RESUMEN
AIM: Abiraterone acetate for metastatic castration-resistant prostate cancer is an acetylated prodrug to be hydrolyzed to abiraterone. Abiraterone acetate is known to be hydrolyzed by pancreatic cholesterol esterase secreted into the intestinal lumen. This study aimed to investigate the possibility that arylacetamide deacetylase (AADAC) expressed in enterocytes contributes to the hydrolysis of abiraterone acetate based on its substrate preference. MATERIALS AND METHODS: Abiraterone acetate hydrolase activity was measured using human intestinal (HIM) and liver microsomes (HLM) as well as recombinant AADAC. Correlation analysis between activity and AADAC expression was performed in 14 individual HIMs. The in vivo pharmacokinetics of abiraterone acetate was examined using wild-type and Aadac knockout mice administered abiraterone acetate with or without orlistat, a pancreatic cholesterol esterase inhibitor. KEY FINDINGS: Recombinant AADAC showed abiraterone acetate hydrolase activity with similar Km value to HIM and HLM. The positive correlation between activity and AADAC levels in individual HIMs supported the responsibility of AADAC for abiraterone acetate hydrolysis. The area under the plasma concentration-time curve (AUC) of abiraterone after oral administration of abiraterone acetate in Aadac knockout mice was 38% lower than that in wild-type mice. The involvement of pancreatic cholesterol esterase in abiraterone formation was revealed by the decreased AUC of abiraterone by coadministration of orlistat. Orlistat potently inhibited AADAC, implying its potential as a perpetrator of drug-drug interactions. SIGNIFICANCE: AADAC is responsible for the hydrolysis of abiraterone acetate in the intestine and liver, suggesting that concomitant use of abiraterone acetate and drugs potently inhibiting AADAC should be avoided.
Asunto(s)
Acetato de Abiraterona/metabolismo , Hidrolasas de Éster Carboxílico/metabolismo , Acetato de Abiraterona/sangre , Acetato de Abiraterona/química , Acetato de Abiraterona/farmacocinética , Adolescente , Adulto , Anciano , Androstenos/sangre , Animales , Carboxilesterasa/metabolismo , Femenino , Humanos , Hidrólisis , Concentración 50 Inhibidora , Intestinos/efectos de los fármacos , Cinética , Masculino , Ratones Noqueados , Microsomas Hepáticos/metabolismo , Persona de Mediana Edad , Orlistat/administración & dosificación , Orlistat/farmacología , Proteínas Recombinantes/metabolismoRESUMEN
OBJECTIVES: Abiraterone acetate is registered for the treatment of metastatic castration-sensitive and resistant prostate cancer (mCRPC). Treatment outcome is associated with plasma trough concentrations (Cmin) of abiraterone. Patients with a plasma Cmin below the target of 8.4 ng/mL may benefit from treatment optimization by dose increase or concomitant intake with food. This study aims to investigate the cost-effectiveness of monitoring abiraterone Cmin in patients with mCRPC. METHODS: A Markov model was built with health states progression-free survival, progressed disease, and death. The benefits of monitoring abiraterone Cmin followed by a dose increase or food intervention were modeled via a difference in the percentage of patients achieving adequate Cmin taking a healthcare payer perspective. Deterministic and probabilistic sensitivity analyses were performed to assess uncertainties and their impac to the incremental cost-effectiveness ratio (ICER). RESULTS: Monitoring abiraterone followed by a dose increase resulted in 0.149 incremental quality-adjusted life-years (QALYs) with 22 145 incremental costs and an ICER of 177 821/QALY. The food intervention assumed equal effects and estimated incremental costs of 7599, resulting in an ICER of 61 019/QALY. The likelihoods of therapeutic drug monitoring (TDM) with a dose increase or food intervention being cost-effective were 8.04%and 81.9%, respectively. CONCLUSIONS: Monitoring abiraterone followed by a dose increase is not cost-effective in patients with mCRPC from a healthcare payer perspective. Monitoring in combination with a food intervention is likely to be cost-effective. This cost-effectiveness assessment may assist decision making in future integration of abiraterone TDM followed by a food intervention into standard abiraterone acetate treatment practices of mCRPC patients.
