RESUMEN
Prospective studies on epidermal growth factor receptor (EGFR) inhibitors in African Americans with non-small cell lung cancer (NSCLC) have not previously been performed. In this phase II randomized study, 55 African Americans with NSCLC received 150 mg/day erlotinib or a body weight-adjusted dose with subsequent escalations to the maximum-allowable dose, 200 mg/day, to achieve rash. Erlotinib and OSI-420 exposures were lower than those observed in previous studies, consistent with CYP3A pharmacogenetics implying higher metabolic activity. Tumor genetics showed only two EGFR mutations, EGFR amplification in 17/47 samples, eight KRAS mutations, and five EML4-ALK translocations. Although absence of rash was associated with shorter time to progression (TTP), disease-control rate, TTP, and 1-year survival were not different between the two dose groups, indicating the dose-to-rash strategy failed to increase clinical benefit. Low incidence of toxicity and low erlotinib exposure suggest standardized and maximum-allowable dosing may be suboptimal in African Americans.
Asunto(s)
Negro o Afroamericano/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Quinazolinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Clorhidrato de Erlotinib , Femenino , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Persona de Mediana Edad , Farmacogenética , Estudios Prospectivos , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinazolinas/farmacocinéticaRESUMEN
PURPOSE: Based on the preclinical evidence of topoisomerase I (Topo-1) upregulation by mitomycin C(MMC) and decreased NF-kappaB activation by celecoxib, we evaluated combinations of irinotecan/MMC and irinotecan/MMC/celecoxib in patients with advanced solid malignancies. PATIENTS-METHODS: Initially, patients received MMC on day 1 and irinotecan on days 2, 8, 15 and 22, every 6 weeks. MMC dose was fixed at 6 mg/m(2) and cumulative doses of >36 mg/m(2) were not permitted. Irinotecan was escalated in 25 mg/m(2) increments. Due to late-onset diarrhea, the schedule was subsequently shortened to 4 weeks, omitting irinotecan on days 15 and 22. In the second part of the study, celecoxib 400 mg orally twice daily was added to irinotecan/MMC regimen. Potential pharmacokinetic interactions and Topo-1 and DT-diaphorase (NQ01) gene expressions in peripheral-mononuclear cells were evaluated. RESULTS: Forty-five patients were enrolled. Irinotecan 125 mg/m(2) on days 2 and 8 in combination with MMC 6 mg/m(2) on day 1 every 4 weeks is recommended for future studies; myelosuppression and diarrhea are dose-limiting. The addition of celecoxib resulted in unacceptable toxicities despite reductions on irinotecan's dose. No relevant pharmacokinetic interactions occurred between irinotecan and MMC, and mean increases in Topo-1, were observed. Sixteen of 36 patients evaluable for response-assessment had discernable anti-tumor activity, including 1 complete, 4 partial, 10 minor and 1 tumor marker response. Four patients had prolonged (>4 months) disease-stability (stable disease, not included in CR or PR). Patients experiencing complete and partial responses had higher increments in Topo-1 expression. CONCLUSIONS: Modulation of irinotecan by MMC is feasible, devoid of pharmacological interactions and active in solid malignancies. The lack of improvement in therapeutic index does not support the addition of celecoxib.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Camptotecina/análogos & derivados , Camptotecina/farmacocinética , Celecoxib , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Irinotecán , Masculino , Persona de Mediana Edad , Mitomicina/administración & dosificación , Mitomicina/efectos adversos , Mitomicina/farmacocinética , Neoplasias/metabolismo , Pirazoles/administración & dosificación , Pirazoles/efectos adversos , Pirazoles/farmacocinética , Sulfonamidas/administración & dosificación , Sulfonamidas/efectos adversos , Sulfonamidas/farmacocinética , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVES: This trial was performed to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetic profile of irinotecan (CPT-11) when administered on a once-every-2-week schedule. PATIENTS AND METHODS: CPT-11 was administered to successive cohorts of patients at progressively increasing starting doses ranging from 125 to 350 mg/m2. The MTD and DLTs were determined both for CPT-11 alone and for CPT-11 followed by filgrastim (G-CSF). Plasma samples were obtained during the first 24 hours after initial dosing to determine the total concentrations (lactone + carboxylate forms) of CPT-11; of the active metabolite SN-38; and of SN-38 glucuronide (SN-38G). RESULTS: Neutropenic fever was the DLT for CPT-11 at the 300 mg/m2 dose level. When G-CSF was added, dose escalation beyond 350 mg/m2 could not be achieved due to grade 2-3 toxicities that prevented on-time retreatment with CPT-11. Severe, late diarrhea was uncommon on this schedule. Peak plasma concentrations of SN-38 and SN-38G were approximately 2.5% and 4.2% of the corresponding peak plasma concentration for CPT-II, respectively The harmonic mean terminal half-lives for CPT-11, SN-38, and SN-38G were 7.1 hours, 13.4 hours, and 12.7 hours, respectively. No predictive correlation was observed between CPT-11 or SN-38 peak concentration or AUC and first-cycle diarrhea, neutropenia, nausea, or vomiting. Across the range of doses studied, mean CPT-11 clearance was 14.0 +/- 4.0 l/h/m2 and volume of distribution was 146 +/- 45.9 l/m2. CONCLUSIONS: When administered every two weeks, the recommended phase II starting dose of CPT-11 is 250 mg/m2 when given alone and 300 mg/m2 when supported by G-CSF. This every-two-week regimen offers a tolerable and active alternative to weekly or every-three-week single-agent CPT-11 therapy.
