RESUMO
Platinum-based drugs are among the most active anticancer agents and are successfully used in a wide variety of human malignancies. However, acquired and/or intrinsic resistance still represent a major limitation. Lately, in particular mechanisms leading to impaired uptake and/or decreased cellular accumulation of platinum compounds have attracted attention. In this review, we focus on the role of active platinum uptake and efflux systems as determinants of platinum sensitivity and -resistance and their contribution to platinum pharmacokinetics (PK) and pharmacodynamics (PD). First, the three mostly used platinum-based anticancer agents as well as the most promising novel platinum compounds in development are put into clinical perspective. Next, we describe the presently known potential platinum transporters--with special emphasis on organic cation transporters (OCTs)--and discuss their role on clinical outcome (i.e. efficacy and adverse events) of platinum-based chemotherapy. In addition, transporter-mediated tumour resistance, the impact of potential platinum transporter-mediated drug-drug interactions, and the role of drug transporters in the renal elimination of platinum compounds are discussed.
Assuntos
Antineoplásicos/farmacocinética , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Compostos Organoplatínicos/farmacocinética , Animais , Antineoplásicos/farmacologia , Transporte Biológico , Carboplatina/farmacocinética , Carboplatina/farmacologia , Cisplatino/farmacocinética , Cisplatino/farmacologia , Interações Medicamentosas , Resistencia a Medicamentos Antineoplásicos , Humanos , Compostos Organoplatínicos/farmacologia , OxaliplatinaRESUMO
PURPOSE: Cisplatin is predominantly eliminated in the urine through active secretion. As the solute carrier organic cation transporter 2 (OCT2) is highly expressed in the basolateral membrane of proximal tubules, we determined its contribution to cisplatin transport and assessed the relation of variation in the gene encoding OCT2 (SLC22A2) with the disposition of cisplatin. EXPERIMENTAL DESIGN: Cell lines were transfected using the Flp-In 293 system with the full-length OCT2 cDNA, and platinum concentrations were measured using flameless atomic absorption spectrometry. Pharmacokinetic data were available from 106 cancer patients, and DNA was screened for eight nonsynonymous SLC22A2 variants using direct sequencing. RESULTS: mRNA expression was 36-fold higher and uptake of the model substrate tetraethylammonium was significantly increased (P < 0.0001) in OCT2-transfected cells compared with empty vector-transfected controls. OCT2-mediated transport of cisplatin was saturable, and uptake was increased by approximately 4-fold (P < 0.0001) relative to control cells. Cisplatin inhibited OCT2-mediated transport of tetraethylammonium by up to 97%. The mean +/- SD systemic clearance of unbound cisplatin-derived platinum in the patient population was 29.2 +/- 8.39 L/h, and renal clearance was particularly variable. Only one single nucleotide polymorphism (Ala270Se; rs316019) was identified (minor allele frequency, 7.6%), and it was not found to be associated with any of the studied pharmacokinetic variables (P > 0.05). CONCLUSION: These findings support the hypothesis that OCT2 is a key renal transporter involved in cisplatin elimination. However, known variants in SLC22A2 do not substantially contribute to explaining interindividual pharmacokinetic variability, suggesting that other mechanisms, controlling OCT2 expression, might be involved.
Assuntos
Cisplatino/farmacocinética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inativação Metabólica/genética , Proteínas de Transporte de Cátions Orgânicos/genética , Antineoplásicos/farmacocinética , Antineoplásicos/urina , Células Cultivadas , Cisplatino/urina , Feminino , Genótipo , Humanos , Masculino , Taxa de Depuração Metabólica/genética , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Transportador 2 de Cátion Orgânico , Fenótipo , Polimorfismo de Nucleotídeo Único , Transfecção , Regulação para Cima/efeitos dos fármacosRESUMO
PURPOSE: Administration of chemotherapy in patients with renal failure, treated with hemodialysis or continuous ambulatory peritoneal dialysis (CAPD) is still a challenge and literature data is scarce. Here we present a case study of a patient on CAPD, treated with weekly and three-weekly paclitaxel/carboplatin for recurrent ovarian cancer. EXPERIMENTAL: During the first, second and ninth cycle of treatment, blood, urine and CAPD samples were collected for pharmacokinetic analysis of paclitaxel and total and unbound carboplatin-derived platinum. RESULTS: Treatment was well tolerated by the patient. No excessive toxicity was observed and at the end of treatment she was in a complete remission. The plasma pharmacokinetics of paclitaxel were unaltered compared to historical data, with neglectable urinary and CAPD clearance. In contrast, the pharmacokinetics of carboplatin were altered, with doubled half-lives compared to patients with normal renal function. Of the administered carboplatin dose, up to 20% was cleared via the dialysate, while only up to 8% was cleared via the urine. CONCLUSION: Paclitaxel and carboplatin can be safely administered to patients with chronic renal failure on CAPD. For paclitaxel the generally applied dose can be administered, and although for carboplatin dose-adjustment is required due to the diminished renal function, the dose can be calculated using Calvert's formula.