Asunto(s)
Acetato de Abiraterona/uso terapéutico , Antineoplásicos/uso terapéutico , Monitoreo de Drogas/economía , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Acetato de Abiraterona/sangre , Acetato de Abiraterona/economía , Anciano , Antineoplásicos/sangre , Antineoplásicos/economía , Análisis Costo-Beneficio , Supervivencia sin Enfermedad , Humanos , Masculino , Cadenas de Markov , Antígeno Prostático Específico/sangre , Años de Vida Ajustados por Calidad de VidaRESUMEN
Δ4-abiraterone (Δ4A) is an activemetabolite of abiraterone (ABI), which is approved in the treatment of metastatic castration resistant prostate cancer (mCRPC). The contribution of Δ4A to the clinical antitumor activity of ABI remains unknown. The aim of this study was to explore the relationship between plasma Δ4A concentration and survival in 36 mCRPC patients treated with abiraterone acetate (1000 mg/day) plus prednisone (10 mg/day). Plasma trough ABI and Δ4A concentrations were monthly assayed using liquid chromatography during the first 3 months of treatment. ABI and Δ4A Cmin were defined as the mean of trough concentrations measured for each patient. Predictive factors regarding progression-free survival (PFS) and overall survival (OS) were explored using univariate Cox model. Mean plasma ABI and Δ4A Cmin were 12.6 ± 6.8 ng/mL and 1.6 ± 1.3 ng/mL, respectively. The mean metabolic ratio Δ4A/ABI was of 0.18 ± 0.25. In regard with in vitro pharmacodynamic data, effective plasma concentrations for ABI and Δ4A were reached in 30 patients (83.3%) and only 2 patients (5.6%), respectively. Higher Δ4A Cmin was associated with shorter OS (Hazard ratio, HR 1.54; CI95% 1.06-2.22; p = 0.022) but not with PFS. The HR associated with the metabolic Δ4A/ABI ratio for PFS and OS were 7.80 (CI 95% 1.63-37.38; p = 0.010) and 12.52 (CI 95% 1.95-80.47, p = 0.0078), respectively. The present study shows Δ4A is unlikely to have meaningful contribution to pharmacodynamic activity of ABI in mCPRC, rather that higher plasma Δ4A concentration is associated with worse clinical outcomes. A high Δ4A/ABI metabolic ratio could help to identify mCRPC patients with poorer survival.
Asunto(s)
Acetato de Abiraterona/farmacocinética , Acetato de Abiraterona/uso terapéutico , Antagonistas de Receptores Androgénicos/farmacocinética , Antagonistas de Receptores Androgénicos/uso terapéutico , Androstenos/sangre , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Acetato de Abiraterona/sangre , Anciano , Anciano de 80 o más Años , Antagonistas de Receptores Androgénicos/sangre , Humanos , Masculino , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/patología , Análisis de SupervivenciaRESUMEN
ADVERSE EVENT: Decreased abiraterone exposure after introducing carbamazepine. DRUGS IMPLICATED: Abiraterone acetate and carbamazepine. THE PATIENT: A 65-year-old man with metastatic castration resistant prostate cancer, was treated with abiraterone acetate and prednisolone, and received concomitant carbamazepine for treatment of facial neuropathy. EVIDENCE THAT LINKS THE DRUG TO THE EVENT: The interaction was confirmed by a decrease in abiraterone exposure >2-fold (area-under-the-curve and trough levels). After discontinuation of carbamazepine therapy, the abiraterone exposure normalized. No alternative causes were found that explain the decrease in abiraterone exposure. MECHANISM: Induction of CYP3A and potentially phase I metabolism (SULT2A1) by carbamazepine. IMPLICATIONS FOR THERAPY: Clinicians and pharmacists should be aware of this clinically relevant interaction. The national drug-drug interaction checker does not warn for this interaction, whereas both the Lexicomp® and Micromedex® advice to avoid if possible or to increase the abiraterone dose frequency to twice daily. Carbamazepine should not be combined with abiraterone to avoid underexposure and suboptimal therapy. Therapeutic drug monitoring of abiraterone is useful to guide therapy when drug-drug interactions cannot be avoided.