Asunto(s)
Antineoplásicos Fitogénicos/farmacocinética , Camptotecina/farmacocinética , Neoplasias/metabolismo , Adulto , Anciano , Antineoplásicos Fitogénicos/administración & dosificación , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Cromatografía Líquida de Alta Presión , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Humanos , Irinotecán , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/tratamiento farmacológicoRESUMEN
A Phase I study was performed to determine the maximum tolerated dose (MTD), toxicities, and pharmacokinetic profile of irinotecan (CPT-11) and its active metabolites when given on a once-every-3-week schedule. Thirty-four patients with advanced refractory solid malignancies were treated with CPT-11 (240-340 mg/m2) administered as a 90-min i.v. infusion every 3 weeks. Patients were divided into two groups: those with and those without prior abdominal/pelvic (AP) radiotherapy. Gastrointestinal toxicity (nausea, vomiting, and diarrhea) and hematological toxicity (leukopenia and neutropenia) were dose-limiting side effects. Other common toxicities included anorexia, asthenia, and acute cholinergic symptoms (abdominal cramps, diaphoresis, and lacrimation). For patients with no prior AP radiation therapy, the MTD was determined to be 320 mg/m2, whereas those with prior AP radiation therapy had a MTD of 290 mg/m2. Dose-proportional increases in the mean area under the concentration-time curves for CPT-11, SN-38, and SN-38G were not observed over the narrow dose range studied. Mean values of terminal phase half-life, clearance, terminal phase volume of distribution, and steady-state volume of distribution for CPT-11 were 12.4 +/- 1.8 h, 13.0 +/- 3.8 liters/h/m2, 234 +/- 83 liters/m2, and 123 +/- 38 liters/m2, respectively. The pharmacodynamic analyses indicated the strongest correlation to be between SN-38 area under the concentration-time curves and neutropenia (p = 0.60; P = 0.001). A total of five responses (one complete response and four partial responses) were observed in the cohort of 32 patients with previously treated metastatic colorectal carcinoma. In conclusion, gastrointestinal toxicity and hematological toxicity were the dose-limiting toxicities of CPT-11 when administered as a 90-min infusion every 3 weeks. In this trial, the recommended Phase II starting dose for patients with no prior AP radiation therapy was found to be 320 mg/m2; for patients with prior AP radiation, the recommended Phase II starting dose was 290 mg/m2. This once-every-3-week schedule has been incorporated into a Phase I trial of CPT-11 combined with 5-fluorouracil and leucovorin.
Asunto(s)
Antineoplásicos Fitogénicos/uso terapéutico , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias de la Vesícula Biliar/tratamiento farmacológico , Adyuvantes Anestésicos/farmacología , Adulto , Anciano , Anciano de 80 o más Años , Antidiarreicos/farmacología , Antieméticos/farmacología , Antineoplásicos Fitogénicos/sangre , Antineoplásicos Fitogénicos/farmacocinética , Antineoplásicos Fitogénicos/toxicidad , Área Bajo la Curva , Atropina/farmacología , Camptotecina/sangre , Camptotecina/farmacocinética , Camptotecina/toxicidad , Dexametasona/farmacología , Sistema Digestivo/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Glucuronatos/sangre , Glucuronatos/farmacocinética , Humanos , Irinotecán , Loperamida/farmacología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Factores de TiempoRESUMEN
This study determined the disposition of irinotecan hydrochloride trihydrate (CPT-11) after i.v. infusion of 125 mg/m(2) (100 microCi) [(14)C]CPT-11 in eight patients with solid tumors. Mean +/- S.D. recovery of radioactivity in urine and feces was 95.8 +/- 2.7% (range 92.2-100.3%, n = 7) of dose. Radioactivity in blood, plasma, urine, and feces was determined for at least 168 h after dosing. Fecal excretion accounted for 63.7 +/- 6.8 (range 54.2-74.9%, n = 7) of dose, whereas urinary excretion accounted for 32.1 +/- 6.9% (range 21.7-43.8%; n = 7) of dose. One patient with a biliary T-tube excreted 30.1% of dose in bile, 14.2% in feces, and 48.2% in urine. Quantitative radiometric HPLC revealed that CPT-11 was the major excretion product in urine, bile, and feces. Aminopentane carboxylic acid (APC) and SN-38 glucuronide (SN-38G) were the most significant metabolites in urine and bile, whereas SN-38 and NPC, a primary amine metabolite, were relatively minor excretion products. SN-38 and APC were the most significant metabolites in feces. The relatively higher amount of SN-38 in feces compared with bile is presumably due to hydrolysis of SN-38G to SN-38 by enteric bacterial beta-glucuronidases. There was close correspondence between quantitative fluorescence HPLC and mass balance findings. CPT-11 was the major circulating component in plasma (55% of the mean radiochemical area under the curve), and CPT-11, SN-38, SN-38G, and APC accounted for 93% of the mean radiochemical AUC. These results show that the parent drug and its three major metabolites account for virtually all CPT-11 disposition, with fecal excretion representing the major elimination pathway.
