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1.
Poujol S Bressolle F Duffour J Abderrahim AG Astre C Ychou M Pinguet F 《Cancer chemotherapy and pharmacology》2006,58(3):292-305
Purpose: Irinotecan is extensively metabolized into at least four compounds and previous pharmacokinetic–pharmacodynamic studies have given varying results. We hypothesized that saliva, a noninvasive, safe and painless biological sampling process, could be a good predictor of the behavior of irinotecan and its metabolites. Methods: Thirty-five patients with metastatic digestive cancer were treated with a Folfiri regimen every 2 weeks. The irinotecan-administered dose was 180 mg/m²; 17 patients participated in a dose-escalating study. Irinotecan and its metabolites (SN-38, SN-38G, APC, NPC) were quantified in plasma and saliva by high-performance liquid chromatography with fluorescence detection. Results: The mean irinotecan systemic clearance and steady-state volume of distribution values were 14.3 l/h/m² and 211 l/m², respectively. The intrapatient variability (22–28%) was far lower than the interindividual variability (33–88%). Age and weight were the two physiological parameters that influenced drug disposition. For irinotecan, SN-38, APC and NPC, similar pharmacokinetic profiles were observed from plasma and saliva data. The saliva/plasma AUC ratios averaged 1 for irinotecan, 0.3 for SN-38, 0.17 for APC and 0.27 for NPC. Neutropenia, diarrhea and nausea were the main toxicities encountered. From both plasma and saliva data, the percentage decrease in neutrophil count appeared to be related to irinotecan and SN-38 AUCs. Conclusions: All these findings provide a rationale for an individual adaptation of irinotecan dosing. In case of difficult venous access, the titration of irinotecan and of its active metabolite SN-38 in saliva may prove relevant. 相似文献
2.
Rouits E Charasson V Pétain A Boisdron-Celle M Delord JP Fonck M Laurand A Poirier AL Morel A Chatelut E Robert J Gamelin E 《British journal of cancer》2008,99(8):1239-1245
This study aims at establishing relationships between genetic and non-genetic factors of variation of the pharmacokinetics of irinotecan and its metabolites; and also at establishing relationships between the pharmacokinetic or metabolic parameters and the efficacy and toxicity of irinotecan. We included 49 patients treated for metastatic colorectal cancer with a combination of 5-fluorouracil and irinotecan; a polymorphism in the UGT1A1 gene (TA repeat in the TATA box) and one in the CES2 gene promoter (830C>G) were studied as potential markers for SN-38 glucuronidation and irinotecan activation, respectively; and the potential activity of CYP3A4 was estimated from cortisol biotransformation into 6beta-hydroxycortisol. No pharmacokinetic parameter was directly predictive of clinical outcome or toxicity. The AUCs of three important metabolites of irinotecan, SN-38, SN-38 glucuronide and APC, were tentatively correlated with patients' pretreatment biological parameters related to drug metabolism (plasma creatinine, bilirubin and liver enzymes, and blood leukocytes). SN-38 AUC was significantly correlated with blood leukocytes number and SN-38G AUC was significantly correlated with plasma creatinine, whereas APC AUC was significantly correlated with plasma liver enzymes. The relative extent of irinotecan activation was inversely correlated with SN-38 glucuronidation. The TATA box polymorphism of UGT1A1 was significantly associated with plasma bilirubin levels and behaved as a significant predictor for neutropoenia. The level of cortisol 6beta-hydroxylation predicted for the occurrence of diarrhoea. All these observations may improve the routine use of irinotecan in colorectal cancer patients. UGT1A1 genotyping plus cortisol 6beta-hydroxylation determination could help to determine the optimal dose of irinotecan. 相似文献
3.
