RESUMO
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.
Assuntos
Biotransformação , Rifampina/farmacocinética , Tamoxifeno/farmacocinética , Adulto , Antineoplásicos/farmacocinética , Biotransformação/efeitos dos fármacos , Biotransformação/fisiologia , Neoplasias da Mama/tratamento farmacológico , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Interações Medicamentosas , Monitoramento de Medicamentos , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
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.
Assuntos
Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Cisplatino/farmacocinética , Cisplatino/uso terapêutico , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Animais , Antineoplásicos/efeitos adversos , Linhagem Celular Tumoral , Cisplatino/efeitos adversos , Estudos de Coortes , DNA/genética , Variação Genética , Humanos , Nefropatias/induzido quimicamente , Camundongos , Camundongos Knockout , Proteína 2 Associada à Farmacorresistência Múltipla , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , RNA/genética , Reação em Cadeia da Polimerase em Tempo Real , População Branca , Imagem Corporal TotalRESUMO
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.
Assuntos
Meio Ambiente , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/metabolismo , Piperazinas/metabolismo , Pirimidinas/metabolismo , Animais , Benzamidas , Transporte Biológico Ativo/fisiologia , Feminino , Células HeLa , Humanos , Mesilato de Imatinib , Piperazinas/antagonistas & inibidores , Pirimidinas/antagonistas & inibidores , Xenopus laevisRESUMO
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.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ifosfamida/administração & dosagem , Indóis/administração & dosagem , Neoplasias/tratamento farmacológico , Pirróis/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Esquema de Medicação , Interações Medicamentosas , Feminino , Humanos , Ifosfamida/efeitos adversos , Ifosfamida/farmacocinética , Indóis/efeitos adversos , Indóis/farmacocinética , Masculino , Dose Máxima Tolerável , Pirróis/efeitos adversos , Pirróis/farmacocinética , SunitinibeRESUMO
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.
Assuntos
Antineoplásicos/metabolismo , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Compostos Organoplatínicos/metabolismo , Compostos de Platina/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Transporte Biológico , Carboplatina/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/metabolismo , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Cinética , Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores , Proteínas de Transporte de Cátions Orgânicos/genética , Transportador 2 de Cátion Orgânico , Compostos Organoplatínicos/farmacologia , Compostos Organoplatínicos/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Oxaliplatina , Compostos de Platina/farmacologia , Compostos de Platina/uso terapêutico , RNA Mensageiro/metabolismo , Espectrofotometria Atômica , Transfecção , Resultado do TratamentoRESUMO
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.
Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Microdiálise/métodos , Taxoides/administração & dosagem , Taxoides/farmacocinética , Cromatografia Líquida , Protocolos Clínicos , Docetaxel , Humanos , Espectrometria de MassasRESUMO
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.
Assuntos
Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias/tratamento farmacológico , Oligopeptídeos/efeitos adversos , Oligopeptídeos/farmacocinética , Adulto , Idoso , Inibidores da Angiogênese/administração & dosagem , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Interações Medicamentosas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oligopeptídeos/administração & dosagem , Trombospondina 1/química , Trombospondina 1/farmacologia , GencitabinaRESUMO
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.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/farmacocinética , Fluoruracila/farmacocinética , Neoplasias/tratamento farmacológico , Taxoides/farmacocinética , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Área Sob a Curva , Cisplatino/administração & dosagem , Cisplatino/sangue , Docetaxel , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/sangue , Meia-Vida , Humanos , Infusões Intravenosas , Leucopenia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia , Neoplasias/metabolismo , Neutropenia/induzido quimicamente , Taxoides/administração & dosagem , Taxoides/sangue , Resultado do TratamentoRESUMO
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.
Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Neoplasias/tratamento farmacológico , Paclitaxel/farmacocinética , Adulto , Idoso , Análise de Variância , Antineoplásicos Fitogênicos/efeitos adversos , Estudos de Coortes , Tomada de Decisões , Progressão da Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Meia-Vida , Humanos , Infusões Intravenosas , Lipossomos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Paclitaxel/efeitos adversos , Resultado do TratamentoRESUMO
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.