Asunto(s)
Antineoplásicos Fitogénicos/farmacocinética , Camptotecina/análogos & derivados , Anciano , Antineoplásicos Fitogénicos/administración & dosificación , Área Bajo la Curva , Bilis/química , Bilis/metabolismo , Biotransformación , Camptotecina/administración & dosificación , Camptotecina/farmacocinética , Cromatografía Líquida de Alta Presión , Heces/química , Femenino , Humanos , Infusiones Intravenosas , Irinotecán , Masculino , Espectrometría de Masas , Persona de Mediana Edad , Neoplasias/metabolismoRESUMEN
PURPOSE: To evaluate the antitumor efficacy and safety of a combination of irinotecan (CPT-11) and cisplatin in patients with inoperable non-small-cell lung cancer (NSCLC). A secondary objective was to characterize the pharmacokinetics and pharmacodynamics of CPT-11 and its active metabolite, SN-38. PATIENTS AND METHODS: Patients with stage IIIB or IV NSCLC were treated with repeated 4-week courses comprising CPT-11 (60 mg/m(2)) administered on days 1, 8, and 15, and a single dose of cisplatin (80 mg/m(2)) after CPT-11 administration on day 1. RESULTS: Fifty-two patients were enrolled, including 33 men and 19 women. The median age was 61 years (range, 29 to 79 years). Southwest Oncology Group performance status was 0 in 12 patients, 1 in 32 patients, and 2 in eight patients. Eleven and 41 patients had stage IIIB and IV disease, respectively. Objective responses occurred in 28.8% of patients (15 of 52; 95% confidence interval, 16.5% to 41.2%). The median survival duration was 9.9 months (range, 1.6 to 30.8 months). The 1-year survival rate was 37%. Grade 3/4 adverse events consisted primarily of nausea (32. 7% ) or vomiting (13.5%), late-onset diarrhea (17.3%), and neutropenia (46.1%). The study design led to preferential modification of CPT-11 doses, resulting in CPT-11 dose attenuations to < or = 40 mg/m(2) in the majority of patients (31 of 52; 60%), whereas dose reductions of cisplatin were uncommon. CPT-11 pharmacokinetic parameters were comparable to those reported previously in single-agent studies. CONCLUSION: CPT-11/cisplatin is an active combination regimen with manageable toxicity in the therapy of stage IIIB/IV NSCLC. Future studies should be designed with schedules and dose modification provisions that avoid unnecessary CPT-11 dose reductions to exploit more directly the therapeutic synergy of these agents.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Área Bajo la Curva , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Camptotecina/análogos & derivados , Camptotecina/sangre , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/patología , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Esquema de Medicación , Femenino , Humanos , Irinotecán , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de NeoplasiasRESUMEN
PURPOSE: To determine the activity, toxicity, and pharmacokinetics of irinotecan (CPT-11, Camptosar; Pharmacia & Upjohn, Kalamazoo, MI) in the treatment of adults with progressive, persistent, or recurrent malignant glioma. PATIENTS AND METHODS: Patients with progressive or recurrent malignant gliomas were enrolled onto this study between October 1996 and August 1997. CPT-11 was given as a 90-minute intravenous (i.v.) infusion at a dose of 125 mg/m2 once weekly for 4 weeks followed by a 2-week rest, which comprised one course. Plasma concentrations of CPT-11 and its metabolites, SN-38 and SN-38 glucuronide (SN-38G), were determined in a subset of patients. RESULTS: All 60 patients who enrolled (36 males and 24 females) were treated with CPT-11 and all were assessable for toxicity, response, and survival. Pharmacokinetic data were available in 32 patients. Nine patients (15%; 95% confidence interval, 6% to 24%) had a confirmed partial response, and 33 patients (55%) achieved stable disease lasting more than two courses (12 weeks). Toxicity observed during the study was limited to infrequent neutropenia, nausea, vomiting, and diarrhea. CPT-11, SN-38, and SN-38G area under the plasma concentration-time curves through infinite time values in these patients were approximately 40%, 25%, and 25%, respectively, of those determined previously in patients with metastatic colorectal cancer not receiving antiepileptics or chronic dexamethasone treatment. CONCLUSION: Response results document that CPT-11, given with a standard starting dose and treatment schedule, has activity in patients with recurrent malignant glioma. However, the low incidence of severe toxicity and low plasma concentrations of CPT-11 and SN-38 achieved in this patient population suggest that concurrent treatment with anticonvulsants and dexamethasone enhances drug clearance.