Guemei AA Cottrell J Band R Hehman H Prudhomme M Pavlov MV Grem JL Ismail AS Bowen D Taylor RE Takimoto CH 《Cancer chemotherapy and pharmacology》2001,47(4):283-290
PURPOSE: To characterize the relationships between human plasma irinotecan carboxylesterase-converting enzyme activity, caboxylesterase-mediated hydrolysis of p-nitrophenyl acetate (pNPA), and the butyrylcholinesterase-mediated hydrolysis of butyrylthiocholine in human plasma and to test the ability of these in vitro tests to predict the variability in SN-38 pharmacokinetics in adult patients during a prolonged infusion of irinotecan. METHODS: Individual plasma-converting enzyme activity was measured in 20 adult cancer patients participating in a pharmacokinetic and phase I clinical trial of a prolonged 96-h intravenous infusion of irinotecan. The pNPA and butyrylthiocholine hydrolysis in patient plasma was also assayed. RESULTS: The irinotecan carboxylesterase-converting enzyme in human plasma had a Vmax of 89.9 +/- 22.7 pmol/h per ml plasma and a Km of 207 +/- 56 microM (mean +/- SD, n = 3). The mean value of the specific activity of this enzyme in 20 adult cancer patients was 10.08 +/- 2.96 pmol/h per ml plasma ranging from 5.43 to 15.39 pmol/h per ml. The area-under-the-concentration-versus time curve (AUC) ratio of SN-38 to irinotecan (AUCSN-38/AUCCPT-11) was used to assess the relative SN-38 exposure to the active metabolite in individual patients. Pharmacokinetic variations in the relative exposure to SN-38 did not correlate with the measured carboxylesterase-converting enzyme activity nor with plasma butyrylcholinesterase activity in our patient population. However, it did correlate with the measured pNPA hydrolysis activity in patient plasma (r2 = 0.350, P = 0.0124, n = 18). CONCLUSIONS: Determination of patient plasma pNPA hydrolysis activity may have utility in predicting SN-38 pharmacokinetics during prolonged infusions of irinotecan. 相似文献
4.
Modulation of irinotecan metabolism by ketoconazole. 总被引:4,自引:0,他引:4
Diederik F S Kehrer Ron H J Mathijssen Jaap Verweij Peter de Bruijn Alex Sparreboom 《Journal of clinical oncology》2002,20(14):3122-3129
PURPOSE: Irinotecan (CPT-11) is a prodrug of SN-38 and has been registered for the treatment of advanced colorectal cancer. It is converted by the cytochrome P450 3A4 isozyme (CYP3A4) into several inactive metabolites, including 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin (APC). To investigate the role of CYP3A4 in irinotecan pharmacology, we evaluated the consequences of simultaneous treatment of irinotecan with a potent enzyme inhibitor, ketoconazole, in a group of cancer patients. PATIENTS AND METHODS: A total of seven assessable patients was treated in a randomized, cross-over design with irinotecan (350 mg/m(2) intravenously for 90 minutes) given alone and followed 3 weeks later by irinotecan (100 mg/m(2)) in combination with ketoconazole (200 mg orally for 2 days) or vice versa. Serial plasma, urine, and feces samples were obtained up to 500 hours after dosing and analyzed for irinotecan, metabolites (7-ethyl-10-hydroxycamptothecin [SN-38], SN-38 glucuronide [SN-38G], and APC), and ketoconazole by high-performance liquid chromatography. RESULTS: With ketoconazole coadministration, the relative formation of APC was reduced by 87% (P =.002), whereas the relative exposure to the carboxylesterase-mediated SN-38 as expected on the basis of dose (area under the plasma concentration-time curve normalized to dose) was increased by 109% (P =.004). These metabolic alterations occurred without substantial changes in irinotecan clearance (P =.90) and formation of SN-38G (P =.93). CONCLUSION: Inhibition of CYP3A4 in cancer patients treated with irinotecan leads to significantly increased formation of SN-38. Simultaneous administration of various commonly prescribed inhibitors of CYP3A4 can potentially result in fatal outcomes, and up to four-fold reductions in irinotecan dose are indicated. 相似文献
5.
