RESUMEN
Tamoxifen undergoes biotransformation into several metabolites, including endoxifen. Differences in metabolism contribute to the interindividual variability in endoxifen concentrations, potentially affecting treatment efficacy. We evaluated the effects of cytochrome P450 (CYP) induction by rifampicin on the exposure levels of tamoxifen and its metabolites and found that coadministration of rifampicin resulted in markedly reduced (up to 86%, P ≤ 0.040) concentrations of tamoxifen and its metabolites. Given the extensive metabolism undergone by tamoxifen, several factors may have contributed to this effect. Similar drug-drug interactions may exist between tamoxifen and other strong CYP inducers.
Asunto(s)
Biotransformación , Rifampin/farmacocinética , Tamoxifeno/farmacocinética , Adulto , Antineoplásicos/farmacocinética , Biotransformación/efectos de los fármacos , Biotransformación/fisiología , Neoplasias de la Mama/tratamiento farmacológico , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Interacciones Farmacológicas , Monitoreo de Drogas , Quimioterapia Combinada/efectos adversos , Quimioterapia Combinada/métodos , Femenino , Genotipo , Humanos , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
ABCC2 (MRP2, cMOAT) expression has been implicated in cisplatin resistance in vitro. In mice, cisplatin disposition and toxicity were unaffected by Abcc2 knockout (Abcc2−/−). Moreover, in cancer patients (n = 237), cisplatin pharmacokinetics (P > 0.12) and efficacy (P > 0.41) were not associated with seven of the single-nucleotide polymorphisms (SNPs) in ABCC2. These SNPs were also not correlated with ABCC2 expression in the NCI60 panel (P > 0.26) or with cisplatin-induced cytotoxicity (P = 0.21). These findings highlight the importance of verifying drug-transporter interactions with in vitro tests in humans.
Asunto(s)
Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Cisplatino/farmacocinética , Cisplatino/uso terapéutico , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Animales , Antineoplásicos/efectos adversos , Línea Celular Tumoral , Cisplatino/efectos adversos , Estudios de Cohortes , ADN/genética , Variación Genética , Humanos , Enfermedades Renales/inducido químicamente , Ratones , Ratones Noqueados , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Polimorfismo Genético , Polimorfismo de Nucleótido Simple , ARN/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Población Blanca , Imagen de Cuerpo EnteroRESUMEN
The bioavailability of orally administered imatinib is >90%, although the drug is monocationic under the acidic conditions in the duodenum. In vitro, we found that imatinib is transported by the intestinal uptake carrier organic anion transporting polypeptide (OATP1A2) and that this process is sensitive to pH, rosuvastatin, and genetic variants. However, in a study in patients with cancer, imatinib absorption was not associated with OATP1A2 variants and was unaffected by rosuvastatin. These findings highlight the importance of verifying in a clinical setting the drug-transporter interactions observed in in vitro tests.
Asunto(s)
Ambiente , Transportadores de Anión Orgánico/genética , Transportadores de Anión Orgánico/metabolismo , Piperazinas/metabolismo , Pirimidinas/metabolismo , Animales , Benzamidas , Transporte Biológico Activo/fisiología , Femenino , Células HeLa , Humanos , Mesilato de Imatinib , Piperazinas/antagonistas & inhibidores , Pirimidinas/antagonistas & inhibidores , Xenopus laevisRESUMEN
BACKGROUND: This study aimed to define the maximally tolerated dose (MTD) of sunitinib combined with two different infusion schedules of ifosfamide. METHODS: Patients with advanced solid tumours, good performance score, good organ function, and no standard therapy available were eligible. Continuous once daily sunitinib, in escalating doses per cohort, was combined with ifosfamide, 9 g m(-2) for 3 days or 6 g m(-2) for 5 days, administered every 3 weeks. Pharmacokinetic (PK) and pharmacodynamic (PD) assessments were performed. RESULTS: With growth-factor support, the MTD of sunitinib combined with either ifosfamide schedule was 12.5 mg in 32 patients enrolled. Neutropenia-related adverse events were dose-limiting toxicities. Sunitinib did not affect ifosfamide PK. Ifosfamide significantly decreased exposure to sunitinib and increased exposure to its metabolite, SU12662. No consistent changes in PD parameters were observed. CONCLUSION: With growth-factor support, the MTD of sunitinib with both ifosfamide schedules was 12.5 mg. Ifosfamide produced decreased sunitinib blood levels because of CYP3A induction. As PK interactions cannot explain the relatively low sunitinib doses that can be combined with ifosfamide, synergy in toxicity is likely. Whether this also holds true for anti-tumour activity needs to be further explored.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ifosfamida/administración & dosificación , Indoles/administración & dosificación , Neoplasias/tratamiento farmacológico , Pirroles/administración & dosificación , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Esquema de Medicación , Interacciones Farmacológicas , Femenino , Humanos , Ifosfamida/efectos adversos , Ifosfamida/farmacocinética , Indoles/efectos adversos , Indoles/farmacocinética , Masculino , Dosis Máxima Tolerada , Pirroles/efectos adversos , Pirroles/farmacocinética , SunitinibRESUMEN
