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1.
Xenobiotica ; 43(4): 379-89, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23020788

RESUMO

1. Metabolic disposition of (14)C-abiraterone acetate (AA), a prodrug of abiraterone was assessed in a phase I, open-label, single-dose (1000 mg, approximately 100 µCi) study in healthy males (18-55 years, N = 8). Blood, urine, and faecal samples were obtained at specified timepoints for determination of abiraterone concentrations in the plasma, total radioactivity (TR), and the metabolite profile. 2. Most plasma AA concentrations were below the limit of quantification. The mean maximum plasma concentration (Cmax) of abiraterone was 10.4 ng/mL, mean area under the plasma concentration-time curve (AUC) from 0 to the last measurable plasma concentration (AUC0-last) was 74.8 ng·h/mL. The exposures for TR in plasma (Cmax = 3429 ng·eq/mL; AUC0-last = 26,683 ng eq·h/mL) and whole blood (Cmax = 1836 ng·eq/mL; AUC0-last = 12,162 ng·eq·h/mL) were >300-fold higher than abiraterone exposure in plasma. The majority of TR resided in the plasma compartment of blood. 3. Main circulating metabolites were abiraterone sulfate and N-oxide abiraterone sulfate. The main metabolite excreted in urine was N-oxide abiraterone sulfate (4.22% of TR). Major components of TR in faeces were unchanged AA (55.3% of TR) and abiraterone (22.3% of TR). Mean recovery of TR in faeces was 87.9%, indicating faeces as primary route of excretion.


Assuntos
Androstenóis/administração & dosagem , Androstenóis/farmacocinética , Saúde , Administração Oral , Adolescente , Adulto , Androstenos , Androstenóis/sangue , Androstenóis/química , Radioisótopos de Carbono , Relação Dose-Resposta a Droga , Humanos , Masculino , Redes e Vias Metabólicas , Metabolômica , Pessoa de Meia-Idade , Radioatividade , Fatores de Tempo , Adulto Jovem
2.
Clin Pharmacokinet ; 48(3): 199-209, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19385713

RESUMO

BACKGROUND AND OBJECTIVE: Bortezomib, an antineoplastic for the treatment of relapsed multiple myeloma and mantle cell lymphoma, undergoes metabolism through oxidative deboronation by cytochrome P450 (CYP) enzymes, primarily CYP3A4 and CYP2C19. Omeprazole, a proton-pump inhibitor, is primarily metabolized by and demonstrates high affinity for CYP2C19. This study investigated whether coadministration of omeprazole affected the pharmacokinetics, pharmacodynamics and safety profile of bortezomib in patients with advanced cancer. The variability of bortezomib pharmacokinetics with CYP enzyme polymorphism was also investigated. PATIENTS AND METHODS: This open-label, crossover, pharmacokinetic drug-drug interaction study was conducted at seven institutions in the US and Europe between January 2005 and August 2006. Patients who had advanced solid tumours, non-Hodgkin's lymphoma or multiple myeloma, were aged >/=18 years, weighed >/=50 kg and had a life expectancy of >/=3 months were eligible. Patients received bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11 for two 21-day cycles, plus omeprazole 40 mg in the morning of days 6-10 and in the evening of day 8 in either cycle 1 (sequence 1) or cycle 2 (sequence 2). On day 21 of cycle 2, patients benefiting from therapy could continue to receive bortezomib for six additional cycles. Blood samples for pharmacokinetic/pharmacodynamic evaluation were collected prior to and at various timepoints after bortezomib administration on day 8 of cycles 1 and 2. Blood samples for pharmacogenomics were also collected. Pharmacokinetic parameters were calculated by noncompartmental analysis of plasma concentration-time data for bortezomib administration on day 8 of cycles 1 and 2, using WinNonlin version 4.0.1.a software. The pharmacodynamic profile was assessed using a whole-blood 20S proteasome inhibition assay. RESULTS: Twenty-seven patients (median age 64 years) were enrolled, 12 in sequence 1 and 15 in sequence 2, including eight and nine pharmacokinetic-evaluable patients, respectively. Bortezomib pharmacokinetic parameters were similar when bortezomib was administered alone or with omeprazole (maximum plasma concentration 120 vs 123 ng/mL; area under the plasma concentration-time curve from 0 to 72 hours 129 vs 135 ng . h/mL). The pharmacodynamic parameters were also similar (maximum effect 85.8% vs 93.7%; area under the percent inhibition-time curve over 72 hours 4052 vs 3910 % x h); the differences were not statistically significant. Pharmacogenomic analysis revealed no meaningful relationships between CYP enzyme polymorphisms and pharmacokinetic/pharmacodynamic parameters. Toxicities were generally similar between patients in sequence 1 and sequence 2, and between cycle 1 and cycle 2 in both treatment sequences. Among 26 evaluable patients, 13 (50%) were assessed as benefiting from bortezomib at the end of cycle 2 and continued to receive treatment. CONCLUSION: No impact on the pharmacokinetics, pharmacodynamics and safety profile of bortezomib was seen with coadministration of omeprazole. Concomitant administration of bortezomib and omeprazole is unlikely to cause clinically significant drug-drug interactions and is unlikely to have an impact on the efficacy or safety of bortezomib.


