RESUMO
The goal of the present analysis is to fit a Bayesian population pharmacokinetic pharmacodynomic (PK-PD) model to characterize the relationship between the concentration of ispinesib and changes in absolute neutrophil counts (ANC). Ispinesib, a kinesin spindle protein (KSP) inhibitor, blocks assembly of a functional mitotic spindle, leading to G2/M arrest. A first time in human, phase I open-label, non-randomized, dose-escalating study evaluated ispinesib at doses ranging from 1 to 21 mg/m(2). PK-PD data were collected from 45 patients with solid tumors. The pharmacokinetics of ispinesib were well characterized by a two-compartment model. A semimechanistic model was fit to the ANC. The PK and PD data were successfully modelled simultaneously. This is the first presentation of simultaneously fitting a PK-PD model to ANC using Bayesian methods. Bayesian methods allow for the use of prior information for some system-related parameters. The model may be used to examine different schedules, doses, and infusion times.
Assuntos
Antineoplásicos/farmacologia , Teorema de Bayes , Benzamidas/farmacologia , Neutropenia/induzido quimicamente , Quinazolinas/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Benzamidas/efeitos adversos , Benzamidas/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Humanos , Contagem de Leucócitos , Masculino , Cadeias de Markov , Pessoa de Meia-Idade , Modelos Biológicos , Método de Monte Carlo , Neutropenia/sangue , Quinazolinas/efeitos adversos , Quinazolinas/farmacocinéticaRESUMO
PURPOSE: A phase I study was conducted to determine the maximum-tolerated dose (MTD), toxicity profile, and pharmacokinetics of a novel purine nucleoside, nelarabine, a soluble prodrug of 9-beta-D-arabinosylguanine (araG; Nelarabine), in pediatric and adult patients with refractory hematologic malignancies. PATIENTS AND METHODS: Between April 1994 and April 1997, 93 patients with refractory hematologic malignancies were treated with one to 16 cycles of study drug. Nelarabine was administered daily, as a 1-hour intravenous infusion for 5 consecutive days, every 21 to 28 days. First-cycle pharmacokinetic data, including plasma nelarabine and araG levels, were obtained on all patients treated. Intracellular phosphorylation of araG was studied in samples of leukemic blasts from selected patients. RESULTS: The MTDs were defined at 60 mg/kg/dose and 40 mg/kg/dose daily x 5 days in children and adults, respectively. Dose-limiting toxicity (DLT) was neurologic in both children and adults. Myelosuppression and other significant organ toxicities did not occur. Pharmacokinetic parameters were similar in children and adults. Accumulation of araGTP in leukemic blasts was correlated with cytotoxic activity. The overall response rate was 31%. Major responses were seen in patients with T-cell malignancies, with 54% of patients with T-lineage acute lymphoblastic leukemia achieving a complete or partial response after one to two courses of drug. CONCLUSION: Nelarabine is a novel nucleoside with significant cytotoxic activity against malignant T cells. DLT is neurologic. Phase II and III trials in patients with T-cell malignancies are encouraged.
Assuntos
Arabinonucleosídeos/administração & dosagem , Resistencia a Medicamentos Antineoplásicos , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/patologia , Invasividade Neoplásica/patologia , Adolescente , Adulto , Idoso , Arabinonucleosídeos/efeitos adversos , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Seguimentos , Neoplasias Hematológicas/mortalidade , Humanos , Infusões Intravenosas , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Recidiva , Medição de Risco , Taxa de Sobrevida , Resultado do TratamentoRESUMO
PURPOSE: To characterize the pharmacokinetics of nelarabine (506U78), the water-soluble prodrug of 9-beta-D-arabinofuranosyl guanine (ara-G), and ara-G in pediatric and adult patients with refractory hematologic malignancies. Ara-G is phosphorylated within leukemic cells to form ara-G triphosphate (ara-GTP), which acts to terminate DNA chain elongation, resulting in cell death. PATIENTS AND METHODS: The pharmacokinetics of nelarabine and/or ara-G were evaluated in 71 patients (25 pediatric and 46 adult patients) on the first day of therapy. Blood was collected at specified times for the determination of plasma nelarabine and ara-G concentrations. RESULTS: There were no statistically significant differences in the pharmacokinetics of nelarabine between any of the groups of patients. The harmonic mean half-life (t1/2) of nelarabine in pediatric and adult patients was 14.1 minutes and 16.5 minutes, respectively. The maximum concentrations (C(max)) of ara-G occurred at or near the end of the nelarabine infusion. The C(max) of ara-G ranged from 11.6 micromol/L to 308.7 micromol/L at nelarabine doses of 5 to 75 mg/kg and was linearly related to the nelarabine dose. No statistically significant differences were noted for the pharmacokinetic parameter estimates of ara-G between adult male and female patients. In children versus adults, the dose-normalized C(max), time of the C(max), and the steady-state volume of distribution of ara-G were similar. However, the clearance of ara-G was higher in pediatric patients (0.312 L.h(-1).kg(-1)) as compared with adult patients (0. 213 L.h(-1).kg(-1)) (P <.001). The t1/2 of ara-G was shorter in pediatric patients as compared with adult patients (2.1 hours v 3.0 hours; P <.01). CONCLUSION: Nelarabine is an effective prodrug of ara-G, allowing systemic concentrations of ara-G that result in clinical activity.