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Diálise Peritoneal Ambulatorial Contínua , Antineoplásicos/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Área Sob a Curva , Carboplatina/administração & dosagem , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Paclitaxel/administração & dosagem , Insuficiência Renal/complicações , Insuficiência Renal/terapia , Resultado do TratamentoRESUMO
OBJECTIVE: The anticancer drug docetaxel is extensively metabolized by cytochrome P450 (CYP) 3A isozymes. Furthermore, docetaxel is also a substrate for the transmembrane ATP-binding cassette efflux transporter protein ABCB1. CYP3A-inhibition significantly reduces docetaxel total systemic clearance, on average by 50%. However, data on the effect of CYP3A-inhibition on the fecal and urinary excretion of docetaxel are lacking. To further elucidate the role of CYP3A- and ABCB1-mediated elimination pathways for docetaxel we investigated the effect of the potent CYP3A-inhibitor, and also ABCB1-inhibitor, ketoconazole on the fecal and urinary disposition of docetaxel in cancer patients. METHODS: Fifteen patients were treated with docetaxel (100 mg/m2), followed 3 weeks later by a reduced dose in combination with orally administered ketoconazole, or vice versa. Six patients were also administered [3H]-radiolabeled docetaxel. Fecal and urinary specimens, collected up to 72-h post-infusion, were analyzed for cumulative parent drug and radioactivity excretion. RESULTS: Ketoconazole coadministration increased fecal parent drug excretion twofold from 2.6 +/- 2.8 to 5.2 +/- 5.4% (mean +/- SD, P = 0.03) but did not affect urinary parent drug excretion (P = 0.69). The sum of fecal and urinary parent drug excretion was 5.3 +/- 3.0% for docetaxel alone and 7.8 +/- 5.6% in the presence of ketoconazole, respectively (P = 0.04). Total recovered radioactivity values were 45.8 +/- 19.1 and 32.4 +/- 19.7%, respectively (P = 0.23). CONCLUSION: CYP3A-inhibition by ketoconazole increases fecal parent drug excretion twofold in cancer patients. A more pronounced increase was not achieved, most likely due to concomitant intestinal ABCB1-inhibition.
Assuntos
Inibidores das Enzimas do Citocromo P-450 , Cetoconazol/farmacologia , Neoplasias/tratamento farmacológico , Taxoides/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Administração Oral , Adulto , Idoso , Citocromo P-450 CYP3A , Docetaxel , Fezes/química , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Taxoides/urina , TrítioRESUMO
PURPOSE: Aprepitant, a selective neurokinin-1 (NK-1) receptor antagonist approved for the treatment and prevention of emesis caused by moderately and highly emetogenic chemotherapy, is an inhibitor, inducer, and substrate of the cytochrome P450 3194 pathway. The CYP3A4 pathway is the major pathway of the metabolism of vinorelbine, a vinca alkaloid frequently used in combination with cisplatin. Therefore, we studied the potential interaction of the aprepitant 3-day antiemetic regimen on the pharmacokinetics of vinorelbine. PATIENTS AND METHODS: Fourteen patients with metastatic solid tumors were included in this open-label, balanced, 2-period crossover study. In treatment arm A, vinorelbine (25 mg/m2 weekly) was administered alone, while in treatment arm B the same dose of vinorelbine was administered following the administration of the aprepitant antiemetic regimen on day 1 and alone on day 8. The antiemetic regimen of aprepitant was comprised of the following; on day 1: 125 mg aprepitant, 12 mg dexamethasone, and 32 mg ondansetron; on days 2 and 3: 80 mg aprepitant and 8 mg dexamethasone and on day 4: 8 mg dexamethasone. Blood samples for vinorelbine pharmacokinetic analysis were collected over 96 h. RESULTS: Two patients discontinued the study due to adverse events that were judged not to be drug-related. Complete pharmacokinetic data of vinorelbine administered alone and with the aprepitant antiemetic regimen were obtained in 12 patients. The mean plasma concentration profile of vinorelbine administered with aprepitant was identical to that following vinorelbine administered alone, with geometric mean vinorelbine plasma AUC ratios of treatment B day 1/treatment A day 1 and of treatment B day 8/treatment A day of 1.01 (0.93, 1.10) and 1.00 (0.92, 1.08), respectively. CONCLUSION: As the aprepitant antiemetic regimen has no detectable inhibitory or inductive effect on the pharmacokinetics of vinorelbine, aprepitant when added to a standard antiemetic regimen consisting of ondansetron and dexamethasone can be safely combined with vinorelbine at clinically recommended doses.