Assuntos
Antiulcerosos/farmacocinética , Antineoplásicos/farmacocinética , Hidrocarboneto de Aril Hidroxilases/antagonistas & inibidores , Ácidos Borônicos/farmacocinética , Neoplasias/metabolismo , Omeprazol/farmacocinética , Pirazinas/farmacocinética , Idoso , Antiulcerosos/farmacologia , Antiulcerosos/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Área Sob a Curva , Ácidos Borônicos/farmacologia , Ácidos Borônicos/uso terapêutico , Bortezomib , Estudos Cross-Over , Citocromo P-450 CYP2C19 , Esquema de Medicação , Interações Medicamentosas , Feminino , Humanos , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/metabolismo , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Neoplasias/tratamento farmacológico , Omeprazol/farmacologia , Omeprazol/uso terapêutico , Inibidores da Bomba de Prótons/farmacocinética , Inibidores da Bomba de Prótons/farmacologia , Inibidores da Bomba de Prótons/uso terapêutico , Pirazinas/farmacologia , Pirazinas/uso terapêutico
3.
Haematologica ; 93(12): 1908-11, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18768528

RESUMO

This phase I study compared pharmacokinetics and pharmacodynamics, and assessed safety and efficacy of intravenous and subcutaneous administration of bortezomib. Relapsed or refractory multiple myeloma patients were randomized to receive bortezomib by standard intravenous bolus (n=12) or subcutaneous injection (n=12) at the recommended dose and schedule (1.3 mg/m2, days 1, 4, 8, 11; eight 21-day cycles). Plasma bortezomib concentration and percent 20S proteasome inhibition were measured at multiple time points on days 1 and 11, cycle 1. Systemic bortezomib exposure was similar between arms. As expected, mean maximum plasma concentration was lower and took longer to reach following subcutaneous administration. Overall 20S proteasome inhibition was similar between arms. Safety profile and response rate for the subcutaneous arm did not appear inferior to the intravenous arm, with good local tolerance of subcutaneous injection. Based on these exploratory findings, subcutaneous administration offers an alternative option to intravenous injection (ClinicalTrials.gov identifier: NCT00291538).


Assuntos
Antineoplásicos/administração & dosagem , Ácidos Borônicos/administração & dosagem , Ácidos Borônicos/farmacocinética , Pirazinas/administração & dosagem , Pirazinas/farmacocinética , Ácidos Borônicos/sangue , Bortezomib , Vias de Administração de Medicamentos , Humanos , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Estudos Prospectivos , Inibidores de Proteassoma , Pirazinas/sangue
4.
J Clin Oncol ; 23(17): 3912-22, 2005 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-15851766