E. Gupta Xiaolin Wang Jacqueline Ramirez M. J. Ratain 《Cancer chemotherapy and pharmacology》1997,39(5):440-444
Purpose: Irinotecan (CPT-11) is hydrolyzed to its active metabolite SN-38 which is subsequently conjugated by uridine diphosphate
glucuronosyl transferase (UDP-GT) to the glucuronide (SN-38G). Both preclinical and clinical data indicate that conjugation
is a primary clearance mechanism for SN-38 with the plasma glucuronide levels being substantially higher than those of SN-38.
This investigation was designed to determine the possibility of modulation of glucuronidation of SN-38 and its effect on the
disposition of the parent drug and metabolites. Methods: Female Wistar rats were pretreated with 200 mg/kg valproic acid (VPA), an inhibitor of glucuronidation, 5 min prior to the
administration of 20 mg/kg irinotecan. The control rats were given 20 mg/kg irinotecan only. To study the effect of inducers
of UDP-GT activity, rats were pre- treated with phenobarbital (PB) before irinotecan administration. Results: Pretreatment with VPA caused a 99% inhibition in the formation of SN-38G leading to a 270% increase in the area under plasma
concentration-time curve (AUC) of SN-38 compared with the control rats. The irinotecan estimations were unchanged in the two
groups. PB pretreatment caused a 1.7-fold increase in the AUC of SN-38G and a concomitant 31% and 59% reduction in the AUCs
of SN-38 and irinotecan, respectively. Conclusions: The most plausible explanation for the alterations in SN-38G disposition is inhibition of SN-38 conjugation by VPA and induction
of the conjugation by PB.
Received: 5 February 1996 / Accepted: 30 July 1996 相似文献
6.
Relationship between the Pharmacokinetics of Irinotecan and Diarrhea during Combination Chemotherapy with Cisplatin 总被引:2,自引:0,他引:2
Shinzoh Kudoh Masahiro Fukuoka Noriyuki Masuda Atsuko Yoshikawa Yoko Kusunoki Kaoru Matsui Shun-ichi Negoro Nobuhide Takifuji Kazuhiko Nakagawa Tomonori Hirashima Takashi Yana Minoru Takada 《Cancer science》1995,86(4):406-413
Two phase I trials of irinotecan (CPT-11) in combination with cisplatin were conducted. In both cases, the dose-limiting toxicities were leukopenia and/or diarrhea. During these trials the pharmacokinetics of CPT-11 and its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), were investigated to evaluate the relationship between pharmacokinetic parameters and diarrhea, since this is an unpredictable and severe toxicity of combination chemotherapy using CPT-11 and cisplatin. Twenty-three previously untreated patients with advanced lung cancer were evaluated in the pharmacokinetic study. Ten patients received CPT-11 at 80 or 90 mg/m2 plus cisplatin at 60 mg/m2 . The other 13 patients received CPT-11 at 80 or 90 mg/m2 plus cisplatin at 80 mg/m2 with the granulocyte colony-stimulating factor support (2 μg/kg × 16 days). CPT-11 was given as a 90-min intravenous infusion on days 1, 8, and 15. Cisplatin was given on day 1. The pharmacokinetics of CPT-11 and SN-38 were analyzed on day 8 during the first course of treatment. The maximum tolerated dose of CPT-11 was 90 mg/m2 in both phase I trials. The severity of diarrhea was best correlated with the peak plasma concentration of SN-38 among the pharmacokinetic parameters tested. In addition, patients with a plasma SN-38 level > 12.4 ng/ml at 1.75 h after the start of CPT-11 infusion had a higher incidence of Eastern Cooperative Oncology Group grade 3–4 diarrhea than those with a lower SN-38 level ( P =0.0003). Stepwise logistic regression analysis identified the SN-38 concentration as a significant contributor to the development of diarrhea ( P =0.0021). We conclude that there is a clear relationship between the SN-38 concentration and diarrhea during chemotherapy with CPT-11 plus cisplatin. 相似文献
7.