BACKGROUND: Solute carriers (SLCs), in particular organic cation transporters (OCTs), have been implicated in the cellular uptake of platinum-containing anticancer compounds. The activity of these carriers may determine the pharmacokinetics and the severity of side effects, including neuro- and nephrotoxicity of platinum-based chemotherapy. As decreased drug accumulation is a key mechanism of platinum resistance, SLCs may also contribute to the development of resistance. Here, we define the role of hSLC22A2 (OCT2) in the cellular uptake of platinum compounds. EXPERIMENTAL APPROACH: Human embryonic kidney (HEK) 293 cells stably expressing the hSLC22A2 gene (HEK293/hSLC22A2) were used in platinum accumulation studies. Following a 2 h exposure to various platinum compounds (100 microM), intracellular platinum levels were determined by flameless atomic absorption spectrometry. KEY RESULTS: HEK293/hSLC22A2 cells, compared with HEK293/Neo control cells, displayed significant increases in oxaliplatin (28.6-fold), Pt[DACH]Cl(2) (20.6-fold), ormaplatin (8.1-fold), tetraplatin (4.5-fold), transplatin (3.7-fold) and cisplatin (1.3-fold), but not carboplatin. SLC22A2-mediated transport could be inhibited by 1-methyl-4-phenylpyridinium. Furthermore, hSLC22A2-mediated oxaliplatin and cisplatin accumulation was time- and concentration-dependent, but non-saturable. Expression of hSLC22A2 in HEK293 cells resulted in enhanced sensitivity to oxaliplatin (12-fold) and cisplatin (1.8-fold). Although, hSLC22A2 mRNA expression was frequently found in ovarian cancer cell lines, its expression in clinical ovarian cancer specimens (n= 80) was low and did not correlate with the treatment outcome of platinum-based regimens. CONCLUSIONS AND IMPLICATIONS: The hSLC22A2 drug transporter is a critical determinant in the uptake and cytotoxicity of various platinum compounds, particularly oxaliplatin.
Asunto(s)
Antineoplásicos/metabolismo , Proteínas de Transporte de Catión Orgánico/metabolismo , Compuestos Organoplatinos/metabolismo , Compuestos de Platino/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Transporte Biológico , Carboplatino/metabolismo , Línea Celular , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cisplatino/metabolismo , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos , Femenino , Humanos , Cinética , Proteínas de Transporte de Catión Orgánico/antagonistas & inhibidores , Proteínas de Transporte de Catión Orgánico/genética , Transportador 2 de Cátion Orgánico , Compuestos Organoplatinos/farmacología , Compuestos Organoplatinos/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Oxaliplatino , Compuestos de Platino/farmacología , Compuestos de Platino/uso terapéutico , ARN Mensajero/metabolismo , Espectrofotometría Atómica , Transfección , Resultado del TratamientoRESUMEN
PURPOSE: To determine ophthalmologic and systemic factors associated with the presence of cystoid macular oedema (CMO) in patients with uveitis. METHODS: Retrospective cross-sectional study in which 97 consecutive patients with uveitis filled in an extensive questionnaire for the presence of cardiovascular diseases and its risk factors. An analysis of the ophthalmologic and questionnaire data was conducted. RESULTS: CMO was present in 44% (43/97) of patients. Its presence was strongly associated with increasing age (P=0.001) and age at onset of uveitis (P<0.001). For patients older than 50 years, the risk of having CMO was 3.8-fold (95% confidence intervals 1.6-9.0) larger than for younger patients. The most frequent anatomic location of uveitis associated with CMO was panuveitis (49%). Papillary leakage on fluorescein angiography was associated with CMO (P<0.001), independently of other risk factors. After adjustment for age, multivariate logistic regression showed no association between cardiovascular disease and its risk factors and the presence of CMO. CONCLUSIONS: Age, independent of duration of uveitis, was a major risk factor for the presence of CMO in uveitis. A positive correlation between CMO and papillary leakage on angiography was noted.