RESUMO

PURPOSE: The objective of this study was to define the maximum-tolerated dose (MTD), the recommended phase II dose, the dose-limiting toxicity, and determine the pharmacokinetic (PK) and pharmacodynamic profiles of MS-275. PATIENTS AND METHODS: Patients with advanced solid tumors or lymphoma were treated with MS-275 orally initially on a once daily x 28 every 6 weeks (daily) and later on once every-14-days (q14-day) schedules. The starting dose was 2 mg/m2 and the dose was escalated in three- to six-patient cohorts based on toxicity assessments. RESULTS: With the daily schedule, the MTD was exceeded at the first dose level. Preliminary PK analysis suggested the half-life of MS-275 in humans was 39 to 80 hours, substantially longer than predicted by preclinical studies. With the q14-day schedule, 28 patients were treated. The MTD was 10 mg/m2 and dose-limiting toxicities were nausea, vomiting, anorexia, and fatigue. Exposure to MS-275 was dose dependent, suggesting linear PK. Increased histone H3 acetylation in peripheral-blood mononuclear-cells was apparent at all dose levels by immunofluorescence analysis. Ten of 29 patients remained on treatment for > or = 3 months. CONCLUSION: The MS-275 oral formulation on the daily schedule was intolerable at a dose and schedule explored. The q14-day schedule is reasonably well tolerated. Histone deacetylase inhibition was observed in peripheral-blood mononuclear-cells. Based on PK data from the q14-day schedule, a more frequent dosing schedule, weekly x 4, repeated every 6 weeks is presently being evaluated.


Assuntos
Benzamidas/farmacocinética , Inibidores Enzimáticos/farmacocinética , Inibidores de Histona Desacetilases , Linfoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias/tratamento farmacológico , Piridinas/farmacocinética , Administração Oral , Adulto , Idoso , Benzamidas/administração & dosagem , Esquema de Medicação , Inibidores Enzimáticos/administração & dosagem , Feminino , Humanos , Linfoma/metabolismo , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/metabolismo , Piridinas/administração & dosagem
5.
Cancer Chemother Pharmacol ; 57(3): 275-81, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16028097

RESUMO

MS-275 (MS-27-275; 3-pyridylmethyl-N-[4-[(2-aminophenyl)-carbamoyl]-benzyl-carbamate) is a histone deacetylase inhibitor under clinical development as an anticancer agent. Here, we examined the role of protein binding as a possible determinant of the pharmacokinetic behavior of MS-275. The distribution of MS-275 in plasma was studied in vitro using equilibrium dialysis and ex vivo in five cancer patients receiving the drug orally at a dose of 10 mg/m(2). The dialysis method uses a tracer amount of [G-(3)H]MS-275 on a 96-well microdialysis plate with a 5-kDa cut-off membrane, and requires 250 microl sample. The time to equilibrium was established to be within 5 h, and the mean unbound fraction of MS-275 (f (u)) over a presumed therapeutic concentration range in healthy volunteer human plasma was 0.188 +/- 0.0075 as compared to 0.168 +/- 0.0144 in cancer patients. The binding was concentration-independent, indicating a low affinity, possibly non-specific and non-saturable process. MS-275 was found to bind in decreasing order to plasma > alpha(1)-acid glycoprotein > albumin. Among 19 tested drugs, a slightly increased f (u) was observed in the presence of only ibuprofen (f (u), 0.236 +/- 0.001) and metoclopramide (f (u), 0.270 +/- 0.042), suggesting weakly competitive displacement from protein-binding sites (P < 0.01). Compared to humans, f (u) was significantly higher in plasma from mouse (0.376), rat (0.393), rabbit (0.355), dog (0.436), and pig (0.439) (P < 0.01), which may explain, in part, the species-dependent pharmacokinetic profile of MS-275 observed previously.


Assuntos
Benzamidas/metabolismo , Proteínas Sanguíneas/metabolismo , Piridinas/metabolismo , Animais , Área Sob a Curva , Benzamidas/sangue , Benzamidas/farmacocinética , Ligação Competitiva/efeitos dos fármacos , Cães , Glicoproteínas/metabolismo , Meia-Vida , Inibidores de Histona Desacetilases , Humanos , Ibuprofeno/farmacologia , Metoclopramida/farmacologia , Camundongos , Neoplasias/sangue , Neoplasias/metabolismo , Orosomucoide , Ligação Proteica/efeitos dos fármacos , Piridinas/sangue , Piridinas/farmacocinética , Coelhos , Ratos , Albumina Sérica/metabolismo , Especificidade da Espécie , Suínos , Fatores de Tempo
6.
J Clin Oncol ; 22(12): 2489-503, 2004 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-15197212