Asunto(s)
Antineoplásicos Fitogénicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Camptotecina/análogos & derivados , Glioma/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos Fitogénicos/farmacocinética , Astrocitoma/sangre , Astrocitoma/tratamiento farmacológico , Neoplasias Encefálicas/sangre , Camptotecina/farmacocinética , Camptotecina/uso terapéutico , Progresión de la Enfermedad , Femenino , Glioblastoma/sangre , Glioblastoma/tratamiento farmacológico , Glioma/sangre , Humanos , Irinotecán , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/sangre , Oligodendroglioma/sangre , Oligodendroglioma/tratamiento farmacológicoRESUMEN
PURPOSE: We conducted a phase I dose-escalation trial of orally administered irinotecan (CPT-11) to characterize the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetic profile, and antitumor effects in patients with refractory malignancies. PATIENTS AND METHODS: CPT-11 solution for intravenous (IV) use was mixed with CranGrape juice (Ocean Spray, Lakeville-Middleboro, MA) and administered orally once per day for 5 days every 3 weeks to 28 patients. Starting dosages ranged from 20 to 100 mg/m2/d. RESULTS: Grade 4 delayed diarrhea was the DLT at the 80 mg/m2/d dosage in patients younger than 65 years of age and at the 66 mg/m2/d dosage in patients 65 or older. The other most clinically significant toxicity of oral CPT-11 was neutropenia. A linear relationship was found between dose, peak plasma concentration, and area under the concentration-time curve (AUC) for both CPT-11 and SN-38 lactone, implying no saturation in the conversion of irinotecan to SN-38. The mean metabolic ratio ([AUC(SN-38 total) + AUC(SN-38G total)]/AUC(CPT-11 total)) was 0.7 to 0.8, which suggests that oral dosing results in presystemic conversion of CPT-11 to SN-38. An average of 72% of SN-38 was maintained in the lactone form during the first 24 hours after drug administration. One patient with previously treated colorectal cancer and liver metastases who received oral CPT-11 at the 80 mg/m2/d dosage achieved a confirmed partial response. CONCLUSION: The MTD and recommended phase II dosage for oral CPT-11 is 66 mg/m2/d in patients younger than 65 years of age and 50 mg/m2/d in patients 65 or older, administered daily for 5 days every 3 weeks. The DLT of diarrhea is similar to that observed with IV administration of CPT-11. The biologic activity and favorable pharmacokinetic characteristics make oral administration of CPT-11 an attractive option for further clinical development.
Asunto(s)
Antineoplásicos Fitogénicos/farmacocinética , Antineoplásicos Fitogénicos/uso terapéutico , Camptotecina/análogos & derivados , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Fitogénicos/efectos adversos , Camptotecina/efectos adversos , Camptotecina/sangre , Camptotecina/farmacocinética , Camptotecina/uso terapéutico , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Irinotecán , Masculino , Persona de Mediana EdadRESUMEN
PURPOSE: In vitro synergy between cisplatin and irinotecan (CPT-11) has been reported. We designed a combination schedule of these agents to maximize the potential for synergistic interaction. PATIENTS AND METHODS: To maximize the opportunity for synergy, we divided the cisplatin into four consecutive weekly treatments, followed by a 2-week rest. Each dose of cisplatin was immediately followed by a dose of irinotecan. The dose of cisplatin was fixed at 30 mg/m2/wk. The initial irinotecan dose was 50 mg/m2/wk and this was escalated by 30% increments in successive cohorts of three to six patients to establish the maximum-tolerated dose (MTD). Pharmacokinetics of irinotecan and its metabolites, SN-38 and SN-38 glucuronide (SN-38G), were analyzed. RESULTS: Of 35 patients with solid tumors enrolled onto this trial, 30 were assessable for toxicity and response. The MTD for this regimen was 30 mg/m2/wk of cisplatin plus 50 mg/m2/wk of irinotecan in previously treated patients and 30 mg/m2/wk of cisplatin plus 65 mg/m2/wk of irinotecan in chemotherapy-naive patients. Neutropenia was the dose-limiting toxicity (DLT) encountered in this trial. Diarrhea was infrequent and rarely dose-limiting. Seven of 30 assessable patients achieved a partial response. No alteration in irinotecan, SN-38, or SN-38G pharmacokinetics resulted from the administration of cisplatin with irinotecan. CONCLUSION: The administration of cisplatin and irinotecan on this weekly schedule provides a practical and well-tolerated regimen that has the potential to maximize any clinical synergy between the two agents. Evidence of substantial clinical activity was seen in this phase I study.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Camptotecina/farmacocinética , Cisplatino/administración & dosificación , Cisplatino/farmacocinética , Esquema de Medicación , Sinergismo Farmacológico , Femenino , Glucuronatos/farmacocinética , Humanos , Irinotecán , Masculino , Persona de Mediana Edad , Neoplasias/sangre , Resultado del TratamientoRESUMEN
Most of the clinical experience with irinotecan (CPT-11 [Camptosar]) has been with either a weekly or an every-3-week schedule. Recent phase I trials have explored new routes and schedules of administration. One approach attempts to maximize dose frequency and intensity by giving irinotecan every 2 weeks. A phase I trial of this approach is now complete and has led to a phase II trial in patients with recurrent colorectal cancer. Data suggest that smaller doses of a topoisomerase I inhibitor administered repeatedly may result in greater antitumor activity than large doses administered intermittently. A phase I trial has been performed in adults in which irinotecan was administered daily for 5 consecutive days, followed by 2 days off, for 2 weeks out of 3. Similar trials are under way in children. Oral administration, another strategy that has undergone phase I testing, has several theoretical advantages:(1) The acidic pH of the stomach favors maintenance of irinotecan in the active lactone ring form. (2) Irinotecan is more rapidly and extensively converted to SN-38 by tissue carboxylesterases found in high concentrations in the gut and liver. (3) Low doses can be delivered over a protracted period. (4) The oral route enhances patient convenience. These alternative dosing schedules may facilitate integration of irinotecan into combination chemotherapy and combined-modality treatment regimens.