Gianluca Masi Alfredo Falcone Antonello Di Paolo Giacomo Allegrini Romano Danesi Cecilia Barbara Samanta Cupini Mario Del Tacca 《Clinical cancer research》2004,10(5):1657-1663
PURPOSE: The purpose is to determine the plasma pharmacokinetics, the maximum-tolerable dose and to preliminary evaluate the antitumor activity of irinotecan administered as a 7-day continuous infusion every 21 days in metastatic colorectal cancer patients pretreated with 5-fluorouracil or raltitrexed. EXPERIMENTAL DESIGN: A total of 13 patients entered the study. Three received irinotecan at 20 mg/m(2)/day (dose level I), 6 at 25 mg/m(2)/day (dose level II), and 4 at 22.5 mg/m(2)/day (dose level III). In 8 patients, plasma levels of irinotecan and its metabolites SN-38 and SN-38 glucuronide (SN-38glu) were measured by high-performance liquid chromatography and main pharmacokinetic parameters, including steady-state concentration, area under the time-concentration curve, and clearance, were calculated and normalized to the dose level of 22.5 mg/m(2)/day. RESULTS: Dose-limiting toxicity was grade 3-4 diarrhea, which occurred in 4 of 6 patients at dose level II and in 2 of 4 patients at dose level III. Therefore, we defined 22.5 mg/m(2)/day the maximum-tolerable dose and 20.0 mg/m(2)/day the recommended dose for Phase II studies. Hematological toxicity was rare. The pharmacokinetic data provided evidence that continuous infusion increased the metabolism of irinotecan to SN-38 with respect to standard 30/90-min administration. Indeed, the steady-state concentration of irinotecan, SN-38, and SN-38glu were 42.7 +/- 25.2, 14.9 +/- 1.9, and 31.7 +/- 3.5 nmol/liter, respectively, and the area under the time-concentration curves of irinotecan, SN-38, and SN-38glu were 6.94 +/- 0.41, 1.92 +/- 0.30, and 4.23 +/- 0.52 hx micro mol/liter, respectively. Twelve patients were evaluable for activity, and we observed 3 (25%) partial responses, 2 (17%) minor responses, and 4 (33%) disease stabilizations. CONCLUSIONS: The administration of irinotecan as a 7-day continuous infusion every 21 days is feasible with diarrhea being the dose-limiting toxicity; recommended dose for Phase II studies is 20.0 mg/m(2)/day. The comparison of the present data with those obtained after a standard 30-90 min. i.v. infusion of irinotecan demonstrates that continuous infusion improves the transformation of irinotecan to SN-38 and also results in increased glucuronidation of the active metabolite. Antitumor activity in pretreated metastatic colorectal cancer patients is encouraging. 相似文献
8.
Clinton F. Stewart William C. Zamboni William R. Crom Peter J. Houghton 《Cancer chemotherapy and pharmacology》1997,40(3):259-265
The present study was conducted to quantitate the disposition of irinotecan lactone and its active metabolite SN-38 lactone
in mice following oral and intravenous administration, and to evaluate the systemic exposure of irinotecan lactone and SN-38
lactone associated with antitumor doses of irinotecan lactone in mice bearing human tumor xenografts. Nontumor-bearing mice
were given a single oral or intravenous irinotecan dose (5, 10, 40, or 75 mg/kg), and serial plasma samples were subsequently
obtained. Irinotecan and SN-38 lactone plasma concentrations were measured using an isocratic HPLC assay with fluorescence
detection. The disposition of intravenous irinotecan lactone was modeled using a two-compartment pharmacokinetic model, and
the disposition of oral irinotecan and SN-38 lactone was modeled with noncompartmental methods. Irinotecan lactone showed
biphasic plasma disposition following intravenous dosing with a terminal half-life ranging between 1.1 to 3 h. Irinotecan
lactone disposition was linear at lower doses (5 and 10 mg/kg), but at 40 mg/kg irinotecan lactone clearance decreased and
a nonlinear increase in irinotecan lactone AUC was observed. The steady-state volume of distribution ranged from 19.1 to 48.1
l/m2. After oral dosing, peak irinotecan and SN-38 lactone concentrations occurred within 1 h, and the irinotecan lactone bioavailability
was 0.12 at 10 mg/kg and 0.21 at 40 mg/kg. The percent unbound SN-38 lactone in murine plasma at 1000 ng/ml was 3.4 ± 0.67%,
whereas at 100 ng/ml the percent unbound was 1.18 ± 0.14%. Irinotecan and SN-38 lactone AUCs in micebearing human neuroblastoma
xenografts were greater than in nontumor-bearing animals. Systemic exposure to unbound SN-38 lactone in nontumor-bearing animals
after a single oral irinotecan dose of 40, 10, and 5 mg/kg was 28.3, 8.6, and 2.9 ng h/ml, respectively. Data from the present
study provide important information for the design of phase I studies of oral irinotecan.