Assuntos
Antieméticos/uso terapêutico , Antineoplásicos Fitogênicos/farmacocinética , Dexametasona/uso terapêutico , Morfolinas/uso terapêutico , Neoplasias/metabolismo , Ondansetron/uso terapêutico , Vimblastina/análogos & derivados , Aprepitanto , Área Sob a Curva , Estudos Cross-Over , Quimioterapia Combinada , Feminino , Meia-Vida , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Vimblastina/farmacocinética , VinorelbinaRESUMO
OBJECTIVE: The pharmacokinetics (PK) of docetaxel are characterized by large inter-individual variability in systemic drug exposure (AUC) and drug clearance. The PK variability is thought to be largely related to differences in the catalytic function of CYP3A, involved in docetaxel metabolism and elimination. As variability in efficacy and toxicity is associated with variability in docetaxel AUC and clearance, reducing inter-individual PK variability may help improve the risk-benefit ratio of docetaxel therapy. We investigated if high-dose ketoconazole, a potent CYP3A inhibitor, could result in a uniform reduction of docetaxel clearance and reduce the inter-individual variability in docetaxel AUC and clearance. METHODS: Seven patients were treated in a randomized-cross over design with intravenous docetaxel (100 mg/m(2)) followed 3 weeks later by docetaxel (15 mg/m(2)) given in combination with orally administered ketoconazole (400 mg 3 times daily, up to 47 hours after docetaxel infusion) or vice versa. Docetaxel plasma concentration-time data were described by a three-compartment PK model. Ketoconazole plasma concentration-time data were described by a one-compartment PK model. RESULTS: Docetaxel clearance was reduced by 50% (P = .018) from 32.8 +/- 13.7 L/hr to 16.5 +/- 8.15 L/hr upon ketoconazole coadministration, albeit with large inter-individual variability (fractional change in clearance, range 0.31 - 0.66). In the presence of ketoconazole, inter-individual variability in clearance and AUC, expressed as coefficient of variation, was increased from 41.6 to 49.5% and from 28.0 to 35.1%, respectively, and not, as we had hypothesized, reduced. CONCLUSION: Inhibition of CYP3A by concomitant high-dose ketoconazole administration does not result in a uniform reduction of docetaxel clearance and does not reduce the inter-individual variability in docetaxel AUC or clearance. This approach is unsuitable as method to achieve a uniform docetaxel PK profile.
Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica , Inibidores do Citocromo P-450 CYP3A , Cetoconazol/administração & dosagem , Neoplasias/tratamento farmacológico , Taxoides/farmacocinética , Adulto , Idoso , Antineoplásicos Fitogênicos/sangue , Antineoplásicos Fitogênicos/uso terapêutico , Citocromo P-450 CYP3A , Sistema Enzimático do Citocromo P-450/genética , Docetaxel , Feminino , Humanos , Cetoconazol/sangue , Cetoconazol/farmacocinética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Taxoides/administração & dosagem , Taxoides/sangueRESUMO
BACKGROUND: Irinotecan is metabolized by various enzymes, including carboxylesterases, cytochrome P450 3A isozymes (CYP3A) and uridine-diphosphate glucuronosyltransferase 1A isoforms (UGT1A). Here we report on the disposition of irinotecan and its metabolites in plasma, urine, bile and feces of a single cancer patient with an external bile drain. METHODOLOGY: Irinotecan (450 mg) was administered during a 90-minutes continuous infusion to a cancer patient with an external bile drain. Blood samples were collected up to 55 hours after infusion, while bile, feces and urine were collected during six consecutive days after administration. Samples were analyzed using high-performance liquid chromatography (HPLC)-assays with fluorescence detection. RESULTS: Plasma pharmacokinetics were characterized by a relatively slow clearance of irinotecan and a relatively high exposure to 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxycamptothecin (APC). Exposures to the other metabolites was within the normal range. Overall, 83.4% of the administered dose was recovered in the excreta, with the majority excreted during the first 24 hours. CONCLUSIONS: Enterohepatic recirculation is of minor importance for the plasma disposition of irinotecan and its metabolites. The high percentage of the dose recovered in urine, the relatively slow clearance of irinotecan and the preferential urinary over biliary excretion of APC in this particular patient are likely related to reduced functioning of ABC-transporters. Circumstantial evidence was found that APC is subject to further intestinal biotransformation indicating a role in the etiology of irinotecan-induced diarrhea. Since intra-luminal exposure to SN-38 in patients with an external bile drain is limited, neutropenia will be the dose-limiting toxicity. Based on presented data, although collected from only one patient, irinotecan therapy in patients with an external bile drain is feasible. No a priori dose adjustments are recommended, although in the absence of severe side-effects in previous courses, a higher dose may be considered.