Asunto(s)
Antineoplásicos Fitogénicos/uso terapéutico , Camptotecina/análogos & derivados , Adulto , Camptotecina/uso terapéutico , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Humanos , IrinotecánRESUMEN
Carzelesin is a novel cyclopropylpyrroloindole prodrug analogue that has recently been tested in Phase I clinical trials. To increase our understanding in the pharmacology of this new class of cytotoxic drugs, we have compared the pharmacology of this drug in mice, rats, and humans. The mouse was the most tolerant [10% lethal dose (LD10), 500 microg/kg], the rat was intermediate (LD10, 40 microg/kg), and humans were the least tolerant species in this series (maximum tolerated dose, 300 microg/m2 corresponding to 7.5 microg/kg). In both mice and humans, bone marrow toxicity was the primary toxic side effect. Pharmacokinetic studies, using a validated high-performance liquid chromatographic procedure, revealed that differences in drug clearance and conversion to the active drug (U-76,074) could not explain the substantial interspecies differences. The area under the plasma concentration time curve (AUCs) of carzelesin in mice and rats at their LD10s were about 80- and 20-fold higher, respectively, than in humans receiving the maximum tolerated dose, whereas the respective AUCs of U-76,074 in mice and rats were 50- and 10-fold higher. By using a colony-forming assay with bone marrow stem cells from mice and humans, we observed only a 3-fold higher toxicity in the latter. Although some of this discrepancy may be explained by the fact that the in vitro and the in vivo assays probably reflect the toxicity on different populations of colony-forming units, the tolerance of the mouse bone marrow in vivo against the very high drug levels in plasma suggest the presence of a protective mechanism, which is less active in humans. An important consequence of the much higher susceptibility of the human bone marrow for carzelesin is that the target plasma levels in humans are much below active concentrations achieved in mice, and it is clear that this may compromise the successful use of this agent in the clinic. Ultimately, however, the efficacy of this drug will be established in Phase II clinical trials.
Asunto(s)
Antineoplásicos/farmacología , Benzofuranos/farmacología , Indoles/farmacología , Profármacos/farmacología , Animales , Antineoplásicos/toxicidad , Benzofuranos/toxicidad , Células Cultivadas , Cromatografía Líquida de Alta Presión , Estabilidad de Medicamentos , Duocarmicinas , Células Madre Hematopoyéticas/efectos de los fármacos , Humanos , Indoles/toxicidad , Masculino , Ratones , Modelos Químicos , Profármacos/toxicidad , Ratas , Reproducibilidad de los ResultadosRESUMEN
We investigated the pharmacokinetic behavior of carzelesin in 31 patients receiving this drug by 10-min intravenous infusion in a Phase I clinical trial, which was conducted at institutions in Nijmegen (institution 1) and Brussels (institution 2). The dose steps were 24, 48, 96, 130, 150, 170, 210, 250, and 300 microg/m2. Carzelesin is a cyclopropylpyrroloindole prodrug that requires metabolic activation via U-76,073 to U-76,074. The lower limit of quantitation (LLQ) of the high-performance liquid chromatography (HPLC) method used in this study was 1 ng/ml for the parent drug and its metabolic products. Carzelesin was rapidly eliminated from plasma (elimination half-life 23 +/- 9 min; mean value +/- SD). At all dose levels, U-76,073 was found as early as in the first samples taken after the start of the infusion. However, the concentration of U-76,074 exceeded the LLQ for only short periods and only at the higher dose levels. Although the plasma levels of all three compounds were well above the respective IC50 values obtained by in vitro clonogenic assays, they were much lower than those observed in a preclinical study in mice. There was a substantial discrepancy in the mean plasma clearance observed between patients from institution 1 (7.9 +/- 2.1 l h[-1] m[-2]) and those from institution 2 (18.4 +/- 13.6 l h[-1] m[-2]; P = 0.038), probably reflecting problems with drug administration in the latter institution. The results recorded for patients in institution 1 indicated that the AUC increased proportionately with increasing doses. There was a good correlation between the maximal plasma concentration and the AUC, enabling future monitoring of drug exposure from one timed blood sample. Urinary excretion of carzelesin was below 1% of the delivered dose.