Asunto(s)
Edema Macular/etiología , Uveítis/complicaciones , Adolescente , Adulto , Factores de Edad , Edad de Inicio , Anciano , Anciano de 80 o más Años , Enfermedades Cardiovasculares/complicaciones , Niño , Métodos Epidemiológicos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Panuveítis/complicacionesRESUMEN
Microdialysis is a novel and minimally invasive sampling technique, based on the diffusion of analytes from the interstitial compartment through a semi-permeable membrane, and enables direct assessment of tissue disposition and penetration of drugs. Variable antitumor responses may be associated with differences in tumor vascularity, capillary permeability or tumor interstitial pressure resulting in variable delivery of anticancer agents. In preparation of pharmacokinetic studies, aimed at measuring docetaxel concentrations in healthy and malignant tissues in vivo, in pre-clinical as well as clinical studies, in vitro recovery experiments were performed. In contrast to published data, the recovery experiments suggest that docetaxel has a very low recovery as a result of non-specific binding to currently available microdialysis catheters. Here we discuss our findings with docetaxel in a historical perspective and we report on our experience using polysorbate 80 to eliminate the non-specific binding and its effects on the recovery of docetaxel.
Asunto(s)
Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Microdiálisis/métodos , Taxoides/administración & dosificación , Taxoides/farmacocinética , Cromatografía Liquida , Protocolos Clínicos , Docetaxel , Humanos , Espectrometría de MasasRESUMEN
BACKGROUND: The aim of the study was to determine the safety profile, pharmacokinetics and potential drug interactions of the angiogenesis inhibitor ABT-510 combined with gemcitabine-cisplatin chemotherapy in patients with solid tumors. PATIENTS AND METHODS: Patients with advanced solid tumors received gemcitabine 1250 mg/m2 intravenously (i.v.) on days 1 and 8 and cisplatin 80 mg/m2 on day 1 of a 3-week cycle in combination with ABT-510. ABT-510 was administered subcutaneously twice daily at doses of 50 mg or 100 mg. Plasma samples for pharmacokinetics were obtained on days 1 (gemcitabine, cisplatin as single agents), 15 (ABT-510 as single agent) and 22 (gemcitabine, cisplatin and ABT-510 as combination). RESULTS: Thirteen patients received ABT-510 as either 50 mg b.i.d. (seven patients) or 100 mg b.i.d. (six patients) in combination with gemcitabine-cisplatin. The most common reported adverse events reflected the known toxicity profile induced by gemcitabine-cisplatin without ABT-510. One episode of hemoptysis occurred in a patient with non-small-cell lung cancer (NSCLC) after 13 days of treatment. No clinically significant pharmacokinetic interactions between ABT-510, gemcitabine and platinum were observed. Three partial responses were observed in 12 evaluable patients (one head and neck cancer, one melanoma and one NSCLC). CONCLUSIONS: Combining ABT-510 at doses of 50 mg and 100 mg with gemcitabine-cisplatin is feasible. Pharmacokinetic interactions were not observed and adding ABT-510 does not appear to increase toxicity.