Assuntos
Adenocarcinoma/metabolismo , Ductos Biliares/cirurgia , Sistema Biliar/metabolismo , Camptotecina/análogos & derivados , Fígado/metabolismo , Neoplasias Pancreáticas/metabolismo , Pró-Fármacos/farmacocinética , Adenocarcinoma/sangue , Adenocarcinoma/tratamento farmacológico , Idoso , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/sangue , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/urina , Camptotecina/administração & dosagem , Camptotecina/sangue , Camptotecina/farmacocinética , Camptotecina/urina , Drenagem , Fezes/química , Humanos , Irinotecano , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundário , Masculino , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/tratamento farmacológico , Pró-Fármacos/administração & dosagemRESUMO
PURPOSE: To retrospectively evaluate the effects of six known allelic variants in the CYP2C8, CYP3A4, CYP3A5, and ABCB1 genes on the pharmacokinetics of the anticancer agent paclitaxel (Taxol). EXPERIMENTAL DESIGN: A cohort of 97 Caucasian patients with cancer (median age, 57 years) received paclitaxel as an i.v. infusion (dose range, 80-225 mg/m(2)). Genomic DNA was analyzed using PCR RFLP or using Pyrosequencing. Pharmacokinetic variables for unbound paclitaxel were estimated using nonlinear mixed effect modeling. The effects of genotypes on typical value of clearance were evaluated with the likelihood ratio test within NONMEM. In addition, relations between genotype and individual pharmacokinetic variable estimates were evaluated with one-way ANOVA. RESULTS: The allele frequencies for the CYP2C8*2, CYP2C8*3, CYP2C8*4, CYP3A4*3, CYP3A5*3C, and ABCB1 3435C>T variants were 0.7%, 9.2%, 2.1%, 0.5%, 93.2%, and 47.1%, respectively, and all were in Hardy-Weinberg equilibrium. The population typical value of clearance of unbound paclitaxel was 301 L/h (individual clearance range, 83.7-1055 L/h). The CYP2C8 or CYP3A4/5 genotypes were not statistically significantly associated with unbound clearance of paclitaxel. Likewise, no statistically significant association was observed between the ABCB1 3435C>T variant and any of the studied pharmacokinetic variables. CONCLUSIONS: This study indicates that the presently evaluated variant alleles in the CYP2C8, CYP3A4, CYP3A5, and ABCB1 genes do not explain the substantial interindividual variability in paclitaxel pharmacokinetics.
Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Paclitaxel/farmacocinética , Farmacogenética , Polimorfismo Genético/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Antineoplásicos Fitogênicos/administração & dosagem , Hidrocarboneto de Aril Hidroxilases/genética , Citocromo P-450 CYP2C8 , Citocromo P-450 CYP3A , Sistema Enzimático do Citocromo P-450/genética , Feminino , Frequência do Gene , Genótipo , Humanos , Infusões Intravenosas , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Paclitaxel/administração & dosagem , Fenótipo , Estudos Retrospectivos , População Branca/genéticaRESUMO
St. John's wort (SJW), a widely used herbal product, has been implicated in drug interactions resulting from the induced expression of the cytochrome P450 CYP3A4 isoform. In this study, we determined the effect of SJW on the metabolism of irinotecan, a pro-drug of SN-38 and a known substrate for CYP3A4. Five cancer patients were treated with irinotecan (350 mg/m(2), intravenously) in the presence and absence of SJW (900 mg daily, orally for 18 days) in an unblinded, randomized crossover study design. The plasma levels of the active metabolite SN-38 decreased by 42% (95% confidence interval [CI] = 14% to 70%) following SJW cotreatment with 1.0 micro M x h (95% CI = 0.34 micro M x h to 1.7 micro M x h) versus 1.7 micro M x h (95% CI = 0.83 micro M x h to 2.6 micro M x h) (P =.033, two-sided paired Student's t test). Consequently, the degree of myelosuppression was substantially worse in the absence of SJW. These findings indicate that patients on irinotecan treatment should refrain from taking SJW because plasma levels of SN-38 were dramatically reduced, which may have a deleterious impact on treatment outcome.
Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Camptotecina/antagonistas & inibidores , Camptotecina/farmacocinética , Sistema Enzimático do Citocromo P-450/metabolismo , Inibidores Enzimáticos/farmacocinética , Hypericum/efeitos adversos , Oxigenases de Função Mista/metabolismo , Inibidores da Topoisomerase I , Antidepressivos/efeitos adversos , Antineoplásicos Fitogênicos/sangue , Área Sob a Curva , Camptotecina/análogos & derivados , Camptotecina/sangue , Intervalos de Confiança , Estudos Cross-Over , Citocromo P-450 CYP3A , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Inibidores Enzimáticos/sangue , Humanos , Irinotecano , Oxigenases de Função Mista/efeitos dos fármacosRESUMO
PURPOSE: To determine the maximum-tolerated and recommended dose, toxicity profile, and pharmacokinetics of the liposomal topoisomerase I inhibitor lurtotecan (NX 211) administered as a 30-minute intravenous infusion once every 3 weeks in cancer patients. PATIENTS AND METHODS: NX 211 was administered by peripheral infusion. Dose escalation decisions were based on all toxicities during the first cycle as well as pharmacokinetic parameters. Serial plasma, whole blood, and urine samples were collected for up to 96 hours after the end of infusion, and drug levels were determined by high-performance liquid chromatography. RESULTS: Twenty-nine patients (16 women; median age, 56 years; range, 39 to 74 years) received 77 courses of NX 211 at dose levels of 0.4 (n = 3), 0.8 (n = 6), 1.6 (n = 3), 3.2 (n = 6), 3.8 (n = 6), and 4.3 mg/m(2) (n = 5). Neutropenia and thrombocytopenia were the dose-limiting toxicities and were not cumulative. Other toxicities were mild to moderate. Nine patients had stable disease while undergoing treatment. The systemic clearance of lurtotecan in plasma and whole blood was 0.82 +/- 0.78 L/h/m(2) and 1.15 +/- 0.96 L/h/m(2), respectively. Urinary recovery (Fu) of lurtotecan was 10.1% +/- 4.05% (range, 4.9% to 18.9%). In contrast to systemic exposure measures, the dose excreted in urine (ie, dose x Fu) was significantly related to the percent decrease in neutrophil and platelet counts at nadir (P <.00001). CONCLUSION: The dose-limiting toxicities of NX 211 are neutropenia and thrombocytopenia. The recommended dose for phase II studies is 3.8 mg/m(2) once every 3 weeks. Pharmacologic data suggest a relationship between exposure to lurtotecan and NX 211-induced clinical effects.