Asunto(s)
Antineoplásicos/farmacocinética , Benzofuranos/farmacocinética , Indoles/farmacocinética , Linfoma/metabolismo , Antineoplásicos/administración & dosificación , Antineoplásicos/sangre , Antineoplásicos/química , Área Bajo la Curva , Benzofuranos/administración & dosificación , Benzofuranos/sangre , Benzofuranos/química , Cromatografía Líquida de Alta Presión , Duocarmicinas , Humanos , Indoles/administración & dosificación , Indoles/sangre , Indoles/química , Infusiones Intravenosas , Tasa de Depuración MetabólicaRESUMEN
Human hepatic microsomes were used to investigate the carboxylesterase-mediated bioactivation of CPT-11 to the active metabolite, SN-38. SN-38 formation velocity was determined by HPLC over a concentration range of 0.25-200 microM CPT-11. Biphasic Eadie Hofstee plots were observed in seven donors, suggesting that two isoforms catalyzed the reaction. Analysis by nonlinear least squares regression gave KM estimates of 129-164 microM with a Vmax of 5.3-17 pmol/mg/min for the low affinity isoform. The high affinity isoform had KM estimates of 1.4-3.9 microM with Vmax of 1.2-2.6 pmol/mg/min. The low KM carboxylesterase may be the main contributor to SN-38 formation at clinically relevant hepatic concentrations of CPT-11. Using standard incubation conditions, the effects of potential inhibitors of carboxylesterase-mediated CPT-11 hydrolysis were evaluated at concentrations >/= 21 microM. Positive controls bis-nitrophenylphosphate (BNPP) and physostigmine decreased CPT-11 hydrolysis to 1.3-3.3% and 23% of control values, respectively. Caffeine, acetylsalicylic acid, coumarin, cisplatin, ethanol, dexamethasone, 5-fluorouracil, loperamide, and prochlorperazine had no statistically significant effect on CPT-11 hydrolysis. Small decreases were observed with metoclopramide (91% of control), acetaminophen (93% of control), probenecid (87% of control), and fluoride (91% of control). Of the compounds tested above, based on these in vitro data, only the potent inhibitors of carboxylesterase (BNPP, physostigmine) have the potential to inhibit CPT-11 bioactivation if administered concurrently. The carboxylesterase-mediated hydrolysis of alpha-naphthyl acetate (alpha-NA) was used to determine whether CPT-11 was an inhibitor of hydrolysis of high turnover substrates of carboxylesterases. Inhibition of alpha-NA hydrolysis by CPT-11 was determined relative to positive controls BNPP and NaF. Incubation with microsomes pretreated with CPT-11 (80-440 microM) decreased alpha-naphthol formation to approximately 80% of control at alpha-NA concentrations of 50-800 microM. The inhibitors BNPP (360 microM) and NaF (500 microM) inhibited alpha-naphthol formation to 9-10% of control and to 14-20% of control, respectively. Therefore, CPT-11-sensitive carboxylesterase isoforms may account for only 20% of total alpha-NA hydrolases. Thus, CPT-11 is unlikely to significantly inhibit high turnover, nonselective substrates of carboxylesterases.
Asunto(s)
Antineoplásicos Fitogénicos/metabolismo , Camptotecina/análogos & derivados , Hidrolasas de Éster Carboxílico/metabolismo , Microsomas Hepáticos/metabolismo , Biotransformación , Camptotecina/metabolismo , Interacciones Farmacológicas , Humanos , IrinotecánRESUMEN
PURPOSE: To evaluate irinotecan (CPT-11; Yakult Honsha, Tokyo, Japan) in patients with metastatic colorectal carcinoma that had recurred or progressed following fluorouracil (5-FU)-based therapy. PATIENTS AND METHODS: Patients were treated with irinotecan 125 to 150 mg/m2 intravenously (IV) every week for 4 weeks, followed by a 2-week rest. Forty-eight patients were entered onto the study and all were assessable for toxicity. Forty-three patients completed one full course of therapy and were assessable for response. RESULTS: One complete and nine partial responses were observed (response rate, 23%; 95% confidence interval [CI], 10% to 36%). The median response duration was 6 months (range, 2 to 13). The median survival time was 10.4 months and the 1-year survival rate was 46% (95% CI, 39% to 53%). Grade 4 diarrhea occurred in four of the first nine patients (44%) treated on this study at the 150-mg/m2 dose level. The study was amended to reduce the starting dose of irinotecan to 125 mg/m2. At this dose, nine of 39 patients (23%) developed grade 4 diarrhea. Aggressive administration of loperamide also reduced the incidence of grade 4 diarrhea. Grade 4 neutropenia occurred in eight of 48 patients (17%), but was associated with bacteremia and sepsis in only case. CONCLUSION: Irinotecan has significant single-agent activity against colorectal cancer that has progressed during or shortly after treatment with 5-FU-based chemotherapy. The incidence of severe diarrhea is reduced by using a starting dose of irinotecan 125 mg/m2 and by initiating loperamide at the earliest signs of diarrhea. These results warrant further clinical evaluation to define the role of irinotecan in the treatment of individuals with colorectal cancer.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Antineoplásicos Fitogénicos/uso terapéutico , Camptotecina/análogos & derivados , Neoplasias Colorrectales/tratamiento farmacológico , Terapia Recuperativa , Adenocarcinoma/sangre , Adenocarcinoma/secundario , Antidiarreicos/uso terapéutico , Antineoplásicos Fitogénicos/efectos adversos , Antineoplásicos Fitogénicos/farmacocinética , Camptotecina/efectos adversos , Camptotecina/farmacocinética , Camptotecina/uso terapéutico , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/patología , Diarrea/inducido químicamente , Diarrea/tratamiento farmacológico , Progresión de la Enfermedad , Esquema de Medicación , Resistencia a Antineoplásicos , Humanos , Infusiones Intravenosas , Irinotecán , Loperamida/uso terapéutico , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