Asunto(s)
Inhibidores de la Angiogénesis/efectos adversos , Inhibidores de la Angiogénesis/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias/tratamiento farmacológico , Oligopéptidos/efectos adversos , Oligopéptidos/farmacocinética , Adulto , Anciano , Inhibidores de la Angiogénesis/administración & dosificación , Cisplatino/administración & dosificación , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Interacciones Farmacológicas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oligopéptidos/administración & dosificación , Trombospondina 1/química , Trombospondina 1/farmacología , GemcitabinaRESUMEN
BACKGROUND: The purpose of this study was to look at the pharmacokinetics of docetaxel, cisplatin-derived platinum and 5-fluorouracil (5-FU), when used in combination, to exclude potential clinically relevant pharmacokinetic interactions. METHODS: Fifteen patients with recurrent or metastatic solid tumors were randomized to receive docetaxel 75 mg/m2 and cisplatin 75 mg/m2 in the first treatment course on day 1 and the same combination plus 5-FU 750 mg/m2/day on days 1-5 in the second course, or the two treatment courses in reversed order. Cycles were repeated every 3 weeks. A pharmacokinetic analysis was performed during the first two cycles. RESULTS: Full pharmacokinetic data was available for 12 of the 15 patients. Treatment was tolerated well, with frequency of toxicity consistent with the safety profile known for docetaxel, cisplatin and 5-FU. Mean clearance values for docetaxel and cisplatin showed no statistically significant difference across the "triple" and the "double" combination treatments, and the mean pharmacokinetic parameters of all agents were within the ranges for previously reported single agent treatment. CONCLUSION: No clinically relevant pharmacokinetic interactions between docetaxel, cisplatin and 5-FU used in combination were noticed in this study.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cisplatino/farmacocinética , Fluorouracilo/farmacocinética , Neoplasias/tratamiento farmacológico , Taxoides/farmacocinética , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Área Bajo la Curva , Cisplatino/administración & dosificación , Cisplatino/sangre , Docetaxel , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/sangre , Semivida , Humanos , Infusiones Intravenosas , Leucopenia/inducido químicamente , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia , Neoplasias/metabolismo , Neutropenia/inducido químicamente , Taxoides/administración & dosificación , Taxoides/sangre , Resultado del TratamientoRESUMEN
XR11576 is an oral topoisomerase I and II inhibitor. The objectives of this phase I study were to assess the dose-limiting toxicities (DLTs), to determine the maximum tolerated dose (MTD) and to describe the pharmacokinetics (PKs) of XR11576 when administered orally on days 1-5 every 3 weeks to patients with advanced solid tumours. Patients were treated with escalating doses of XR11576 at doses ranging from 30 to 180 mg day(-1). For PK analysis, plasma sampling was performed during the first and second courses of treatment and XR11576 concentrations were assayed using a validated high-performance liquid chromatographic assay with mass spectrometric detection. In all, 21 patients received a total of 47 courses. The MTD was reached at 180 mg day(-1), with diarrhoea and fatigue as DLT. Nausea and vomiting, although not qualifying for DLT, was ubiquitous. Only in combination with an extensive prophylactic antiemetic regimen consisting of a combination of both dexamethasone and a 5HT3 antagonist was treatment with XR11576 at 120 mg day(-1) tolerable. The systemic exposure of XR11576 increased more than proportionally with increasing dose, with a large interpatient variability. No objective responses were seen; four patients experienced stable disease for periods of 12-30 weeks. In this study, the DLTs of XR11576 were diarrhoea and fatigue. The recommended dose for phase II studies of XR11576 is 120 mg administered orally, on days 1-5 every 21 days. Alternative regimens are currently being explored.
Asunto(s)
Inhibidores Enzimáticos/farmacocinética , Neoplasias/tratamiento farmacológico , Fenazinas/farmacocinética , Inhibidores de Topoisomerasa I , Inhibidores de Topoisomerasa II , Administración Oral , Adolescente , Adulto , Anciano , Área Bajo la Curva , Cromatografía Líquida de Alta Presión , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/uso terapéutico , Femenino , Humanos , Masculino , Espectrometría de Masas , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/metabolismo , Fenazinas/uso terapéuticoRESUMEN
The purpose of this weekly schedule phase I study of liposome encapsulated paclitaxel (LEP) was to define the maximum-tolerated dose (MTD), the recommended dose (RD), the dose-limiting toxicities (DLTs), the pharmacokinetic profiles, and to evaluate preliminarily antitumour effects in patients with refractory solid malignancies. LEP was administered as an intravenous (i.v.) infusion over 45 min once every week for 6 out of 8 weeks. Fourteen patients were treated at doses ranging from 90 to 150 mg/m(2)/week. In one patient, DLT was observed at the dose level of 150 mg/m(2)/week, who received less than 70% of the intended cumulative dose. No cumulative toxicities were observed. Stabilisation of disease for 8 weeks was documented in two patients. The whole blood clearance of total paclitaxel was similar for LEP (15.3+/-8.98 l/h/m(2)) and Taxol (17.5+/-3.43 l/h/m(2)), and the extraliposomal to total drug ratio increased rapidly to unity at later sampling time points. The trial was discontinued upon completion of enrolment of the 150 mg/m(2)/week cohort because an assessment of the pharmacokinetics and clinical data suggested that LEP was unlikely to have any advantages over Taxol. It is concluded that this formulation of LEP is unlikely to provide improvements over the taxanes currently in clinical use.