Assuntos
Antineoplásicos/toxicidade , Camptotecina/toxicidade , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/urina , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Camptotecina/farmacocinética , Camptotecina/urina , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Infusões Intravenosas , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Trombocitopenia/induzido quimicamenteRESUMO
PURPOSE: Taxol contains paclitaxel formulated in Cremophor EL-P (CrEL-P) and ethanol. Paxene is similar to Taxol, except for the use of Cremophor EL (CrEL) and the addition of citric acid. Here, we investigated the physicochemical properties and clinical pharmacokinetics of the two paclitaxel formulations. EXPERIMENTAL DESIGN: The size and modality of distribution of CrEL-P and CrEL micelles was determined by dynamic-light scattering. The effect of vehicle composition on the fraction unbound paclitaxel in vitro was determined by equilibrium dialysis. Paclitaxel pharmacokinetics were studied in 61 cancer patients receiving Taxol and 26 patients receiving Paxene. Comparative pharmacokinetics of CrEL-P and CrEL were obtained in 14 and 6 patients, respectively. RESULTS: The size of micelles present in Taxol was slightly smaller (9 to 13%) than those present in Paxene. Surface tension and critical micellar concentration were also similar for the two formulations, with mean values of 37.0 and 38.1 mN/m and 0.0387 and 0.0307 mg/mL, respectively. The fraction unbound paclitaxel was not significantly different for Taxol and Paxene (p > 0.05). Over the tested dose range, the mean clearance of paclitaxel decreased from 45.1 to 16.9 L/h for Taxol, and from 50.7 to 16.4 L/h for Paxene (p > 0.05). Concentrations of the excipient following the administration of CrEL-P or CrEL were also similar. CONCLUSION: The differences in formulation between Taxol and Paxene do not significantly affect micelle formation and/or quantitative aspects of the vehicle-paclitaxel interaction in vitro and in vivo.
Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Paclitaxel/farmacocinética , Tensoativos/farmacocinética , Adulto , Idoso , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/sangue , Química Farmacêutica , Relação Dose-Resposta a Droga , Excipientes/administração & dosagem , Excipientes/farmacologia , Feminino , Glicerol/análogos & derivados , Humanos , Técnicas In Vitro , Masculino , Matemática , Micelas , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Paclitaxel/sangue , Solventes/administração & dosagem , Solventes/farmacologia , Tensão Superficial , Água/químicaRESUMO
ABCG2 (BCRP/MXR/ABCP) functions as an efflux transporter for many agents, including topotecan, and the protein is expressed at high levels in the human intestine. Some individuals possess a nonsynonymous variant in the ABCG2 gene at nucleotide 421, substituting lysine for glutamine on position 141 at exon 5. The present pilot study indicates that this genotype results in a 30% reduced efflux transport of topotecan in vitro compared to the wild-type. In a preliminary fashion, the heterozygous CA allele observed in two patients was associated with a 1.34-fold increased oral bioavailability of topotecan compared to the bioavailability in ten patients with the wild-type allele (42.0% versus 31.4%; p = 0.037). It is suggested that the high frequency of the A allele in certain ethnic groups may have therapeutic implications for individuals treated with topotecan or other ABCG2 substrates.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Antineoplásicos/farmacocinética , Carcinoma de Células Pequenas/genética , Proteínas de Neoplasias/genética , Neoplasias Ovarianas/genética , Topotecan/farmacocinética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Administração Oral , Adulto , Idoso , Substituição de Aminoácidos , Antineoplásicos/administração & dosagem , Disponibilidade Biológica , DNA de Neoplasias/genética , Feminino , Frequência do Gene , Genótipo , Heterozigoto , Humanos , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Farmacogenética , Projetos Piloto , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Topotecan/administração & dosagem , Células Tumorais CultivadasRESUMO
An additional chromatographic peak was observed in plasma samples of patients receiving NX 211, a liposomal formulation of the topoisomerase I inhibitor lurtotecan. We have isolated and purified this product by sequential solid-phase extractions, and we report its structure and cytotoxicity relative to lurtotecan and related agents. Nuclear magnetic resonance data indicate that cleavage of the piperazino moiety occurred at the N-C bond of the B-ring, yielding 7-methyl-10,11-ethylenedioxy-20(S)-camptothecin (MEC). Tests of the growth inhibition potential of MEC in seven human tumor cell lines showed that the compound was approximately 2-18-fold more cytotoxic than lurtotecan, topotecan, and 7-ethyl-10-hydroxy-20(S)-camptothecin (SN-38). Subsequently, we found that MEC was the product of rapid photolysis of lurtotecan, with the rate of degradation inversely proportional to NX 211 concentrations, and greatly depends on light intensity. Furthermore, MEC concentrations were found to increase significantly in plasma samples exposed to laboratory light but not in blood. MEC was not produced from NX 211 in the presence of human liver microsomes, suggesting that it is not a product of cytochrome P-450 metabolism. Using a validated analytical method, trace levels of MEC were quantitated in blood samples of two patients. These observations confirm that the precautions for protection from light currently specified for preparation and administration of NX 211 dose solutions are critical. Procedures to minimize formation of MEC, by the use of amber vials for NX 211 and by preparation of dilutions immediately before clinical use in a fashion completely protected from light, are now being routinely implemented.