RESUMO

PURPOSE: Interest in the use of herbal products has grown dramatically in the Western world. Recent estimates suggest an overall prevalence for herbal preparation use of 13% to 63% among cancer patients. With the narrow therapeutic range associated with most anticancer drugs, there is an increasing need for understanding possible adverse drug interactions in medical oncology. METHODS: In this article, a literature overview is provided of known or suspected interactions of the 15 best-selling herbs in the United States with conventional allopathic therapies for cancer. RESULTS: Herbs with the potential to significantly modulate the activity of drug-metabolizing enzymes (notably cytochrome p450 isozymes) and/or the drug transporter P-glycoprotein include garlic (Allium sativum), ginkgo (Ginkgo biloba), echinacea (Echinacea purpurea), ginseng (Panax ginseng), St John' s wort (Hypericum perforatum), and kava (Piper methysticum). All of these products participate in potential pharmacokinetic interactions with anticancer drugs. CONCLUSION: It is suggested that health care professionals and consumers should be aware of the potential for adverse interactions with these herbs, question their patients on their use of them, especially among patients whose disease is not responding to treatments as expected, and urge patients to avoid herbs that could confound their cancer care.


Assuntos
Antineoplásicos/farmacologia , Suplementos Nutricionais/efeitos adversos , Interações Ervas-Drogas , Preparações de Plantas/efeitos adversos , Humanos , Estados Unidos
7.
Cancer Biol Ther ; 4(8): 815-8, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16210916

RESUMO

Interindividual variability in paclitaxel and docetaxel pharmacokinetics, toxicity and response is extensive, and largely unexplained. We hypothesized that this is due to affinity of taxanes for an uptake transporter that indirectly regulates elimination pathways. Here, we studied accumulation of [3H]docetaxel and [3H]paclitaxel in Xenopus laevis oocytes injected with cRNA of the liver-specific organic anion transporting polypeptide (OATP) family members OATP1B1 (OATP2) or OATP1B3 (OATP8). Taxane transport by OATP1B1 expressing oocytes was not significantly different from that by water-injected controls, whereas uptake by OATP1B3 was 2.2-fold higher for docetaxel (p = 0.0007) and 3.3-fold higher for paclitaxel (p < 0.0001). OATP1B3-mediated paclitaxel transport was saturable (Michaelis-Menten constant, 6.79 microM), time-dependent, and highly sensitive to chemical inhibition. Paclitaxel uptake was not inhibited by ketoconazole or tariquidar. However, uptake was inhibited by the formulation excipient Cremophor (74.4% inhibition, p < 0.0001), cyclosporin A (25.2%, p = 0.005), glycyrrhizic acid (24.6%, p = 0.012), and hyperforin (28.4%, p = 0.003). Consistent with this finding, Cremophor was found to significantly affect the hepatic uptake of paclitaxel in mice. These data suggest that OATP1B3 is a key regulator of hepatic uptake, and may therefore play a role in the variable response to treatment with taxanes.


Assuntos
Antineoplásicos Fitogênicos/metabolismo , Fígado/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/fisiologia , Paclitaxel/metabolismo , Animais , Feminino , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Cetoconazol/farmacologia , Fígado/citologia , Fígado/efeitos dos fármacos , Transportador 1 de Ânion Orgânico Específico do Fígado , Camundongos , Camundongos Endogâmicos , Oócitos/metabolismo , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/fisiologia , Transportadores de Ânions Orgânicos Sódio-Independentes/antagonistas & inibidores , Transportadores de Ânions Orgânicos Sódio-Independentes/genética , Quinolinas/farmacologia , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto , Xenopus laevis
8.
Pharmacogenomics ; 6(2): 115-38, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15882131

RESUMO

ATP-binding cassette (ABC) genes play a role in the resistance of malignant cells to anticancer agents. The ABC gene products, including ABCB1 (P-glycoprotein) and ABCG2 (breast cancer-resistance protein [BCRP], mitoxantrone-resistance protein [MXR], or ABC transporter in placenta [ABCP]), are also known to influence oral absorption and disposition of a wide variety of drugs. As a result, the expression levels of these proteins in humans have important consequences for an individual's susceptibility to certain drug-induced side effects, interactions, and treatment efficacy. Naturally occurring variants in ABC transporter genes have been identified that might affect the function and expression of the protein. This review focuses on recent advances in the pharmacogenetics of the ABC transporters ABCB1 and ABCG2, and discusses potential implications of genetic variants for the chemotherapeutic treatment of cancer.


