isomerases/metabolismo , Idoso , Idoso de 80 Anos ou mais , Androstenos/administração & dosagem , Androstenos/farmacocinética , Humanos , Masculino , Pessoa de Meia-Idade , Complexos Multienzimáticos/genética , Proteínas de Neoplasias/genética , Progesterona Redutase/genética , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Esteroide 17-alfa-Hidroxilase/genética , Esteroide 17-alfa-Hidroxilase/metabolismo , Esteroide Isomerases/genéticaRESUMO
PURPOSE: Abiraterone acetate (AA) was recently approved for castration-resistant prostate cancer in Japan. Two phase 1 studies were conducted to assess the pharmacokinetics of abiraterone after single-dose administration in Japanese healthy men and to evaluate the effects of food timing on abiraterone pharmacokinetics after single-dose administration of AA in Japanese and Caucasian healthy men. METHODS: In the dose-proportionality study, subjects (n = 30 Japanese) were randomly assigned to receive single doses of 250, 500, and 1,000 mg AA, and in the food-timing study, subjects (n = 22 Japanese and n = 23 Caucasian) randomly received single doses of 1,000 mg AA under fasted (overnight) and three different modified fasting conditions. RESULTS: Mean C(max) and AUC(∞) for abiraterone increased dose-dependently in Japanese healthy men; however, 90 % confidential interval (CI) was outside the predefined dose-proportionality criteria. Based on geometric mean ratios and 90 % CIs (versus overnight fasting condition), abiraterone exposure (AUC) increased significantly with dosing 1 h premeal, 2 h postmeal, or in between two meals 4 h apart by 57 %, 595 %, and 649 %, respectively. CONCLUSION: No clinically meaningful difference was observed in the pharmacokinetics of abiraterone between Caucasian and Japanese subjects.
Assuntos
Androstenos/farmacocinética , Antineoplásicos Hormonais/farmacocinética , Inibidores das Enzimas do Citocromo P-450/farmacocinética , Interações Alimento-Droga , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Acetato de Abiraterona , Adulto , Androstenos/administração & dosagem , Androstenos/efeitos adversos , Androstenos/sangue , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/efeitos adversos , Antineoplásicos Hormonais/sangue , Asiático , Estudos Cross-Over , Inibidores das Enzimas do Citocromo P-450/administração & dosagem , Inibidores das Enzimas do Citocromo P-450/efeitos adversos , Inibidores das Enzimas do Citocromo P-450/sangue , Relação Dose-Resposta a Droga , Interações Alimento-Droga/etnologia , Meia-Vida , Humanos , Japão/etnologia , Masculino , Refeições , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/etnologia , Comprimidos , Estados Unidos , População Branca , Adulto JovemRESUMO
PURPOSE: This phase I/II study investigated JNJ-40346527, a selective inhibitor of the colony-stimulating factor-1 receptor (CSF-1R) tyrosine kinase as treatment for relapsed or refractory classical Hodgkin lymphoma (cHL). EXPERIMENTAL DESIGN: Patients ≥18 years with histopathologically confirmed initial diagnosis of cHL that had relapsed or was refractory after ≥1 appropriate therapies were assigned to sequential cohorts of oral daily doses of JNJ-40346527 (150, 300, 450, 600 mg every day, and 150 mg twice a day). For the dose-escalation phase, the primary endpoint was to establish the recommended phase II dose. Secondary endpoints included safety, pharmacokinetics, and pharmacodynamics. RESULTS: Twenty-one patients [(150 mg: 3; 300 mg: 5; 450 mg: 3, 600 mg: 3) every day, and 150 mg twice a day: 7] were enrolled, 10 men, median age 40 (range, 19-75) years, median number of prior systemic therapies 6 (range, 3-14). No dose-limiting toxicities were observed; maximum-tolerated dose was not established. Best overall response was complete remission in 1 patient (duration, +352 days) and stable disease in 11 patients: (duration, 1.5-8 months). Median number of cycles: 4 (range, 1-16). Most common (≥20% patients) possibly drug-related adverse events (per investigator assessment) were nausea (n = 6), headache, and pyrexia (n = 5 each). JNJ-40346527 exposure increased in near dose-proportional manner over a dose range of 150 to 450 mg every day, but plateaued at 600 mg every day. Target engagement was confirmed (>80% inhibition of CSF-1R phosphorylation, 4 hours after dosing). CONCLUSIONS: JNJ-40346527, a selective inhibitor of CSF-1R was well tolerated, and preliminary antitumor results suggested limited activity in monotherapy for the treatment of cHL.
Assuntos
Antineoplásicos/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/patologia , Imidazóis/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Adulto , Idoso , Antineoplásicos/farmacologia , Biomarcadores , Feminino , Doença de Hodgkin/metabolismo , Humanos , Imidazóis/farmacologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Retratamento , Resultado do TratamentoRESUMO
We evaluated the impact of a strong CYP3A4 inhibitor, ketoconazole, and a strong inducer, rifampicin, on the pharmacokinetic (PK) exposure of abiraterone in two studies in healthy men. All subjects received 1,000 mg of abiraterone acetate on Days 1 and 14. Study A subjects (n = 20) received 400 mg ketoconazole on Days 11-16. Study B subjects (n = 19) received 600 mg rifampicin on Days 8-13. Serial PK sampling was done on Days 1 and 14. Study A: When given with ketoconazole, abiraterone exposure increased by 9% for maximum plasma concentration (Cmax ) and 15% for area under the plasma concentration-time curve from 0 to time of the last quantifiable concentration (AUClast ) and AUC from time 0 to infinity (AUC∞ ) compared to abiraterone acetate alone. Study B: When given with rifampicin, abiraterone exposure was reduced to 45% for Cmax and AUC∞ and to 42% for AUClast compared to abiraterone acetate alone. Ketoconazole had no clinically meaningful impact on abiraterone exposure. Rifampicin decreased abiraterone exposure by half. Hence, strong CYP3A4 inducers should be avoided or used with careful evaluation of clinical efficacy when administered with abiraterone acetate.