Assuntos
Antineoplásicos/efeitos da radiação , Camptotecina/química , Camptotecina/farmacologia , Camptotecina/efeitos da radiação , Adulto , Camptotecina/análogos & derivados , Camptotecina/isolamento & purificação , Divisão Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Sistema Enzimático do Citocromo P-450/metabolismo , Humanos , Luz , Masculino , Pessoa de Meia-Idade , Estrutura Molecular , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
Topotecan and irinotecan (CPT-11) are both anticancer agents active in the inhibition of topoisomerase I, an enzyme involved in DNA replication and RNA transcription. During the last decades, an immense amount of research into this class of anticancer agents has been conducted, the positive results of which led to the clinical use of topotecan and CPT-11 in ovarian cancer and colorectal cancer, respectively. Here, we review the currently most important pharmacologic aspects of these drugs, including their mechanisms of action, metabolism, activity- and toxicity-profiles and mechanisms of resistance, to provide a global insight into their pharmacology. We also discuss the effects of combinations with other anticancer agents, which have been tested for synergistic antitumor effects. Pharmacokinetic and pharmacodynamic biomodulation, to enhance the bioavailability of the active anticancer agent or to reduce drug related toxicities have currently reached clinical application. As pharmacogenetics enters the clinical stage, this will lead to more "fine-tuning" in anticancer treatment (for instance by individualized dosing). The clarification of the mechanisms of action and resistance of topotecan and CPT-11 should enable us to understand their pharmacological behavior even better and might lead to the development of more potent camptothecin-derivatives in the future.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos/farmacologia , Camptotecina/farmacologia , Inibidores Enzimáticos/farmacologia , Neoplasias/tratamento farmacológico , Inibidores da Topoisomerase I , Topotecan/farmacologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/farmacocinética , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/análogos & derivados , Camptotecina/farmacocinética , Fenômenos Químicos , Físico-Química , Ensaios Clínicos como Assunto , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Humanos , Irinotecano , Topotecan/administração & dosagem , Topotecan/efeitos adversos , Topotecan/farmacocinéticaRESUMO
BACKGROUND: Tivozanib hydrochloride (tivozanib) is a potent and selective tyrosine kinase inhibitor of all 3 vascular endothelial growth factor receptors with antitumor activity additive to 5-fluorouracil in preclinical models. This study was conducted to determine maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics (PKs), and antitumor activity of escalating doses of tivozanib with a modified (m)FOLFOX-6 (leucovorin, 5-fluorouracil [5-FU], and 85 mg/kg(2) oxaliplatin) regimen in patients with advanced gastrointestinal tumors. PATIENTS AND METHODS: Tivozanib was administered orally once daily for 21 days in 28-day cycles, with mFOLFOX-6 administered every 14 days. Patients were allowed to continue tivozanib after discontinuation of mFOLFOX-6. RESULTS: Thirty patients were assigned to tivozanib 0.5 mg (n = 9), 1.0 mg (n = 3), or 1.5 mg (n = 18) with mFOLFOX-6. Patients received a median of 5.2 (range, 0.03-26.9) months of tivozanib. DLTs were observed in 2 patients: Grade 3/4 transaminase level increases with tivozanib 0.5 mg, and Grade 3 dizziness with tivozanib 1.5 mg. Other Grade 3/4 adverse events included hypertension (n = 8), fatigue (n = 8), and neutropenia (n = 6). MTD for tivozanib with mFOLFOX-6 was confirmed as 1.5 mg. No PK interactions between tivozanib and mFOLFOX-6 were observed. One patient had an ongoing clinical complete response, 10 had a partial response, and 11 obtained prolonged stable disease. CONCLUSION: Tivozanib and mFOLFOX-6 is feasible and appears to be safe. The recommended dose for tivozanib with mFOLFOX-6 is 1.5 mg/d. Observed clinical activity merits further exploration in gastrointestinal tumors.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Colorretais/patologia , Relação Dose-Resposta a Droga , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Humanos , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Leucovorina/uso terapêutico , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/efeitos adversos , Compostos Organoplatínicos/uso terapêutico , Compostos de Fenilureia/administração & dosagem , Quinolinas/administração & dosagem , Resultado do TratamentoRESUMO
OBJECTIVE: Our objectives were to study the extent of docetaxel binding to plasma in the presence and absence of its excipient, polysorbate 80 (Tween 80; Imperial Chemical Industries PLC, London, United Kingdom), in vitro and to evaluate the pharmacokinetics of unbound docetaxel in vivo. METHODS: Equilibrium dialysis was used for determination of the fraction unbound (f(u)) docetaxel and was applied to study the pharmacokinetic behavior of unbound docetaxel in 23 patients with cancer receiving an intravenous infusion of the drug formulated in polysorbate 80 (Taxotere; Aventis Pharma SA, Vitry-sur-Seine Cedex, France). RESULTS: Polysorbate 80, added at clinically relevant concentrations (up to 1.0 microL/mL), increased f(u) in vitro by 13% (7.84% +/- 0.0752% versus 6.95% +/- 0.0678%, P <.00001). Similarly, f(u) calculated on the basis of the observed area under the plasma concentration-time curve (AUC) values [f(u)(AUC)] in vivo was 12% higher than f(u) in pretreatment samples [f(u)(pre)] (6.00% +/- 1.03% versus 5.49% +/- 1.01%, P =.038). Of various serum proteins evaluated, only alpha(1)-acid glycoprotein was significantly related to f(u) (P <.0018), with higher f(u) in the presence of lower protein levels. Total docetaxel clearance was related to alpha(1)-acid glycoprotein (R(2) = 0.13, P =.058), f(u)(pre) (R(2) = 0.15, P =.039), and f(u)(AUC) (R(2) = 0.29, P =.0048). CONCLUSION: This study demonstrates that the plasma binding of docetaxel is influenced by both alpha(1)-acid glycoprotein and its formulation vehicle. Further investigation is required to resolve the potential clinical significance of these observations.
Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Proteínas Sanguíneas/metabolismo , Neoplasias/metabolismo , Paclitaxel/análogos & derivados , Paclitaxel/farmacocinética , Polissorbatos , Taxoides , Adulto , Idoso , Antineoplásicos Fitogênicos/metabolismo , Antineoplásicos Fitogênicos/uso terapêutico , Área Sob a Curva , Química Farmacêutica , Docetaxel , Excipientes , Feminino , Humanos , Infusões Intravenosas , Modelos Lineares , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Orosomucoide/metabolismo , Paclitaxel/metabolismo , Paclitaxel/uso terapêuticoRESUMO
OBJECTIVE: In vitro studies indicate that the anticancer drug docetaxel is primarily eliminated by cytochrome P450 (CYP) 3A4-mediated metabolism. Coadministration of drugs that modulate the activity of CYP3A4 is, therefore, likely to have undesirable clinical consequences. We investigated the effects of the potent CYP3A4 inhibitor ketoconazole on the pharmacokinetics of docetaxel in patients with cancer. METHODS: Seven patients were treated in a randomized crossover design with docetaxel (100 mg/m(2)), followed 3 weeks later by docetaxel (10 mg/m(2)) given in combination with orally administered ketoconazole (200 mg once daily for 3 days), or the reverse sequence. Plasma concentration-time data were analyzed by noncompartmental analysis. RESULTS: Ketoconazole coadministration resulted in a 49% decrease in clearance of docetaxel (P =.018). The mean (+/-SD) clearance values were 35.0 +/- 11.8 L/h (95% confidence interval, 24.1-45.9 L/h) for docetaxel alone and 18.2 L/h (95% confidence interval, 9.22-27.1 L/h) in the presence of ketoconazole, respectively. The docetaxel clearance ratio in the presence and absence of ketoconazole was weakly related to the area under the curve of ketoconazole (R(2) = 0.529, P =.064). CONCLUSION: Inhibition of CYP3A4 by ketoconazole in vivo results in docetaxel clearance values that have previously been shown to be associated with a several-fold increase in the odds for febrile neutropenia at standard doses. Caution should be taken and substantial dose reductions are required if docetaxel has to be administered together with potent inhibitors of CYP3A4.
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Antifúngicos/farmacocinética , Antineoplásicos Fitogênicos/farmacocinética , Inibidores das Enzimas do Citocromo P-450 , Inibidores Enzimáticos/farmacologia , Cetoconazol/farmacologia , Taxoides/farmacocinética , Administração Oral , Adulto , Antifúngicos/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Estudos Cross-Over , Citocromo P-450 CYP3A , Docetaxel , Esquema de Medicação , Interações Medicamentosas , Inibidores Enzimáticos/administração & dosagem , Feminino , Humanos , Cetoconazol/administração & dosagem , Masculino , Pessoa de Meia-Idade , Taxoides/administração & dosagemRESUMO
OBJECTIVE: A semiphysiologic pharmacokinetic-pharmacodynamic model was applied to describe topotecan-induced neutropenia, to quantify interindividual and intraindividual pharmacodynamic variability, and to study the effect of covariates on the model. METHODS: Data were obtained from patients treated with topotecan given either orally (118 patients) or intravenously (71 patients), according to different schedules (5 to 21 consecutive days), with or without cisplatin. The model mimics the maturation chain of neutrophils. Topotecan concentration-time profiles affected the proliferation of neutrophil precursors (sensitive cells) through an inhibitory linear model (topotecan is assumed to induce cell loss by a function, E drug, proportional to the topotecan concentration in the central compartment: E drug = Slope . Concentration). The topotecan plasma concentration versus time profile was generated for each patient by modeling the data according to a 2-compartment pharmacokinetic model and first-order absorption for oral administration by use of NONMEM. RESULTS: The model described the time course of neutrophil values well. Topotecan neutropenic effect exhibited a large interpatient variability (coefficient of variation of 82% for the slope values). The oral route was associated with a 43% lower value for slope, corresponding to a lower toxicity. The combination with cisplatin increased the neutropenic effect compared with topotecan alone by a factor 3.5. The intrapatient variability between cycle 1 and cycle 2 on slope was lower for the intravenous administration than for the oral administration. By application of the model to a new weekly schedule of topotecan, neutrophil values at the nadir were consistent with those observed during a phase I study of this regimen. CONCLUSION: This model can be used to describe both the duration and intensity of neutropenia; the area between the curve of neutrophil count versus time and a critical neutrophil count (such as 0.500 x 10(3) /mm 3 ) would be a better toxic endpoint than the unique observed value of neutrophil at nadir. The model may be used to predict neutropenia corresponding to regimens of topotecan not yet explored.