OBJECTIVE: To investigate the potential interaction between cimetidine or famotidine and cyclosporine in healthy men. DESIGN: All subjects received oral cyclosporine at baseline, after the first week of 1 histamine2 (H2)-blocker, and a third time after a 1-week washout plus 1 week of the second H2-blocker. Blood samples were collected just before each dose of cyclosporine and for up to 36 hours afterward for pharmacokinetic analysis. SETTING: A college of pharmacy in a university teaching hospital. PARTICIPANTS: The study population consisted of 8 healthy men at least 19 years of age. MAIN OUTCOME MEASURES: Cyclosporine concentrations in whole blood were measured using a polyclonal fluorescence polarization immunoassay. Cyclosporine pharmacokinetic parameters during each of the 3 treatment periods were compared. RESULTS: The average times to maximum cyclosporine concentrations were similar between baseline (3.2 h), cimetidine (2.9 h), and famotidine (3.6 h) dosing periods. There were no significant differences in area under the curve, half-life, or maximum concentration during the 3 dosing periods. CONCLUSIONS: Neither cimetidine or famotidine produced a significant change in the pharmacokinetics of single-dose oral cyclosporine in healthy men.
Asunto(s)
Cimetidina/farmacología , Ciclosporina/farmacocinética , Famotidina/farmacología , Antagonistas de los Receptores H2 de la Histamina/farmacología , Adulto , Estudios Cruzados , Interacciones Farmacológicas , Hospitales Universitarios , Humanos , MasculinoRESUMEN
Published reports regarding the stability of morphine are at variance, especially in syringes used in patient-controlled analgesia (PCA) devices. In addition to the effects of container type and vehicle, reasons for this variation include the effect of excipients temperature and light during storage. Furthermore, the literature varies regarding the mechanisms of decomposition for morphine. To our knowledge, the stability of meperidine (pethidine) stored in plastic syringes has not been reported. The purposes of this study were to investigate the stability of morphine sulphate (1 and 5 mg/ml) and meperidine hydrochloride (5 and 10 mg/ml) in plastic syringes for use in PCA devices for a duration of 12 weeks, and evaluate the influence of light (240 foot-candles), temperature (-20, 4 and 23 degrees C), diluent (5% dextrose or normal saline), and drug concentration on the stability of these narcotic analgesics. Samples were taken bi-weekly for solutions protected from light and weekly for solutions exposed to light. Morphine sulphate and meperidine hydrochloride concentrations were quantified using independent, stability-indicating, high performance liquid chromatographic assays. The within-day and between-day coefficients of variation for these assays were < or = 4% over each of the concentration ranges studied. Under the conditions of this study, it is proposed that although decomposition of morphine to its main product, pseudomorphine, can be interpreted using first-order kinetics, consecutive (to form the N-oxide) and parallel mechanisms (to form apomorphine) exist. Morphine solutions were more stable in normal saline than in 5% dextrose. Shelf-life data indicate that morphine is stable for at least 6 weeks when protected from light.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Meperidina/química , Morfina/química , Analgésicos Opioides , Composición de Medicamentos , Estabilidad de Medicamentos , Almacenaje de Medicamentos , Equipos y Suministros , Autoadministración , JeringasRESUMEN
Carzelesin (U80,244, I) is a cyclopropylpyrroloindole prodrug analog. The compound exerts its cytotoxic activity after conversion, via U-76,073 (II) to U-76,074 (III) by binding to the DNA minor groove in a sequence selective fashion. In pre-clinical investigations the drug displayed a broad spectrum activity against human xenografts in mice. To enable pharmacokinetic monitoring during the phase I clinical trials, we have developed a selective and sensitive assay for the parent compound and its two metabolites. Sample pre-treatment has been automated by using the ASPEC system and involves solid-phase extraction of the diluted plasma sample (1:3 in 20% v/v acetic acid) on an SPE-C18 precolumn followed by two consecutive washings with water and acetonitrile. The compounds are eluted with 600 microliters of dimethylacetamide and 500 microliters is injected on a Spherisorb-CN column. The sample is chromatographed using a linear gradient from 24% to 60% (v/v) acetonitrile in 20 mM phosphate buffer (pH 6.5). The eluate fraction containing the three compounds is heart-cutted in a 2-ml sample loop, switched onto a Spherisorb-ODS column and separation is accomplished using a mobile phase of acetonitrile-20 mM phosphate buffer pH 6.5 (64:36, v/v). UV detection is used with absorbance monitored at 360 nm. This highly selective method offers a lower limit of detection of less than 1 ng/ml for each of the compounds using 1000 microliters of plasma and enables the quantification of the analytes with an acceptable precision and accuracy over a range of 1 to 50 ng/ml. The assay has been implemented in a phase I clinical trial.