Assuntos
Antineoplásicos/farmacocinética , Resistencia a Medicamentos Antineoplásicos/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/fisiologia , Antineoplásicos/farmacologia , Área Sob a Curva , Transporte Biológico/fisiologia , Humanos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/fisiologia , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/fisiologia , Polimorfismo Genético
9.
Clin Cancer Res ; 10(20): 6840-6, 2004 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-15501960

RESUMO

OBJECTIVE: UCN-01 (7-hydroxystaurosporine) is a small molecule cyclin-dependent kinase modulator currently under clinical development as an anticancer agent. In vitro studies have demonstrated that UCN-01 is strongly bound to the acute-phase reactant alpha (1)-acid glycoprotein (AAG). Here, we examined the role of protein binding as a determinant of the pharmacokinetic behavior of UCN-01 in patients. EXPERIMENTAL DESIGN: Pharmacokinetic data were obtained from a group of 41 patients with cancer receiving UCN-01 as a 72-hour i.v. infusion (dose, 3.6 to 53 mg/m(2)/day). RESULTS: Over the tested dose range, total drug clearance was distinctly nonlinear (P = 0.0076) and increased exponentially from 4.33 mL/hour (at 3.6 mg/m(2)/day) to 24.1 mL/hour (at 54 mg/m(2)/day). As individual values for AAG increased, values for clearance decreased in a linear fashion (R(2) = 0.264; P = 0.0008), although the relationship was shallow, and the data showed considerable scatter. Interestingly, no nonlinearity in the unbound concentration (P = 0.083) or fraction at the peak plasma concentration of UCN-01 was apparent (P = 0.744). CONCLUSION: The results suggest the following: (1) that extensive binding to AAG may explain, in part, the unique pharmacokinetic profile of UCN-01 described previously with a small volume of distribution and slow systemic clearance, and (2) that measurement of total UCN-01 concentrations in plasma is a poor surrogate for that of the pharmacologically active fraction unbound drug.


Assuntos
Antineoplásicos/farmacocinética , Orosomucoide/farmacologia , Estaurosporina/análogos & derivados , Estaurosporina/farmacocinética , Antineoplásicos/administração & dosagem , Antineoplásicos/metabolismo , Feminino , Meia-Vida , Humanos , Infusões Intravenosas , Masculino , Neoplasias/tratamento farmacológico , Estaurosporina/administração & dosagem , Estaurosporina/metabolismo
10.
Clin Pharmacol Drug Dev ; 4(1): 63-73, 2015 01.
Artigo em Inglês | MEDLINE | ID: mdl-27128004

RESUMO

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 Jovem
11.
J Clin Pharmacol ; 55(12): 1406-14, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26096139

RESUMO

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 ∼5- and ∼10-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 ∼2-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.


Assuntos
Acetato de Abiraterona/farmacocinética , Gorduras na Dieta/farmacologia , Interações Alimento-Droga , Neoplasias de Próstata Resistentes à Castração/metabolismo , Acetato de Abiraterona/efeitos adversos , Acetato de Abiraterona/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores das Enzimas do Citocromo P-450/efeitos adversos , Inibidores das Enzimas do Citocromo P-450/sangue , Inibidores das Enzimas do Citocromo P-450/farmacocinética , Quimioterapia Combinada , Jejum/metabolismo , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Prednisona/efeitos adversos , Neoplasias de Próstata Resistentes à Castração/sangue
12.
Cancer Biol Ther ; 3(8): 719-20, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15254393