Asunto(s)
Antineoplásicos Fitogénicos/farmacocinética , Neoplasias/tratamiento farmacológico , Paclitaxel/farmacocinética , Adulto , Anciano , Análisis de Varianza , Antineoplásicos Fitogénicos/efectos adversos , Estudios de Cohortes , Toma de Decisiones , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Semivida , Humanos , Infusiones Intravenosas , Liposomas , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Paclitaxel/efectos adversos , Resultado del TratamientoRESUMEN
The aim of this study was to characterise the pharmacokinetics of the anticancer agent topotecan, and explore the influence of patient covariates and interoccasion variability on drug disposition. Data were obtained from 190 patients who received the drug as a 30-min infusion (N=72) or orally (N=118). The population model was built with the use of NONMEM to identify candidate covariates, and obtain models for clearance (CL) and volume of distribution. The final models were based on first-order absorption with lag-time (oral data), and a two-compartment model with linear elimination from the central compartment. The Cockcroft-Gault creatinine clearance (CrCl) and WHO performance status (PS) were the only significant covariates: CL=(12.8+2.1 x CrCl) x (1-0.12 x PS). For the volume of distribution, a correlation was found between body weight and the central volume (V1)=0.58 x body weight. Based on the structural models, a limited-sampling strategy was developed with minor bias and good precision that can be applied a posteriori using timed samples obtained at 1.5, and 6 h after the administration of topotecan. In conclusion, a population pharmacokinetic model for topotecan has been developed that incorporates measures of renal function and PS to predict CL. In combination with drug monitoring, the limited sampling strategy allows individualised treatment for patients receiving oral topotecan.
Asunto(s)
Antineoplásicos/farmacocinética , Modelos Teóricos , Topotecan/farmacocinética , Administración Oral , Adolescente , Adsorción , Adulto , Anciano , Antineoplásicos/administración & dosificación , Disponibilidad Biológica , Creatinina/metabolismo , Femenino , Humanos , Infusiones Intravenosas , Riñón/fisiología , Masculino , Persona de Mediana Edad , Topotecan/administración & dosificaciónRESUMEN
The study described here was designed to investigate the influence of the hydration schedule of cisplatin on the pharmacokinetics of topotecan. To test this hypothesis, 13 adult cancer patients were treated with intravenous (i.v.) cisplatin followed by i.v. topotecan for 5 days every 3 weeks using a short hydration schedule (SHS) for cisplatin in the first course and a hyper-hydration schedule (HHS) in the second course or vice versa. Topotecan pharmacokinetic analysis was performed in plasma, whole blood and red blood cells in both courses on days 1, 2 and 5. 11 patients received both courses and were pharmacokinetically evaluable. No significant differences between the two studied schedules were noted in the clearances of topotecan on day 1 in the different matrices. However, in both hydration schedules, on average, slightly lower topotecan clearances were observed on both days 2 and 5 compared with day 1 in all of the matrices, while no differences were noted between days 2 and 5. This alteration was independent of the schedule used and was less pronounced than that which has been initially reported for SHS and, overall, will not have clinical consequences.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Cisplatino/farmacología , Neoplasias/tratamiento farmacológico , Topotecan/farmacocinética , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Cisplatino/administración & dosificación , Esquema de Medicación , Interacciones Farmacológicas , Femenino , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Topotecan/administración & dosificaciónRESUMEN
We have shown previously that the terminal disposition half-life of SN-38, the active metabolite of irinotecan, is much longer than earlier thought. Currently, it is not known whether this prolonged exposure has any relevance toward SN-38-induced toxicity. Here, we found that SN-38 concentrations present in human plasma for up to 3 weeks after a single irinotecan infusion induce significant cytotoxicity in vitro. Using pharmacokinetic data from 26 patients, with sampling up to 500 h, relationships were evaluated between systemic exposure (AUC) to SN-38 and the per cent decrease in absolute neutrophil count (ANC) at nadir, or by taking the entire time course of ANC into account (AOC). The time course of SN-38 concentrations (AUC(500 h)) was significantly related to this AOC (P<0.001). Based on these findings, a new limited-sampling model was developed for SN-38 AUC(500 h) using only two timed samples: AUC(500 h)=(6.588 x C(2.5 h))+(146.4 x C(49.5 h))+15.53, where C(2.5 h) and C(49.5 h) are plasma concentrations at 2.5 and 49.5 h after start of infusion, respectively. The use of this limited-sampling model may open up historic databases to retrospectively obtain information about SN-38-induced toxicity in patients treated with irinotecan.
