RESUMO
PURPOSE: Pemetrexed is an antimetabolite that is structurally similar to methotrexate. Because nonsteroidal anti-inflammatory drugs (NSAID) impair methotrexate clearance and increase its toxicity, we evaluated the pharmacokinetics and toxicity of pemetrexed when coadministered with aspirin or ibuprofen in advanced cancer patients. EXPERIMENTAL DESIGN: In two independent, randomized, crossover drug interaction studies, cancer patients with a creatinine clearance (CrCl) > or =60 mL/min received an NSAID (aspirin or ibuprofen) with either the first or the second dose of pemetrexed (cycle 1 or 2). Pemetrexed (500 mg/m(2)) was infused i.v. on day 1 of a 21-day cycle, and all patients were supplemented with oral folic acid and i.m. vitamin B(12). Aspirin (325 mg) or ibuprofen (400 mg; 2 x 200 mg) was given orally every 6 hours, starting 2 days before pemetrexed administration, with the ninth and final dose taken 1 hour before infusion. Pemetrexed pharmacokinetics with and without concomitant NSAID treatment were compared for cycles 1 and 2. RESULTS: Data from 27 patients in each study were evaluable for the analysis of pemetrexed pharmacokinetics. Coadministration of aspirin did not alter pemetrexed pharmacokinetics; however, ibuprofen coadministration was associated with a 16% reduction in clearance, a 15% increase in maximum plasma concentration, and a 20% increase in area under the plasma concentration versus time curve but no significant change in V(ss) compared with pemetrexed alone. No febrile neutropenia occurred in any patient, and no increase in pemetrexed-related toxicity was associated with NSAID administration. CONCLUSIONS: Pemetrexed (500 mg/m(2)) with vitamin supplementation is well tolerated and requires no dosage adjustment when coadministered with aspirin (in patients with CrCl > or =60 mL/min) or ibuprofen (in patients with CrCl > or =80 mL/min).
Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Antimetabólitos Antineoplásicos/farmacocinética , Aspirina/farmacocinética , Glutamatos/farmacocinética , Guanina/análogos & derivados , Ibuprofeno/farmacocinética , Neoplasias/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Anti-Inflamatórios não Esteroides/toxicidade , Antimetabólitos Antineoplásicos/toxicidade , Aspirina/toxicidade , Creatinina/sangue , Estudos Cross-Over , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Glutamatos/toxicidade , Guanina/farmacocinética , Guanina/toxicidade , Humanos , Ibuprofeno/toxicidade , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Pemetrexede , Timidilato Sintase/antagonistas & inibidores , Resultado do TratamentoRESUMO
Although traditionally reserved for proteomic analysis, nanoESI has found increased use for small molecule applications related to drug metabolism/pharmacokinetics (DMPK). NanoESI, which refers to ESI performed at flow rates in the range of 200 to 1000 nL/min using smaller diameter emitters (10 to 100 microm id), produces smaller droplets than conventional ESI resulting in more efficient ionization. Benefits include greater sensitivity, enhanced dynamic range, and a reduced competition for ionization. These advantages may now be harnessed largely due to the introduction of a commercial system for automated nanoESI infusion. This development in turn has allowed ADME (absorption, distribution, metabolism, and excretion) scientists to consider novel approaches to mass spectrometric analysis without direct LC interfacing. While it is freely acknowledged that nanoESI infusion is not likely to supplant LC-MS as the primary analytical platform for ADME, nanoESI infusion has been successfully applied to both quantitative (bioanalysis) and qualitative (metabolite identification) applications. This review summarizes published applications of this technology and offers a perspective on where it fits best into the DMPK laboratory.
Assuntos
Preparações Farmacêuticas/metabolismo , Farmacocinética , Espectrometria de Massas por Ionização por Electrospray , Animais , Avaliação Pré-Clínica de Medicamentos , Humanos , Nanotecnologia , Espectrometria de Massas por Ionização por Electrospray/instrumentação , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em TandemRESUMO
BACKGROUND: The adoption of dried blood spot (DBS) sampling and analysis to support drug discovery and development requires the understanding of its bioanalytical feasibility as well as the distribution of the analyte in blood. RESULTS: Demonstrated the feasibility of adopting DBS for four test analytes representing diverse physico-chemical as well as pharmacokinetic parameters. The key findings include the use of a single extraction procedure across all four analytes, assay range of 1 to 5000 ng/ml, stability in whole blood as well as on-card, and the non-impact of blood volume. In vivo data were used to calculate the blood-to-plasma ratio (using both AUC and average of individual time points), which was then used to predict plasma concentration from DBS data. The predicted data showed an excellent correlation with actual plasma data. CONCLUSION: Transition from plasma to DBS can be supported for preclinical studies by conducting a few well-defined bioanalytical experiments followed by an in vivo bridging study. Blood:plasma ratio derived from the bridging study can be used to predict plasma concentrations from DBS data.