Received: 30 August 1996 / Accepted: 27 November 1996 相似文献
9.
Edward J Licitra Viral Vyas Kathy Nelson Rita Musanti Stephanie Beers Cecilia Thomas Elizabeth Poplin Sharon Smith Yong Lin Larry J Schaaf Joseph Aisner Murugesan Gounder Rajeev Rajendra Ahamed Saleem Deborah Toppmeyer Eric H Rubin 《Clinical cancer research》2003,9(5):1673-1679
PURPOSE: To investigate pharmacologically guided addition of etoposide to a weekly irinotecan/cisplatin chemotherapy. PATIENTS AND METHODS: Patients with advanced nonhematologic malignancies were eligible. Treatment consisted of i.v. administration of 50 mg/m(2) irinotecan and 20 mg/m(2) cisplatin on days 1, 8, 15, and 22 of a 42-day cycle or on days 1 and 8 of a 21-day cycle. Etoposide was administered in a dose-escalating fashion 2 days after each dose of irinotecan/cisplatin, either i.v. as a single dose or p.o. as two doses administered 12 h apart. Pharmacologic analyses included measurement of plasma concentrations of irinotecan, SN-38, and SN-38 glucuronide, as well as quantitation of topoisomerase protein levels in peripheral blood mononuclear cells (PBMNCs). RESULTS: A total of 40 patients with a variety of malignancies received 122 cycles of therapy. Dose-limiting toxicities included neutropenia and diarrhea, with the 21-day cycle tolerated better than the 42-day cycle. For the 21-day cycle, the maximum tolerated dose was 75 mg/m(2) for i.v. etoposide and 85 mg/m(2) for oral etoposide. Objective responses were observed in four patients with previously treated mesothelioma, gastric, breast, and ovarian cancer, respectively. PBMNC levels of topoisomerase IIalpha were increased at the time of etoposide administration in two patients, with these patients having the highest SN-38 glucuronide peak-plasma-concentration and area-under-the-curve values among 15 patients with available pharmacokinetic data. One of these patients had a partial response to therapy. CONCLUSIONS: Pharmacologically guided administration of etoposide in combination with irinotecan/cisplatin using a 21-day cycle is associated with acceptable toxicity and significant antitumor activity. The finding that PBMNC topoisomerase IIalpha protein levels increased after irinotecan/cisplatin treatment in two of six patients supports the continued development of sequential topoisomerase targeting in the treatment of malignancy. 相似文献
10.