Asunto(s)
Antineoplásicos Fitogénicos/farmacocinética , Camptotecina/farmacocinética , Profármacos/farmacocinética , Adulto , Anciano , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/sangre , Antineoplásicos Fitogénicos/uso terapéutico , Área Bajo la Curva , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Camptotecina/análogos & derivados , Camptotecina/sangre , Camptotecina/farmacología , Camptotecina/uso terapéutico , Neoplasias del Colon/patología , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/tratamiento farmacológico , Esquema de Medicación , Femenino , Humanos , Irinotecán , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Neutropenia/inducido químicamente , Neoplasias Ováricas/patología , Profármacos/administración & dosificación , Profármacos/efectos adversos , Profármacos/uso terapéutico , Distribución Aleatoria , Células Tumorales Cultivadas/efectos de los fármacos , Neoplasias del Cuello Uterino/sangre , Neoplasias del Cuello Uterino/tratamiento farmacológicoRESUMEN
Population pharmacokinetic-dynamic analysis was prospectively integrated in a broad phase II program of lurtotecan (GI147211), a novel camptothecin derived topoisomerase I inhibitor, to determine the population pharmacokinetic profile in a larger population, to estimate individual pharmacokinetic parameters and to investigate relationships with clinical outcome. A sparse sampling method was applied during course one, which involved two sampling time-points. A Bayesian algorithm was used to estimate individual pharmacokinetic parameters, in particular total plasma clearance (CL) and volume of distribution. In total, samples were collected of 109 (63%) of 173 patients. Pharmacokinetic-dynamic evaluation could be carried out successfully in 85 (78%) of the sampled patients. CL of lurtotecan showed substantial variability (mean 87 +/- 28 L/h) and was of the same magnitude as in the phase I studies where full pharmacokinetic curves were used. Residual variability in the population estimate of CL was 9.9%. No significant relationships were observed between exposure parameters and toxicity nor likelihood of tumor response, however the latter relationship may well have been obscured by the heterogeneity of the studied population. Prospective implementation of large scale population pharmacokinetic-dynamic analysis is feasible and important to establish whether interpatient variability in drug exposure is a major determinant of toxicity or activity.