Assuntos
Antineoplásicos/farmacocinética , Arabinonucleosídeos/farmacocinética , Neoplasias Hematológicas/metabolismo , Adolescente , Adulto , Idoso , Antineoplásicos/uso terapêutico , Arabinonucleosídeos/uso terapêutico , Criança , Pré-Escolar , Feminino , Neoplasias Hematológicas/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
PURPOSE: A pilot protocol was designed to evaluate the efficacy of fludarabine with nelarabine (the prodrug of arabinosylguanine [ara-G]) in patients with hematologic malignancies. The cellular pharmacokinetics was investigated to seek a relationship between response and accumulation of ara-G triphosphate (ara-GTP) in circulating leukemia cells and to evaluate biochemical modulation of cellular ara-GTP metabolism by fludarabine triphosphate. PATIENTS AND METHODS: Nine of the 13 total patients had indolent leukemias, including six whose disease failed prior fludarabine therapy. Two patients had T-acute lymphoblastic leukemia, one had chronic myelogenous leukemia, and one had mycosis fungoides. Nelarabine (1.2 g/m(2)) was infused on days 1, 3, and 5. On days 3 and 5, fludarabine (30 mg/m(2)) was administered 4 hours before the nelarabine infusion. Plasma and cellular pharmacokinetic measurements were conducted during the first 5 days. RESULTS: Seven patients had a partial or complete response, six of whom had indolent leukemias. The disease in four responders had failed prior fludarabine therapy. The median peak intracellular concentrations of ara-GTP were significantly different (P =.001) in responders (890 micromol/L, n = 6) and nonresponders (30 micromol/L, n = 6). Also, there was a direct relationship between the peak fludarabine triphosphate and ara-GTP in each patient (r = 0.85). The cellular elimination of ara-GTP was slow (median, 35 hours; range, 18 to > 48 hours). The ratio of ara-GTP to its normal counterpart, deoxyguanosine triphosphate, was higher in each patient (median, 42; range, 14 to 1,092) than that of fludarabine triphosphate to its normal counterpart, deoxyadenosine triphosphate (median, 2.2; range, 0.2 to 27). CONCLUSION: Fludarabine plus nelarabine is an effective, well-tolerated regimen against leukemias. Clinical responses suggest the need for further exploration of nelarabine against fludarabine-refractory diseases. Determination of ara-GTP levels in the target tumor population may provide a prognostic test for the activity of nelarabine.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Prolinfocítica/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Vidarabina/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Arabinonucleosídeos/administração & dosagem , Arabinonucleosídeos/farmacocinética , Arabinonucleosídeos/farmacologia , Arabinonucleotídeos/análise , Arabinonucleotídeos/metabolismo , Biomarcadores/análise , Feminino , Guanosina Trifosfato/análogos & derivados , Guanosina Trifosfato/análise , Guanosina Trifosfato/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Resultado do Tratamento , Vidarabina/administração & dosagem , Vidarabina/farmacocinética , Vidarabina/farmacologiaRESUMO
Pazopanib, an oral inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-kit kinases, inhibits multiple cytochrome P450 (CYP450) enzymes in vitro. This study in patients with advanced cancer evaluated the effect of pazopanib on CYP450 function by comparing the pharmacokinetics of CYP-specific probe drugs in the presence and absence of pazopanib. The probes used included midazolam (CYP3A specific), warfarin (CYP2C9 specific), omeprazole (CYP2C19 specific), caffeine (CYP1A2 specific), and dextromethorphan (CYP2D6 specific). The estimated ratios of the geometric means (90% confidence interval (CI)) for the area under the curve to the last measurable point (AUC(0-t)) for these probe drugs with/without pazopanib were as follows: midazolam, 1.35 (1.18-1.54); omeprazole, 0.81 (0.59-1.12); caffeine, 1.00 (0.77-1.30); and S-warfarin, 0.93 (0.84-1.03). The geometric least-squares (LS) mean ratio of urine dextromethorphan:dextrorphan ranged from 1.33 (0-4-h interval) to 1.64 (4-8-h interval). The data suggest that pazopanib is a weak inhibitor of CYP3A4 and CYP2D6 and has no effect on CYP1A2, CYP2C9, and CYP2C19 in patients with advanced cancer.