Asunto(s)
Acetato de Abiraterona/farmacocinética , Carbamazepina/farmacología , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Acetato de Abiraterona/sangre , Anciano , Analgésicos no Narcóticos/farmacología , Analgésicos no Narcóticos/uso terapéutico , Antineoplásicos/sangre , Antineoplásicos/farmacocinética , Carbamazepina/uso terapéutico , Inductores del Citocromo P-450 CYP3A/farmacología , Interacciones Farmacológicas , Enfermedades del Nervio Facial/tratamiento farmacológico , Humanos , Masculino , Prednisolona/uso terapéuticoAsunto(s)
Acetato de Abiraterona/sangre , Antineoplásicos/sangre , Artefactos , Inhibidores Enzimáticos del Citocromo P-450/sangre , Neoplasias de la Próstata/sangre , Testosterona/sangre , Acetato de Abiraterona/uso terapéutico , Antineoplásicos/uso terapéutico , Estudios de Cohortes , Inhibidores Enzimáticos del Citocromo P-450/uso terapéutico , Humanos , Inmunoensayo , Límite de Detección , Masculino , Espectrometría de Masas , Neoplasias de la Próstata/tratamiento farmacológicoRESUMEN
BACKGROUND AND OBJECTIVE: Abiraterone acetate is approved for the treatment of metastatic castration-resistant prostate cancer. The originator abiraterone acetate (OAA) formulation is poorly absorbed and exhibits large pharmacokinetic variability in abiraterone exposure. Abiraterone acetate fine particle (AAFP) is a proprietary formulation (using SoluMatrix Fine Particle Technology™) designed to increase the oral bioavailability of abiraterone acetate. Here, we report on two phase I studies in healthy male subjects aged 18-50 years. METHODS: In Study 101, 20 subjects were randomized in a crossover design to single doses of AAFP 100, 200, or 400 mg or OAA 1000 mg taken orally under fasting conditions. Results suggested that AAFP 500 mg would be bioequivalent to OAA 1000 mg in the fasted state. To confirm the bioequivalence hypothesis and to further expand the AAFP dose range, in Study 102, 36 subjects were randomized in a crossover design to single doses of AAFP 125, 500, or 625 mg or OAA 1000 mg. Both studies included a 7-day washout period between administrations. RESULTS: Dose-dependent increases in the area under the plasma concentration-time curve and maximum plasma concentration with AAFP were observed in both studies. The AAFP 500-mg bioavailability relative to OAA 1000 mg measured by the geometric mean ratio for area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration was 93.4% (90% confidence interval 85.3-102.4), area under the plasma concentration-time curve from time zero to infinity was 91.0% (90% confidence interval 83.3-99.4), and maximum plasma concentration was 99.8% (90% confidence interval 86.3-115.5). Dose proportionality was seen across all AAFP dose levels (100-625 mg). Abiraterone acetate fine particle was found to be safe and well tolerated in this study. CONCLUSION: Abiraterone acetate fine particle 500 mg was demonstrated to be bioequivalent to OAA 1000 mg in healthy volunteers under fasted conditions.
Asunto(s)
Acetato de Abiraterona/farmacocinética , Antineoplásicos/farmacocinética , Acetato de Abiraterona/sangre , Acetato de Abiraterona/química , Adolescente , Adulto , Antineoplásicos/sangre , Antineoplásicos/química , Área Bajo la Curva , Disponibilidad Biológica , Estudios Cruzados , Composición de Medicamentos , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Equivalencia Terapéutica , Adulto JovenRESUMEN
Purpose: Germline variation in solute carrier organic anion (SLCO) genes influences cellular steroid uptake and is associated with prostate cancer outcomes. We hypothesized that, due to its steroidal structure, the CYP17A inhibitor abiraterone may undergo transport by SLCO-encoded transporters and that SLCO gene variation may influence intracellular abiraterone levels and outcomes.Experimental Design: Steroid and abiraterone levels were measured in serum and tissue from 58 men with localized prostate cancer in a clinical trial of LHRH agonist plus abiraterone acetate plus prednisone for 24 weeks prior to prostatectomy. Germline DNA was genotyped for 13 SNPs in six SLCO genes.Results: Abiraterone levels spanned a broad range (serum median 28 ng/mL, 108 nmol/L; tissue median 77 ng/mL, 271 nmol/L) and were correlated (r = 0.355, P = 0.001). Levels correlated positively with steroids upstream of CYP17A (pregnenolone, progesterone), and inversely with steroids downstream of CYP17A (DHEA, AED, testosterone). Serum PSA and tumor volumes were higher in men with undetectable versus detectable tissue abiraterone at prostatectomy (median 0.10 vs. 0.03 ng/dL, P = 0.02; 1.28 vs. 0.44 cc, P = 0.09, respectively). SNPs in SLCO2B1 associated with significant differences in tissue abiraterone (rs1789693, P = 0.0008; rs12422149, P = 0.03) and higher rates of minimal residual disease (tumor volume < 0.5 cc; rs1789693, 67% vs. 27%, P = 0.009; rs1077858, 46% vs. 0%, P = 0.03). LNCaP cells expressing SLCO2B1 showed two- to fourfold higher abiraterone levels compared with vector controls (P < 0.05).Conclusions: Intraprostatic abiraterone levels and genetic variation in SLCO genes are associated with pathologic responses in high-risk localized prostate cancer. Variation in SLCO genes may serve as predictors of response to abiraterone treatment. Clin Cancer Res; 23(16); 4592-601. ©2017 AACR.