RESUMO

Interest in histone deacetylase (HDAC) inhibitors as antineoplastic agents has been accelerating over the last several years and increasing number of compounds are in or entering clinical trials in humans. Recently, attention has been focused on the ability of HDAC inhibitors to induce perturbations in cell cycle regulatory proteins (e.g. p21CIP1), down regulation of survival signaling pathways (e.g. Raf/MAPkinase/ERK), and disruption of cellular redox state (e.g. reactive oxygen species, ROS). In April 2004 issue of Cancer Research, Maggio et al. report that pre-treatment of human leukemic cells with a histone deacetylase inhibitor, MS-275 significantly enhances the abrogative capacity of an established nucleoside analogue, fludarabine. The study indicates that apart from promoting acetylation of histones and regulation of genes involved in differentiation and apoptosis, MS-275 also induces multiple perturbations in signal transduction, survival and cell cycle regulatory pathways that increase the fludarabine-mediated cell death.


Assuntos
Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Benzamidas/uso terapêutico , Leucemia/tratamento farmacológico , Piridinas/uso terapêutico , Vidarabina/análogos & derivados , Vidarabina/uso terapêutico , Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , DNA (Citosina-5-)-Metiltransferases/antagonistas & inibidores , Sinergismo Farmacológico , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Inibidores de Histona Desacetilases , Histonas/metabolismo , Humanos , Leucemia/metabolismo , Espécies Reativas de Oxigênio/metabolismo
13.
Artigo em Inglês | MEDLINE | ID: mdl-15081922

RESUMO

A rapid method was developed for the quantitative determination of the novel histone deacetylase inhibitor, MS-275, in human plasma. Calibration curves were constructed in the range of 1-100 ng/ml, and were analyzed using a weight factor proportional to the nominal concentration. Sample pretreatment involved a one-step protein precipitation with acetonitrile of 0.1 ml samples. The analysis was performed on a column (75 mm x 4.6 mm i.d.) packed with 3.5 microm Phenyl-SB material, using methanol-10mM ammonium formate (55:45 (v/v)) as the mobile phase. The column effluent was monitored by mass spectrometry with positive electrospray ionization. The values for precision and accuracy were always < or =5.58 and <11.4% relative error, respectively. The method was successfully applied to examine the pharmacokinetics of MS-275 in a cancer patient.


Assuntos
Benzamidas/sangue , Cromatografia Líquida/métodos , Inibidores Enzimáticos/sangue , Inibidores de Histona Desacetilases , Piridinas/sangue , Espectrometria de Massas por Ionização por Electrospray/métodos , Administração Oral , Benzamidas/administração & dosagem , Benzamidas/farmacocinética , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Humanos , Piridinas/administração & dosagem , Piridinas/farmacocinética , Reprodutibilidade dos Testes
14.
J Clin Pharmacol ; 54(7): 732-41, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24374856

RESUMO

Three open-label, single-dose studies investigated the impact of hepatic or renal impairment on abiraterone acetate pharmacokinetics and safety/tolerability in non-cancer patients. Patients (n = 8 each group) with mild/moderate hepatic impairment or end-stage renal disease (ESRD), and age-, BMI-matched healthy controls received a single oral 1,000 mg abiraterone acetate (tablet dose); while patients (n = 8 each) with severe hepatic impairment and matched healthy controls received 125- and 2,000-mg abiraterone acetate (suspension doses), respectively (systemic exposure of abiraterone acetate suspension is approximately half to that of tablet formulation). Blood was sampled at specified timepoints up to 72 or 96 hours postdose to measure plasma abiraterone concentrations. Abiraterone exposure was comparable between healthy controls and patients with mild hepatic impairment or ESRD, but increased by 4-fold in patients with moderate hepatic impairment. Despite a 16-fold reduction in dose, abiraterone exposure in patients with severe hepatic impairment was about 22% and 44% of the Cmax and AUC∞ of healthy controls, respectively. These results suggest that abiraterone pharmacokinetics were not changed markedly in patients with ESRD or mild hepatic impairment. However, the capacity to eliminate abiraterone was substantially compromised in patients with moderate or severe hepatic impairment. A single-dose administration of abiraterone acetate was well-tolerated.