Assuntos
Antineoplásicos/farmacocinética , Modelos Teóricos , Topotecan/farmacocinética , Administração Oral , Adolescente , Adsorção , Adulto , Idoso , Antineoplásicos/administração & dosagem , Disponibilidade Biológica , Creatinina/metabolismo , Feminino , Humanos , Infusões Intravenosas , Rim/fisiologia , Masculino , Pessoa de Meia-Idade , Topotecan/administração & dosagemRESUMO
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.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Cisplatino/farmacologia , Neoplasias/tratamento farmacológico , Topotecan/farmacocinética , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Cisplatino/administração & dosagem , Esquema de Medicação , Interações Medicamentosas , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Topotecan/administração & dosagemRESUMO
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.
Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Camptotecina/farmacocinética , Pró-Fármacos/farmacocinética , Adulto , Idoso , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/sangue , Antineoplásicos Fitogênicos/uso terapêutico , Área Sob a Curva , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/análogos & derivados , Camptotecina/sangue , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Neoplasias do Colo/patologia , Neoplasias Colorretais/sangue , Neoplasias Colorretais/tratamento farmacológico , Esquema de Medicação , Feminino , Humanos , Irinotecano , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Neoplasias Ovarianas/patologia , Pró-Fármacos/administração & dosagem , Pró-Fármacos/efeitos adversos , Pró-Fármacos/uso terapêutico , Distribuição Aleatória , Células Tumorais Cultivadas/efeitos dos fármacos , Neoplasias do Colo do Útero/sangue , Neoplasias do Colo do Útero/tratamento farmacológicoRESUMO
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.
Assuntos
Antineoplásicos/farmacologia , Camptotecina/farmacologia , Inibidores Enzimáticos/farmacologia , Neoplasias/metabolismo , Inibidores da Topoisomerase I , Adulto , Idoso , Antineoplásicos/farmacocinética , Antineoplásicos/toxicidade , Área Sob a Curva , Camptotecina/análogos & derivados , Camptotecina/farmacocinética , Camptotecina/toxicidade , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/toxicidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Estudos Prospectivos , Estudos de AmostragemRESUMO
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.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias/tratamento farmacológico , Paclitaxel/análogos & derivados , Taxoides , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Docetaxel , Sinergismo Farmacológico , Feminino , Humanos , Masculino , Metotrexato/administração & dosagem , Metotrexato/farmacocinética , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Paclitaxel/farmacocinéticaRESUMO
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.
Assuntos
Antineoplásicos/farmacocinética , Cisplatino/farmacocinética , Glicerol/análogos & derivados , Glicerol/farmacologia , Doenças Hematológicas/induzido quimicamente , Neoplasias Ovarianas/metabolismo , Veículos Farmacêuticos/farmacologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Doenças Hematológicas/prevenção & controle , Humanos , Infusões Intravenosas , Infusões Parenterais , Camundongos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/metabolismo , Neoplasias Ovarianas/tratamento farmacológicoRESUMO
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.
Assuntos
Antineoplásicos/síntese química , Pró-Fármacos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Carbamatos/química , Ciclização , Doxorrubicina/administração & dosagem , Doxorrubicina/química , Ensaios de Seleção de Medicamentos Antitumorais , Elétrons , Fibrinolisina/química , Humanos , Hidrólise , Indicadores e Reagentes , Cinética , Oligopeptídeos/química , Paclitaxel/administração & dosagem , Paclitaxel/química , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
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.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/administração & dosagem , Glicerol/análogos & derivados , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Topotecan/administração & dosagem , Administração Oral , Adulto , Idoso , Cisplatino/farmacocinética , Esquema de Medicação , Feminino , Glicerol/administração & dosagem , Humanos , Pessoa de Meia-Idade , Topotecan/farmacocinéticaRESUMO
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.