Asunto(s)
Antineoplásicos/farmacología , Camptotecina/farmacología , Inhibidores Enzimáticos/farmacología , Neoplasias/metabolismo , Inhibidores de Topoisomerasa I , Adulto , Anciano , Antineoplásicos/farmacocinética , Antineoplásicos/toxicidad , Área Bajo la Curva , Camptotecina/análogos & derivados , Camptotecina/farmacocinética , Camptotecina/toxicidad , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/toxicidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Estudios Prospectivos , MuestreoRESUMEN
This phase I study was performed to assess the feasibility and possible enhanced antitumour activity of the sequential administration of methotrexate (MTX) and docetaxel (D) in patients with solid tumours. Pharmacokinetic analysis was performed to investigate the pharmacokinetic interaction of the two agents. A total of 22 patients were enrolled, a total of six dose levels were investigated. MTX (days 1+15) 30, 40 and 50 mg/m(2)+D (day 2 or day 1) 75 and 85 mg/m(2) with supportive care measures. Both haematological and non-haematological toxicities were significant, preventing dose escalation above MTX 40 mg/m(2)+D 75 mg/m(2). Four partial responses were documented, three in patients with breast cancer, one in a patient with urothelial cell cancer. Pharmacokinetic data did not give an explanation for the significant toxicity as they revealed no interaction of D and MTX kinetics. Methotrexate and 7-OH MTX kinetics seemed to be independent of the administration of D and the moment of D administration appeared not to influence MTX kinetics. The sequential administration of MTX and D results in significant toxicity without any evidence of a clinical benefit.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias/tratamiento farmacológico , Paclitaxel/análogos & derivados , Taxoides , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Docetaxel , Sinergismo Farmacológico , Femenino , Humanos , Masculino , Metotrexato/administración & dosificación , Metotrexato/farmacocinética , Persona de Mediana Edad , Paclitaxel/administración & dosificación , Paclitaxel/farmacocinéticaRESUMEN
The paclitaxel vehicle Cremophor EL (CrEL) has been shown to selectively inhibit the accumulation of cisplatin in peripheral blood leucocytes, but not in tumour cells in vitro, and we hypothesised that this phenomenon is responsible for the improvement of the therapeutic index of cisplatin observed in combination studies with paclitaxel. Here, we report on studies assessing the interaction between CrEL and cisplatin in a murine model, and involving the potential clinical applicability of CrEL as a protector for cisplatin-associated haematological side-effects. In mice, CrEL (0.17 ml/kg, intravenous (i.v.)) given in combination with cisplatin (10 mg/kg, intraperitoneal (i.p.)) did not change the pharmacokinetics of cisplatin. Cisplatin-induced haematological toxicity, expressed as white blood cells (WBC) at nadir, was significantly reduced by CrEL from 5.05+/-0.95 to 6.50+/-1.31 x 10(9)/l (P=0.0009). Data obtained from cancer patients treated with cisplatin (70 mg/m(2), 3-h i.v.) and topotecan (0.45 or 0.60 mg/m(2)/day x 2) preceded by CrEL (12 ml, 3-h i.v.) (n=6) or without CrEL (n=10) similarly indicated significant differences in the percent decrease in WBC between the groups (46.5+/-18.7 versus 67.2+/-15.0%; P=0.029). Likewise, the percent decrease in platelet count was significantly greater in the absence of CrEL (23.9+/-5.38 versus 73.3+/-15.5%; P=0.0003). Pharmacokinetic parameters of unbound and total cisplatin and of topotecan lactone and total drug were not significantly different from historic control values (P>or=0.245). Overall, this study provides further evidence on the important role of CrEL in the pharmacological and toxicological profile of cisplatin, and implies that reformulation of cisplatin with CrEL for systemic treatment might achieve an improvement of its therapeutic index, particularly in the setting of a weekly dose-dense concept.
Asunto(s)
Antineoplásicos/farmacocinética , Cisplatino/farmacocinética , Glicerol/análogos & derivados , Glicerol/farmacología , Enfermedades Hematológicas/inducido químicamente , Neoplasias Ováricas/metabolismo , Vehículos Farmacéuticos/farmacología , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Femenino , Enfermedades Hematológicas/prevención & control , Humanos , Infusiones Intravenosas , Infusiones Parenterales , Ratones , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/metabolismo , Neoplasias Ováricas/tratamiento farmacológicoRESUMEN
The design and synthesis of several novel elongated self-elimination spacer systems for application in prodrugs is described. These elongated spacer systems can be incorporated between a cleavable specifier and the parent drug. Naphthalene- and biphenyl-containing spacers were synthesized but did not eliminate. Prodrugs of the anticancer agents doxorubicin and paclitaxel are reported that contain two or three electronic cascade spacers. A novel catalytic application of HOBt was found for the synthesis of N-aryl carbamates through reacting a 4-nitrophenyl carbonate with an aniline derivative, to connect the 1,6-elimination spacers via a carbamate linkage. In addition, a double spacer-containing paclitaxel prodrug was synthesized, comprising a 1,6-elimination spacer and a bis-amine linker connected to paclitaxel via a 2'-carbamate linkage. Prodrugs in which the novel spacer systems were incorporated between a specific tripeptide specifier and the parent drug doxorubicin or paclitaxel proved to be significantly faster activated by plasmin in comparison with prodrugs containing conventional spacer systems. It is expected that the generally applicable novel spacer systems reported herein will contribute to future development of improved enzymatically activated prodrugs.