Assuntos
Androstadienos/farmacocinética , Inibidores das Enzimas do Citocromo P-450/farmacocinética , Insuficiência Hepática/metabolismo , Rim/metabolismo , Fígado/metabolismo , Pró-Fármacos/farmacocinética , Insuficiência Renal/metabolismo , Acetato de Abiraterona , Adulto , Idoso , Idoso de 80 Anos ou mais , Androstadienos/administração & dosagem , Androstadienos/efeitos adversos , Androstadienos/sangue , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/efeitos adversos , Antineoplásicos Hormonais/sangue , Antineoplásicos Hormonais/farmacocinética , 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 , Meia-Vida , Insuficiência Hepática/sangue , Insuficiência Hepática/fisiopatologia , Humanos , Rim/efeitos dos fármacos , Rim/fisiopatologia , Falência Renal Crônica/sangue , Falência Renal Crônica/metabolismo , Falência Renal Crônica/fisiopatologia , Falência Renal Crônica/terapia , Fígado/efeitos dos fármacos , Fígado/fisiopatologia , Masculino , Pessoa de Meia-Idade , Pró-Fármacos/administração & dosagem , Pró-Fármacos/efeitos adversos , Pró-Fármacos/análise , Diálise Renal/efeitos adversos , Eliminação Renal , Insuficiência Renal/sangue , Insuficiência Renal/fisiopatologia , Índice de Gravidade de Doença , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Esteroide 17-alfa-Hidroxilase/metabolismo , Suspensões , Comprimidos
15.
Cancer Chemother Pharmacol ; 67(1): 57-67, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20306195

RESUMO

PURPOSE: Characterize bortezomib pharmacokinetics/pharmacodynamics in relapsed myeloma patients after single and repeat intravenous administration at two doses. METHODS: Forty-two patients were randomized to receive bortezomib 1.0 or 1.3 mg/m(2), days 1, 4, 8, 11, for up to eight 21-day treatment cycles (n = 21, each dose group). Serial blood samples for pharmacokinetic/pharmacodynamic analysis were taken on days 1 and 11, cycles 1 and 3. Observational efficacy and safety data were collected. RESULTS: Twelve patients in each dose group were evaluable for pharmacokinetics/pharmacodynamics. Plasma clearance decreased with repeat dosing (102-112 L/h for first dose; 15-32 L/h following repeat dosing), with associated increases in systemic exposure and terminal half-life. Systemic exposures of bortezomib were similar between dose groups considering the relatively narrow dose range and the observed pharmacokinetic variability, although there was no readily apparent deviation from dose-proportionality. Blood 20S proteasome inhibition profiles were similar between groups with mean maximum inhibition ranging from 70 to 84% and decreasing toward baseline over the dosing interval. Response rate (all 42 patients) was 50%, including 7% complete responses. The safety profile was consistent with the predictable and manageable profile previously established; data suggested milder toxicity in the 1.0 mg/m(2) group. CONCLUSIONS: Bortezomib pharmacokinetics change with repeat dose administration, characterized by a reduction in plasma clearance and associated increase in systemic exposure. Bortezomib is pharmacodynamically active and tolerable at 1.0 and 1.3 mg/m(2) doses, with recovery toward baseline blood proteasome activity over the dosing interval following repeat dose administration, supporting the current clinical dosing regimen.


Assuntos
Antineoplásicos/administração & dosagem , Ácidos Borônicos/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteases/administração & dosagem , Inibidores de Proteassoma , Pirazinas/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Ácidos Borônicos/efeitos adversos , Ácidos Borônicos/farmacocinética , Bortezomib , Relação Dose-Resposta a Droga , Feminino , Meia-Vida , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Inibidores de Proteases/efeitos adversos , Inibidores de Proteases/farmacocinética , Pirazinas/efeitos adversos , Pirazinas/farmacocinética , Recidiva , Resultado do Tratamento
17.
Invest New Drugs ; 24(5): 367-75, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16583304