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Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Neutropenia/induzido quimicamente , Topotecan/efeitos adversos , Topotecan/farmacocinética , Administração Oral , Adolescente , Adulto , Idoso , Análise de Variância , Antineoplásicos/administração & dosagem , Feminino , Humanos , Injeções Intravenosas , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Neutrófilos/fisiologia , Dinâmica não Linear , Reprodutibilidade dos Testes , Topotecan/administração & dosagemRESUMO
The non-ionic surfactants Cremophor EL (CrEL; polyoxyethyleneglycerol triricinoleate 35) and polysorbate 80 (Tween) 80; polyoxyethylene-sorbitan-20-monooleate) are widely used as drug formulation vehicles, including for the taxane anticancer agents paclitaxel and docetaxel. A wealth of recent experimental data has indicated that both solubilisers are biologically and pharmacologically active compounds, and their use as drug formulation vehicles has been implicated in clinically important adverse effects, including acute hypersensitivity reactions and peripheral neuropathy.CrEL and Tween 80 have also been demonstrated to influence the disposition of solubilised drugs that are administered intravenously. The overall resulting effect is a highly increased systemic drug exposure and a simultaneously decreased clearance, leading to alteration in the pharmacodynamic characteristics of the solubilised drug. Kinetic experiments revealed that this effect is primarily caused by reduced cellular uptake of the drug from large spherical micellar-like structures with a highly hydrophobic interior, which act as the principal carrier of circulating drug. Within the central blood compartment, this results in a profound alteration of drug accumulation in erythrocytes, thereby reducing the free drug fraction available for cellular partitioning and influencing drug distribution as well as elimination routes. The existence of CrEL and Tween 80 in blood as large polar micelles has also raised additional complexities in the case of combination chemotherapy regimens with taxanes, such that the disposition of several coadministered drugs, including anthracyclines and epipodophyllotoxins, is significantly altered. In contrast to the enhancing effects of Tween 80, addition of CrEL to the formulation of oral drug preparations seems to result in significantly diminished drug uptake and reduced circulating concentrations. The drawbacks presented by the presence of CrEL or Tween 80 in drug formulations have instigated extensive research to develop alternative delivery forms. Currently, several strategies are in progress to develop Tween 80- and CrEL-free formulations of docetaxel and paclitaxel, which are based on pharmaceutical (e.g. albumin nanoparticles, emulsions and liposomes), chemical (e.g. polyglutamates, analogues and prodrugs), or biological (e.g. oral drug administration) strategies. These continued investigations should eventually lead to more rational and selective chemotherapeutic treatment.
Assuntos
Antineoplásicos/administração & dosagem , Química Farmacêutica , Veículos Farmacêuticos/farmacologia , Tensoativos/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Animais , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Vias de Administração de Medicamentos , Hipersensibilidade a Drogas/etiologia , Interações Medicamentosas , Eritrócitos/metabolismo , Humanos , Hiperlipidemias/etiologia , Doenças do Sistema Nervoso Periférico/etiologia , Veículos Farmacêuticos/efeitos adversos , Veículos Farmacêuticos/farmacocinética , Tensoativos/efeitos adversos , Tensoativos/farmacocinéticaRESUMO
An analytical method was developed for the anticancer agent irinotecan (CPT-11) and its main metabolite SN-38 in human whole blood and in red blood cells (RBCs). Sample pretreatment involved deproteinization of whole blood or plasma-diluted RBCs isolated by MESED instruments, with a mixture of aqueous perchloric acid and methanol (1:1, v/v). Separation was carried out using isocratic elution on a Hypersil ODS stationary phase, with detection at excitation and emission wavelengths of 355 and 515 nm, respectively. The lower limit of quantitation (LLQ) in blood was established at 5.00 ng/ml for both compounds, with values for within-run precision (WRP) and between-run precision (BRP) of less than 10%. The method is currently being applied to investigate the blood distribution of CPT-11 and SN-38 in cancer patients.