Assuntos
Teste em Amostras de Sangue Seco/métodos , Plasma/química , Proteínas Sanguíneas/química , Estudos de Viabilidade , Humanos , Preparações Farmacêuticas/sangueRESUMO
Definitive plasma protein binding (PB) studies in drug development are routinely conducted with radiolabeled material, where the radiochemical purity limits quantitative PB measurement. Recent and emerging regulatory guidances increasingly expect quantitative determination of the fraction unbound (Fu) for key decision making. In the present study, PB of 11 structurally- and therapeutically-diverse drugs spanning the full range of plasma binding was determined by equilibrium dialysis of non-radiolabeled compound and was validated against the respective definitive values obtained by accepted radiolabeled protocols. The extent of plasma binding was in agreement with the radiolabeled studies; however, the methodology reported herein enables reliable quantification of Fu values for highly-bound drugs and is not limited by the radiochemical purity. In order to meet the rigor of a development study, equilibrium dialysis of unlabeled drug must be supported by an appropriately validated bioanalytical method along with studies to determine compound solubility and stability in matrix and dialysis buffer, nonspecific binding to the dialysis device, and ability to achieve equilibrium in the absence of protein. The presented methodology establishes an experimental protocol for definitive PB measurement, which enables quantitative determination of low Fu values, necessary for navigation of new regulatory guidances in clinical drug development.
Assuntos
Proteínas Sanguíneas/metabolismo , Descoberta de Drogas , Preparações Farmacêuticas/sangue , Cromatografia Líquida , Diálise/instrumentação , Diálise/métodos , Descoberta de Drogas/instrumentação , Descoberta de Drogas/métodos , Interações Medicamentosas , Estabilidade de Medicamentos , Humanos , Técnicas In Vitro , Limite de Detecção , Preparações Farmacêuticas/química , Reprodutibilidade dos Testes , Solubilidade , Espectrometria de Massas em TandemRESUMO
Current drug discovery involves a highly iterative process pertaining to three core disciplines: biology, chemistry, and drug disposition. For most pharmaceutical companies the path to a drug candidate comprises similar stages: target identification, biological screening, lead generation, lead optimization, and candidate selection. Over the past decade, the overall efficiency of drug discovery has been greatly improved by a single instrumental technique, liquid chromatography/mass spectrometry (LC/MS). Transformed by the commercial introduction of the atmospheric pressure ionization interface in the mid-1990s, LC/MS has expanded into almost every area of drug discovery. In many cases, drug discovery workflow has been changed owing to vastly improved efficiency. This review examines recent trends for these three core disciplines and presents seminal examples where LC/MS has altered the current approach to drug discovery.
Assuntos
Química Farmacêutica/tendências , Cromatografia Líquida/métodos , Espectrometria de Massas/métodos , Preparações Farmacêuticas/análise , Animais , Técnicas de Química Analítica , Formas de Dosagem , Desenho de Fármacos , Descoberta de Drogas , Indústria Farmacêutica/tendências , HumanosRESUMO
PURPOSE: This phase I study was conducted to determine the toxicities, pharmacokinetics, and recommended doses of pemetrexed in cancer patients with normal and impaired renal function. PATIENTS AND METHODS: Patients received a 10-minute infusion of 150 to 600 mg/m2 of pemetrexed every 3 weeks. Patients were stratified for independent dose escalation by measured glomerular filtration rate (GFR) into four cohorts ranging from > or = 80 to less than 20 mL/min. Pemetrexed plasma and urine pharmacokinetics were evaluated for the first cycle. Patients enrolled after December 1999 were supplemented with oral folic acid and intramuscular vitamin B12. RESULTS: Forty-seven patients were treated with 167 cycles of pemetrexed. Hematologic dose-limiting toxicities occurred in vitamin-supplemented patients (two; 15%) and non-supplemented patients (six; 18%), and included febrile neutropenia (four patients) and grade 4 thrombocytopenia (two patients). Nonhematologic toxicities included fatigue, diarrhea, and nausea, and did not correlate with renal function. Accrual was discontinued in patients with GFR less than 30 mL/min after one patient with a GFR of 19 mL/min died as a result of treatment-related toxicities. Pemetrexed plasma clearance positively correlated with GFR (r2 = 0.736), resulting in increased drug exposures in patients with impaired renal function. With vitamin supplementation, pemetrexed 600 mg/m2 was tolerated by patients with a GFR > or = 80 mL/min, whereas patients with a GFR of 40 to 79 mL/min tolerated a dose of 500 mg/m2. CONCLUSION: Pemetrexed was well tolerated at doses of 500 mg/m2 with vitamin supplementation in patients with GFR > or = 40 mL/min. Additional studies are needed to define appropriate dosing for renally impaired patients receiving higher dose pemetrexed with vitamin supplementation.
Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/farmacocinética , Glutamatos/administração & dosagem , Glutamatos/farmacocinética , Guanina/análogos & derivados , Falência Renal Crônica/complicações , Falência Renal Crônica/metabolismo , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Adulto , Idoso , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/sangue , Antimetabólitos Antineoplásicos/urina , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Diarreia/induzido quimicamente , Esquema de Medicação , Fadiga/induzido quimicamente , Feminino , Ácido Fólico/administração & dosagem , Glutamatos/efeitos adversos , Glutamatos/sangue , Glutamatos/urina , Guanina/administração & dosagem , Guanina/efeitos adversos , Guanina/sangue , Guanina/farmacocinética , Guanina/urina , Humanos , Falência Renal Crônica/sangue , Falência Renal Crônica/urina , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Neutropenia/induzido quimicamente , Pemetrexede , Trombocitopenia/induzido quimicamente , Vitamina B 12/administração & dosagemRESUMO
Automated chip-based infusion nanoelectrospray ionization coupled to tandem mass spectrometry (nanoESI-MS/MS) was used to validate a bioanalytical assay conforming to United States Food and Drug Administration (FDA) regulatory guidelines and Good Laboratory Practices (GLP). Reboxetine was used as the analyte fortified in dog plasma along with an analog internal standard (IS). The best nanoESI response for reboxetine was observed with 90% acetonitrile (ACN)/water without any mobile phase modifiers. The analyte and IS were extracted from dog plasma samples by liquid-liquid extraction (LLE). The supernatant was concentrated to dryness and redissolved in 90% ACN/water for nanoESI. Selected reaction monitoring (SRM) data were collected for all samples to generate ion current profiles with a base width of approximately 20 s. Selectivity experiments showed no interferences in blank plasma samples. Interferences as a result of in-source collision-induced dissociation of metabolites were not an issue due to the previously documented metabolism of reboxetine. Matrix suppression was evaluated across multiple lots of dog plasma as well as over different animal species (rabbit, rat, mouse) and different anticoagulants (heparin, EDTA). Matrix suppression ranged from approximately 30-60% across the different lots, species etc.; however, in all instances, the analyte and the IS were suppressed by similar amounts, suggesting the similarity in ionization properties between the two. A three-batch validation was performed (each batch consisting of four different concentrations, six replicates of each concentration) and demonstrated inter-assay accuracy (% relative error; RE) of less than +/-8% and an inter-assay precision (% relative standard deviation; RSD) of less than 7%, thus meeting regulatory guidelines. A comparison of analyses by nanoESI-MS/MS and liquid chromatography coupled to tandem mass spectrometry (LC/MS/MS) showed that nanoESI-MS/MS had a greater slope for the calibration standard curve compared to LC/MS/MS, indicating greater sensitivity for the former technique. It is also noteworthy that the amount of sample infused during nanoESI-MS/MS was approximately 80-fold less compared to the amount of sample injected during LC/MS/MS. The absence of carryover (attributed to the lack of a common fluid path) in the nanoESI technique enabled the extension of the assay linear dynamic range to 500,000-fold, and the possibility of analyzing samples in a single batch without the need for re-analysis of samples with high concentrations. This technology offers the possibility for increased throughput for studies supporting drug development by providing fast data turnaround for assays conforming to regulatory guidelines and GLPs.