RESUMO

AIMS: To evaluate elimination pathways of the histone deacetylase inhibitor MS-275 in vitro and screen for relationships between demographic factors that may affect its pharmacokinetics in vivo. PATIENTS AND METHODS: Substrate specificity of MS-275 for the liver-specific organic anion transporting polypeptides (OATPs) was assessed using Xenopus laevis oocytes, and in vitro metabolism was evaluated using human liver microsomes. In vivo pharmacokinetic data were obtained from 64 adult patients (36 male/28 female; median age, 57 years) receiving MS-275 orally (dose range, 2 to 12 mg/m2). RESULTS: Accumulation of [G-3H]MS-275 by oocytes expressing OATP1B1 or OATP1B3 was not significantly different from water-injected controls (p = 0.82). Furthermore, no metabolites could be detected after incubation of MS-275 in human liver microsomes, suggesting that hepatic metabolism is a minor pathway of elimination. The mean (+/- SD) apparent oral clearance of MS-275 was 38.5 +/- 18.7 L/h, with a coefficient of variation (%CV) of 48.7%. When clearance was adjusted for body-surface area (BSA), the inter-individual variability was similar (%CV = 50.1%). In addition, in a linear-regression analysis, except for adjusted ideal body weight (p = 0.02, |r| = 0.29), none of the studied measures (BSA, lean-body mass, ideal body weight, body-mass index, height, weight, age, and sex) was a significant covariate (p > 0.13; |r| < 0.11) for oral clearance. CONCLUSIONS: The current analysis has eliminated a number of candidate covariates from further consideration as important determinants of MS-275 absorption and disposition. Furthermore, MS-275 can be added to the list of cancer drugs where BSA-based dosing is not more accurate than fixed dosing.


Assuntos
Antineoplásicos/farmacocinética , Benzamidas/farmacocinética , Inibidores Enzimáticos/farmacocinética , Inibidores de Histona Desacetilases , Neoplasias/metabolismo , Piridinas/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antineoplásicos/sangue , Antineoplásicos/uso terapêutico , Benzamidas/sangue , Benzamidas/uso terapêutico , Índice de Massa Corporal , Superfície Corporal , Peso Corporal , Células Cultivadas , Inibidores Enzimáticos/sangue , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Masculino , Microssomos Hepáticos/metabolismo , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Oócitos/metabolismo , Transportadores de Ânions Orgânicos/metabolismo , Piridinas/sangue , Piridinas/uso terapêutico , Xenopus laevis
18.
Mol Pharmacol ; 68(4): 917-32, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15955865

RESUMO

The epigenome is defined by DNA methylation patterns and the associated post-translational modifications of histones. This histone code determines the expression status of individual genes dependent upon their localization on the chromatin. The histone deacetylases (HDACs) play a major role in keeping the balance between the acetylated and deacetylated states of chromatin and eventually regulate gene expression. Recent developments in understanding the cancer cell cycle, specifically the interplay with chromatin control, are providing opportunities for developing mechanism-based therapeutic drugs. Inhibitors of HDACs are under considerable exploration, in part because of their potential roles in reversing the silenced genes in transformed tumor cells by modulating transcriptional processes. This review is an effort to summarize the nonclinical and clinical status of HDAC inhibitors currently under development in anticancer therapy.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Inibidores de Histona Desacetilases , Animais , Humanos
19.
Drug Resist Updat ; 7(3): 195-208, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15296861

RESUMO

Matrix metalloproteinases belong to a diverse group of enzymes that are not only involved in restructuring the extracellular matrix, but also play a major role in various pathophysiological conditions by virtue of their complicated expression, activation, and regulation processes. They have been widely implicated to function as major contenders in cancer progression, frequently due to their role in invasion, proliferation and metastasis. MMP inhibitors have been specifically designed to target these altered activities of MMPs, mostly by means of inhibiting their function and by diminishing their increased expression in various disease states, particularly cancer. Tetracyclines and chemically modified tetracyclines (CMTs) have been rationally designed to inhibit the activity of MMPs and thus decrease the potential risk of spread of tumor cells to distant sites by invasion and metastasis. Pre-clinical and early clinical data for one of these CMTs, COL-3 (formerly CMT-3) indicate considerable potential for this group of anticancer agents. Further testing and rational modifications of these CMT analogues might lead to new anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Inibidores de Metaloproteinases de Matriz , Tetraciclinas/farmacologia , Animais , Ativação Enzimática , Humanos , Metaloproteinases da Matriz/fisiologia , Neoplasias/patologia
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