Assuntos
Inibidores da Angiogênese/administração & dosagem , Inibidores das Enzimas do Citocromo P-450 , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Sulfonamidas/administração & dosagem , Administração Oral , Idoso , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/farmacocinética , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Interações Medicamentosas , Feminino , Genótipo , Humanos , Indazóis , Isoenzimas , Masculino , Pessoa de Meia-Idade , Sondas Moleculares , Neoplasias/enzimologia , Neoplasias/patologia , New Hampshire , Fenótipo , Polimorfismo Genético , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Singapura , Especificidade por Substrato , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacocinética , Resultado do TratamentoRESUMO
Pazopanib is an oral angiogenesis inhibitor of vascular endothelial growth factor (VEGF) receptor, platelet-derived growth factor receptor, and cytokine receptor. This open-label, randomized, crossover, phase I study evaluated the effect of low- and high-fat meals on the pharmacokinetics (PK) of pazopanib in patients with advanced solid tumors. Patients participated in either the lead-in cohort or randomized food-effect cohort. Patients in the lead-in cohort were administered a single dose of pazopanib 400 mg with a high-fat meal. Patients in the food-effect cohort were randomized to receive single doses of pazopanib 800 mg in fed condition (high- or low-fat meal) or fasting condition, in random sequence 14 days apart. After completion of the study, patients were given the opportunity to continue treatment with daily pazopanib 800 mg. Administration of pazopanib with both low- and high-fat meals increased maximum observed plasma concentration (C(max)) and area under the plasma concentration-time curve (AUC) by approximately twofold as compared with the corresponding values when administered to patients in the fasted condition. Therefore, pazopanib should be administered to patients in the fasted state so as to minimize within- and between-day variability in the systemic exposure to pazopanib in patients with cancer.
Assuntos
Gorduras na Dieta/metabolismo , Interações Alimento-Droga/fisiologia , Neoplasias/metabolismo , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacocinética , Administração Oral , Adulto , Idoso , Estudos de Coortes , Estudos Cross-Over , Fadiga/induzido quimicamente , Feminino , Humanos , Hipertensão/induzido quimicamente , Indazóis , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Pirimidinas/administração & dosagem , Sulfonamidas/administração & dosagemRESUMO
The aim of this study is to define the maximum tolerated dose (MTD), safety, pharmacokinetics (PKs) and efficacy of ispinesib (SB-715992) in combination with docetaxel. Patients with advanced solid tumours were treated with ispinesib (6-12 mg m(-2)) and docetaxel (50-75 mg m(-2)). Docetaxel was administered over 1 h followed by a 1-h infusion of ispinesib on day 1 of a 21-day schedule. At least three patients were treated at each dose level. Blood samples were collected during cycle 1 for PK analysis. Clinical response assessments were performed every two cycles using RECIST guidelines. Twenty-four patients were treated at four dose levels. Prolonged neutropaenia and febrile neutropaenia were dose limiting in six and two patients, respectively. The MTD was ispinesib 10 mg m(-2) with docetaxel 60 mg m(-2). Pharmacokinetic assessment demonstrated concentrations of ispinesib and docetaxel, consistent with published data from single agent studies of the drugs. Seven patients (six hormone refractory prostate cancer (HRPC), one renal cancer) had a best response of stable disease (>or=18 weeks). One patient with HRPC had a confirmed >50% prostatic-specific antigen decrease. The MTD for ispinesib and docetaxel was defined and the combination demonstrated an acceptable toxicity profile. Preliminary PK data suggest no interaction between ispinesib and docetaxel.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzamidas/administração & dosagem , Cinesinas/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Quinazolinas/administração & dosagem , Taxoides/administração & dosagem , Adulto , Idoso , Benzamidas/efeitos adversos , Benzamidas/farmacocinética , Docetaxel , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Quinazolinas/efeitos adversos , Quinazolinas/farmacocinética , Taxoides/efeitos adversos , Taxoides/farmacocinéticaRESUMO
Oxygen tolerance of the microaerophile Campylobacter jejuni subsp. jejuni varied with different brands of complex media which were used for plating the dilute cell suspensions. The tryptone component was one factor. With some tryptones growth occurred at 21% oxygen whereas with others there was no growth at oxygen levels of 15% or higher. A chemically-defined, agar-solidified plating medium was used to estimate the oxygen tolerance of Camp. jejuni subsp. jejuni, Camp. coli and Camp. fetus subsp. fetus, and also to assess the effect of added scavengers of reactive oxygen intermediates on the oxygen tolerance. Some scavengers such as allopurinol, azelaic acid, caffeine, cimetidine, TEMPOL and pyruvate enhanced oxygen tolerance markedly whereas others such as carnosine, dimethyl thiourea, spermidine and superoxide dismutase had little effect.