Assuntos
Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Proteínas Sanguíneas/fisiologia , Proteínas de Transporte/fisiologia , Monitoramento de Medicamentos/métodos , Monitoramento de Medicamentos/normas , Antineoplásicos/química , Viés , Proteínas Sanguíneas/química , Proteínas de Transporte/química , Química Farmacêutica , Fatores de Confusão Epidemiológicos , Monitoramento de Medicamentos/tendências , Previsões , Humanos , Taxa de Depuração Metabólica , Seleção de Pacientes , Reprodutibilidade dos Testes , Fatores de Tempo , Distribuição TecidualRESUMO
PURPOSE: Most anticancer drugs are dosed based on body-surface area (BSA) to reduce interindividual variability of drug effects. We evaluated the relevance of this concept for cisplatin by analyzing cisplatin pharmacokinetics obtained in prospective studies in a large patient population. PATIENTS AND METHODS: Data were obtained from 268 adult patients (163 males/105 females; median age, 54 years [range, 21 to 74 years]) with advanced solid tumors treated in phase I/II trials with cisplatin monotherapy or combination chemotherapy with etoposide, irinotecan, topotecan, or docetaxel. Cisplatin was administered either weekly (n = 93) or once every 3 weeks (n = 175) at dose levels of 50 to 100 mg/m(2) (3-hour infusion). Analysis of 485 complete courses was based on measurement of total and non-protein-bound cisplatin in plasma by atomic absorption spectrometry. RESULTS: No pharmacokinetic interaction was found between cisplatin and the anticancer drugs used in combination therapies. A linear correlation was observed between area under the curves of unbound and total cisplatin (r = 0.63). The mean plasma clearance of unbound cisplatin (CL(free)) was 57.1 +/- 14.7 L/h (range, 31.0 to 116 L/h), with an interpatient variability of 25.6%. BSA varied between 1.43 and 2.40 m(2) (mean, 1.86 +/- 0.19 m(2)), with an interpatient variability of 10.4%. When CL(free) was corrected for BSA, interindividual variability remained in the same order (23.6 v 25.6%). Only a weak correlation was found between CL(free) and BSA (r = 0.42). Intrapatient variability in CL(free), calculated from 90 patients was 12.1% +/- 7.8% (range, 0.30% to 32.7%). CONCLUSION: In view of the high interpatient variability in CL(free) relative to variation in observed BSA, no rationale for continuing BSA-based dosing was found. We recommend fixed-dosing regimens for cisplatin.
Assuntos
Antineoplásicos/farmacocinética , Superfície Corporal , Cisplatino/farmacocinética , Adulto , Idoso , Análise de Variância , Antineoplásicos/administração & dosagem , Cisplatino/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Humanos , Modelos Lineares , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores Sexuais , Estatísticas não ParamétricasRESUMO
Population pharmacokinetic-dynamic analysis was prospectively integrated in the clinical phase II programme of EO9 to determine the population pharmacokinetic profile in a larger population of patients, to estimate individual patient pharmacokinetic parameters, and to investigate relationships between drug exposure and clinical outcome. A sparse sampling method was developed, which involved three sampling times, and was implemented during course 1. A Bayesian algorithm was used to estimate individual pharmacokinetic parameters, in particular total plasma clearance (CL) of EO9 and area under the curve (AUC). In total, samples were collected of 85 (65%) of the patients. Pharmacokinetic evaluation was successful in 61 (72%) of the sampled patients. CL of EO9 showed substantial variability (median 5.08 l/min; range 2.67-6.42) and was of the same magnitude as in the phase I study where full pharmacokinetic profiles were used. No significant relationships were noticed between exposure parameters and safety, but overall limited toxicity was observed. No tumor responses were documented. Prospective implementation of large-scale population pharmacokinetic-dynamic analysis is feasible and may generate important findings, in particular when tumor responses and relevant toxicity are observed.