Assuntos
Acetato de Abiraterona/farmacocinética , Indutores do Citocromo P-450 CYP3A/administração & dosagem , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Citocromo P-450 CYP3A/metabolismo , Cetoconazol/administração & dosagem , Rifampina/administração & dosagem , Acetato de Abiraterona/administração & dosagem , Acetato de Abiraterona/efeitos adversos , Adolescente , Adulto , Área Sob a Curva , Bélgica , Biotransformação , Indutores do Citocromo P-450 CYP3A/efeitos adversos , Inibidores do Citocromo P-450 CYP3A/efeitos adversos , Interações Medicamentosas , Meia-Vida , Voluntários Saudáveis , Humanos , Cetoconazol/efeitos adversos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Modelos Biológicos , Óxidos/farmacocinética , Rifampina/efeitos adversos , Sulfatos/farmacocinética , Adulto JovemRESUMO
OBJECTIVE: To assess the efficacy and safety of JNJ-40346527, a selective inhibitor of colony-stimulating factor-1 (CSF-1) receptor kinase that acts to inhibit macrophage survival, proliferation, and differentiation in patients with active rheumatoid arthritis (RA) despite disease-modifying antirheumatic drug (DMARD) therapy. METHODS: In this randomized, double-blind, placebo-controlled, parallel group study, adults were randomized (2:1) to receive oral JNJ-40346527 100 mg or placebo twice daily through Week 12. Patients with RA had disease activity [≥ 6 swollen/≥ 6 tender joints, C-reactive protein (CRP) ≥ 0.8 mg/dl] despite DMARD therapy for ≥ 6 months. The primary endpoint was change from baseline at Week 12 in the 28-joint Disease Activity Score with CRP (DAS28-CRP). Pharmacokinetic/pharmacodynamic analyses were also performed, and safety was assessed through Week 16. RESULTS: Ninety-five patients were treated (63 JNJ-40346527, 32 placebo); 8 patients discontinued treatment (6 JNJ-40346527, 2 placebo) through Week 12. Mean improvements in DAS28-CRP from baseline to Week 12 were 1.15 for the JNJ-40346527 group and 1.42 for the placebo group (p = 0.30); thus, a statistically significant difference was not observed for the primary endpoint. Pharmacokinetic exposure to JNJ-40346527 and its active metabolites was above the projected concentration needed for pharmacologic activity, and effective target engagement and proof of activity were demonstrated by increased levels of CSF-1 and decreased CD16+ monocytes in JNJ-40346527-treated, but not placebo-treated, patients. Thirty-seven (58.7%) JNJ-40346527-treated and 16 (50.0%) placebo-treated patients reported ≥ 1 adverse event (AE); 1 (1.6%) JNJ-40346527-treated and 3 (9.4%) placebo-treated patients reported ≥ 1 serious AE. CONCLUSION: Although adequate exposure and effective peripheral target engagement were evident, JNJ-40346527 efficacy was not observed in patients with DMARD-refractory active RA. ClinicalTrials.gov identifier: NCT01597739. EudraCT Number: 2011-004529-28.
Assuntos
Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Drogas em Investigação/administração & dosagem , Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Administração Oral , Adulto , Artrite Reumatoide/diagnóstico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada , Drogas em Investigação/efeitos adversos , Feminino , Seguimentos , Humanos , Fator Estimulador de Colônias de Macrófagos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Segurança do Paciente , Medição de Risco , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Food effect on abiraterone pharmacokinetics and safety on abiraterone acetate coadministration with low-fat or high-fat meals was examined in healthy subjects and metastatic castration-resistant prostate cancer (mCRPC) patients. Healthy subjects (n = 36) were randomized to abiraterone acetate (single dose, 1000 mg) + low-fat meal, + high-fat meal, and fasted state. mCRPC patients received repeated doses (abiraterone acetate 1000 mg + 5 mg prednisone twice daily; days 1-7) in a modified fasting state followed by abiraterone acetate plus prednisone within 0.5 hours post-low-fat (n = 6) or high-fat meal (n = 18; days 8-14). In healthy subjects, geometric mean (GM) abiraterone area under plasma concentration-time curve (AUC) increased â¼5- and â¼10-fold, respectively, with low-fat and high-fat meals versus fasted state (GM [coefficient of variation], 1942 [48] and 4077 [37] ng · h/mL vs 421 [67] ng · h/mL, respectively). In mCRPC patients, abiraterone AUC was â¼2-fold higher with a high-fat meal and similar with a low-fat meal versus modified fasting state (GM [coefficient of variation]: 1992 [34] vs 973 [58] ng · h/mL and 1264 [65] vs 1185 [90] ng · h/mL, respectively). Adverse events (all grade ≤ 3) were similar, with high-fat/low-fat meals or fasted/modified fasting state. Short-term dosing with food did not alter abiraterone acetate safety.