Asunto(s)
Acetato de Abiraterona/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Transportadores de Anión Orgánico/metabolismo , Prednisona/metabolismo , Próstata/efectos de los fármacos , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Acetato de Abiraterona/administración & dosificación , Acetato de Abiraterona/sangre , Genotipo , Mutación de Línea Germinal , Hormona Liberadora de Gonadotropina/agonistas , Humanos , Masculino , Transportadores de Anión Orgánico/genética , Polimorfismo de Nucleótido Simple , Prednisona/administración & dosificación , Prednisona/sangre , Próstata/metabolismo , Próstata/patología , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Testosterona/sangre , Resultado del TratamientoRESUMEN
Abiraterone acetate (AA), the prodrug of abiraterone, is FDA-approved for the treatment of castration-resistant prostate cancer. Abiraterone is metabolized in patients to a more potent analogue, D4A. However, we have recently reported that this analogue is further metabolized to additional metabolites in patients treated with AA. Here, we present a liquid chromatography-tandem mass spectrometry method developed to resolve and detect abiraterone and its seven metabolites in human serum using an AB Sciex Qtrap 5500 mass analyzer coupled with a Shimadzu Nexera UPLC station. Analytes and the internal standard (abiraterone-d4) were extracted from human serum using the liquid-liquid extraction procedure. The analytes were separated using a Zorbax Eclipse Plus C18 150×2.1mm, 3.5µm column at 40°C and an isocratic mobile phase 35% A (0.1% formic acid in water), 65% B (0.1% formic acid in methanol:acetonitrile; 60:40). Electrospray ionization in positive mode was applied with multiple reaction monitoring in a total run time of 13min. Abiraterone detection was linear in the range 2-400ng/mL and all metabolites from 0.1-20ng/mL. The method was validated following US FDA guidelines for bioanalytical method validation, and all the metabolite results were within the acceptance limits. Despite the similarity in structure and mass transition between the metabolites, the validated method separated all the metabolites, including diastereomers, to allow accurate identification and quantitation of each compound.
Asunto(s)
Acetato de Abiraterona/aislamiento & purificación , Antineoplásicos Hormonales/sangre , Cromatografía Liquida/métodos , Profármacos/aislamiento & purificación , Neoplasias de la Próstata Resistentes a la Castración/sangre , Espectrometría de Masas en Tándem/métodos , Acetato de Abiraterona/sangre , Biotransformación , Calibración , Cromatografía Liquida/normas , Humanos , Límite de Detección , Extracción Líquido-Líquido/métodos , Masculino , Profármacos/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/patología , Estándares de Referencia , Reproducibilidad de los Resultados , Solventes , Estereoisomerismo , Espectrometría de Masas en Tándem/normasRESUMEN
Abiraterone blocks androgen synthesis and prolongs survival in patients with castration-resistant prostate cancer, which is otherwise driven by intratumoral androgen synthesis. Abiraterone is metabolized in patients to Δ(4)-abiraterone (D4A), which has even greater anti-tumour activity and is structurally similar to endogenous steroidal 5α-reductase substrates, such as testosterone. Here, we show that D4A is converted to at least three 5α-reduced and three 5ß-reduced metabolites in human serum. The initial 5α-reduced metabolite, 3-keto-5α-abiraterone, is present at higher concentrations than D4A in patients with prostate cancer taking abiraterone, and is an androgen receptor agonist, which promotes prostate cancer progression. In a clinical trial of abiraterone alone, followed by abiraterone plus dutasteride (a 5α-reductase inhibitor), 3-keto-5α-abiraterone and downstream metabolites were depleted by the addition of dutasteride, while D4A concentrations rose, showing that dutasteride effectively blocks production of a tumour-promoting metabolite and permits D4A accumulation. Furthermore, dutasteride did not deplete the three 5ß-reduced metabolites, which were also clinically detectable, demonstrating the specific biochemical effects of pharmacological 5α-reductase inhibition on abiraterone metabolism. Our findings suggest a previously unappreciated and biochemically specific method of clinically fine-tuning abiraterone metabolism to optimize therapy.
Asunto(s)
Inhibidores de 5-alfa-Reductasa/farmacología , Andrógenos/biosíntesis , Androstenos/metabolismo , Dutasterida/farmacología , Dutasterida/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , 3-Oxo-5-alfa-Esteroide 4-Deshidrogenasa/metabolismo , Inhibidores de 5-alfa-Reductasa/uso terapéutico , Acetato de Abiraterona/administración & dosificación , Acetato de Abiraterona/sangre , Acetato de Abiraterona/metabolismo , Acetato de Abiraterona/uso terapéutico , Administración Oral , Antagonistas de Andrógenos/farmacología , Antagonistas de Andrógenos/uso terapéutico , Androstenos/administración & dosificación , Androstenos/sangre , Androstenos/farmacología , Animales , Línea Celular Tumoral , Progresión de la Enfermedad , Humanos , Masculino , Ratones , Oxidación-Reducción/efectos de los fármacos , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata Resistentes a la Castración/sangre , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Receptores Androgénicos/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
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.