Asunto(s)
Antineoplásicos/síntesis química , Profármacos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Carbamatos/química , Ciclización , Doxorrubicina/administración & dosificación , Doxorrubicina/química , Ensayos de Selección de Medicamentos Antitumorales , Electrones , Fibrinolisina/química , Humanos , Hidrólisis , Indicadores y Reactivos , Cinética , Oligopéptidos/química , Paclitaxel/administración & dosificación , Paclitaxel/química , Profármacos/química , Profármacos/farmacología , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Both weekly cisplatin chemotherapy and single agent topotecan have proven to be effective in recurrent ovarian cancer. Preclinical data show synergism between cisplatin and topotecan. Side effects for this combination are drug sequence dependent and predominantly haematologic. Since preclinical data suggest that Cremophor EL (CrEL), the formulation vehicle of paclitaxel, has a protective effect on haematological toxicity of cisplatin, CrEL was added to the combination cisplatin and topotecan. In this phase I study, escalating doses of oral topotecan administered on day 1, 2, 8, 9, 15, 16, 29, 30, 36, 37, 43, 44 were combined with weekly cisplatin 70 mg m(-2) d(-1) on day 1, 8, 15, 29, 36, 43 (scheme A) or with the presumably less myelotoxic sequence weekly cisplatin day 2, 9, 16, 30, 37, 44 (scheme B). In scheme C, CrEL 12 ml was administered prior to cisplatin in the sequence of Scheme A. 18 patients have received a total of 85 courses. In scheme A 4/10 patients, all treated with topotecan 0.45 mg m(-2) d(-1), experienced DLT: 1 patient had vomiting grade 4, 1 patient had grade 4 neutropenia >5 days, 1 patient had >2 weeks delay due to thrombocytopenia and 1 patient due to neutropenia. Both patients in scheme B (topotecan 0.45 mg m(-2) d(-1)) had DLT due to a delay > 2 weeks because of prolonged haematological toxicity. No DLT was observed in the first 3 patients in scheme C (topotecan 0.45 mg m(-2) d(-1)). However, 2 out of 3 patients treated at dose level topotecan 0.60 mg m(-2)d(-1) in scheme C experienced DLT due to >2 weeks delay because of persistent thrombocytopenia or neutropenia. We conclude that there is a modest clinical effect of CrEL on haematological toxicity for this cisplatin-based combination regimen, which seems to reduce these side effects but does not really enable an increase of the oral topotecan dose.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cisplatino/administración & dosificación , Glicerol/análogos & derivados , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Topotecan/administración & dosificación , Administración Oral , Adulto , Anciano , Cisplatino/farmacocinética , Esquema de Medicación , Femenino , Glicerol/administración & dosificación , Humanos , Persona de Mediana Edad , Topotecan/farmacocinéticaRESUMEN
The major purpose of therapeutic drug monitoring is to enable drug dosage individualization for differences among patients in rates of drug metabolism and/or excretion. The standard analytical methods for measuring concentrations of drugs in plasma determine drug bound to plasma proteins as well as free drug dissolved in plasma water. For this reason, the relationship between total drug concentration in plasma and treatment outcome (i.e. toxicity and efficacy) will only be good if the degree of plasma protein binding of the agent is constant, or if so little drug is protein bound that changes in binding make insignificant changes in unbound concentration. A review of available literature data indicates that, in general, protein binding of anticancer drugs is not of principal clinical relevance. However, there are several instances, in which monitoring of unbound concentrations might be useful: (i) agents demonstrating protein-concentration-dependent binding, (ii) agents that bind irreversible or near covalently, (iii) when formulation excipients modulate unbound drug levels, and (iv) metabolically interconvertible agents. While available evidence suggests that for these agents unbound drug levels correlate better with clinical effects than total plasma concentrations, there are insufficient data to justify the recommendation of the routine use of unbound drug concentration monitoring for any of these agents at present.