Asunto(s)
Antineoplásicos/sangre , Benzofuranos/sangre , Indoles/sangre , Profármacos/farmacocinética , Antineoplásicos/química , Antineoplásicos/farmacocinética , Autoanálisis , Benzofuranos/química , Benzofuranos/farmacocinética , Fenómenos Químicos , Química Física , Cromatografía Líquida de Alta Presión , Duocarmicinas , Humanos , Indicadores y Reactivos , Indoles/química , Indoles/farmacocinética , Profármacos/química , Espectrofotometría UltravioletaRESUMEN
The effects of injection site and flow rates on drug distribution within an extracorporeal membrane oxygenation (ECMO) circuit were studied. Two commercially available reservoirs (30 mL and 50 mL) were connected to a closed ECMO circuit that did not include the membrane oxygenator and heater. The circuit was filled with 150-170 mL of a 9.5% dextran solution in deionized, distilled water with a viscosity approximating that of blood. Flow rates of the circulating solution were set at 75 mL/min and 375 mL/min. Bordeaux red dye was injected into an ECMO circuit at prereservoir, postreservoir, and intrareservoir sites, and samples were obtained from these sites for analysis. Gentamicin was also injected at the prereservoir site, with samples obtained from the reservoir, reservoir tubing, and the prereservoir and postreservoir sites. Postreservoir dye injections resulted in complete mixing at any flow rate. Prereservoir injections at flow rates less than 250 mL/min resulted in incomplete mixing of dye, whereas intrareservoir injections resulted in incomplete mixing at any flow rate. Gentamicin injection was also affected by flow rate, resulting in higher concentrations within the reservoir and reservoir tubing. In patients on ECMO, drug distribution may be substantially altered if drugs are given as a bolus at prereservoir or intrareservoir sites. Efforts should be made to select injection sites that will provide safe and therapeutic drug delivery while minimizing the effects of the ECMO circuit on drug distribution.
Asunto(s)
Oxigenación por Membrana Extracorpórea , Cuidados Críticos , Oxigenación por Membrana Extracorpórea/instrumentación , Gentamicinas/análisis , Humanos , Lactante , Inyecciones/métodos , Soluciones , Espectrofotometría UltravioletaRESUMEN
The physical and chemical compatibility of enalaprilat in admixtures of dobutamine, dopamine, heparin, nitroglycerin, potassium chloride, or sodium nitroprusside, in 5% dextrose, were studied at room temperature over a 24-h period. Enalaprilat was found to be physically compatible and chemically stable in all admixture solutions tested.
Asunto(s)
Enalaprilato/química , Cuidados Críticos/métodos , Dobutamina/administración & dosificación , Dopamina/administración & dosificación , Combinación de Medicamentos , Incompatibilidad de Medicamentos , Enalaprilato/administración & dosificación , Heparina/administración & dosificación , Concentración de Iones de Hidrógeno , Infusiones Intravenosas , Nitroglicerina/administración & dosificación , Nitroprusiato/administración & dosificación , Cloruro de Potasio/administración & dosificaciónRESUMEN
The visual and chemical compatibility of esmolol hydrochloride mixed with aminophylline, heparin sodium, bretylium tosylate, or procainamide hydrochloride in 5% dextrose injection was studied. Esmolol hydrochloride 600 mg was injected into polyvinyl chloride bags containing 100 mL of 5% dextrose injection with aminophylline 100 mg, heparin sodium 5000 units, bretylium tosylate 100 mg, or procainamide hydrochloride 400 mg. All admixtures were prepared in triplicate and stored at room temperature under fluorescent light. Esmolol concentrations were measured with high-performance liquid chromatography at 0, 2, 4, 8, and 24 hours. Samples were also examined for precipitate formation and pH and color changes by using visual, microscopic, and spectrophotometric methods. No detectable changes in color or pH and no particulate formation were observed in any of the sample bags. Esmolol concentrations varied by less than 5% throughout the 24-hour study period. Esmolol hydrochloride was visually compatible and chemically stable for at least 24 hours when mixed with aminophylline, heparin sodium, bretylium tosylate, or procainamide hydrochloride in polyvinyl chloride bags containing 5% dextrose injection.