T Nakano A P Chahinian M Shinjo N Togawa A Tonomura M Miyake K Ninomiya T Yamamoto K Higashino 《Cancer》1999,85(11):2375-2384
BACKGROUND: The purpose of this study was to assess the efficacy and toxicity of a combination of cisplatin and irinotecan (CPT-11) in the treatment of patients with malignant pleural mesothelioma and to characterize the pharmacokinetic profiles of CPT-11 and its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38). METHODS: Fifteen previously untreated patients with malignant pleural mesothelioma were treated with cisplatin (60 mg/m2 on Day 1) and CPT-11 (60 mg/m2 on Days 1, 8, and 15) administered intravenously and followed by a 1-week rest period. The course of treatment was repeated every 28 days. After intravenous administration, the levels of CPT-11 and SN-38 in the plasma and pleural fluid were determined for each histologic subtype of mesothelioma. RESULTS: All patients were evaluable for response and toxicity. Four partial responses (response rate of 26.7%) with a median response duration of 25.9 weeks and 2 regressions of evaluable disease (overall response rate of 40%) were observed. The median survival time after chemotherapy was 28.3 weeks, and the median time to treatment failure was 22.1 weeks. The 1-year survival rate for all patients was 38.5%. Toxicity was well tolerated, and there were no treatment-related deaths. World Health Organization Grade 3 leukopenia occurred in 3 patients (20%), and Grade 1 or 2 diarrhea occurred in 3 patients (20%). There was no excess toxicity in patients with large pleural effusions compared with those with no pleural effusions. CPT-11 and SN-38 were detected in the pleural fluid 1 hour after intravenous administration. The maximum concentrations of CPT-11 and SN-38 in the pleural fluid were 36.5% and 75.8%, respectively, of the corresponding plasma values. CONCLUSIONS: The combination of cisplatin and CPT-11 had definite activity against malignant pleural mesothelioma and was well tolerated. The intravenous administration of CPT-11 produced adequate distribution of CPT-11 and its active metabolite SN-38 into the pleural fluid and allowed a higher concentration of the more active SN-38 to make contact with mesothelioma cells in the thoracic cavity. These results warrant further clinical evaluation of this combination chemotherapy for the treatment of malignant pleural mesothelioma in a confirmatory Phase II trial. 相似文献
11.
A Pharmacokinetic and Pharmacodynamic Analysis of CPT-11 and Its Active Metabolite SN-38 总被引:1,自引:2,他引:1
Yasutsuna Sasaki Hideo Hakusui Shoichi Mizuno Masashige Morita Toshimichi Miya Kenji Eguchi Tetsu Shinkai Tomohide Tamura Yuichiro Ohe Nagahiro Saijo 《Cancer science》1995,86(1):101-110
In the present study, an attempt was made to determine the precise pharmacokinetics of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) and its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38). The relationship between pharmacokinetic parameters and pharmacodynamic effects was also investigated to elucidate the cause of interpatient variation in side effects. Thirty-six patients entered the study. CPT-11, 100 mg/m2 , was administered by IV infusion over 90 min weekly for four consecutive weeks. The major dose-limiting toxicities were leukopenia and diarrhea. There was a positive correlation between the area under the concentration-time curve (AUC) of CPT-11 and percent decrease of WBC ( r =0.559). On the other hand, episodes of diarrhea had a better correlation with the AUC of SN-38 ( r =0.606) than that of CPT-11 ( r =0.408). Multivariate analysis revealed that the AUC of SN-38, AUC of CPT-11 and indocyanine green retention test were significant variables for the incidence of diarrhea and that both performance status and AUC of CPT-11 were significant variables for percent decrease of WBC. The large interpatient variability of the degree of leukopenia and diarrhea is due to a great plasma pharmacokinetic variation in CPT-11 or SN-38. The AUCs of CPT-11 and SN-38 obtained from the first administration of CPT-11 correlate with toxicities, but it is impossible to predict severe side effects before the administration of CPT-11 at the present time. 相似文献
12.
Morton CL Iacono L Hyatt JL Taylor KR Cheshire PJ Houghton PJ Danks MK Stewart CF Potter PM 《Cancer chemotherapy and pharmacology》2005,56(6):629-636
Purpose: To examine the antitumor activity and the pharmacokinetics of CPT-11 (irinotecan, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin) in a plasma esterase-deficient scid mouse model, bearing human tumor xenografts. Experimental design: Plasma carboxylesterase (CE)-deficient mice were bred with scid animals to develop a strain that would allow growth of human tumor xenografts. Following xenotransplantation, the effect of the plasma esterase on antitumor activity following CPT-11 administration was assessed. In addition, detailed pharmacokinetic studies examining plasma and biliary disposition of CPT-11 and its metabolites were performed. Results: In mice lacking plasma carboxylesterase, the mean SN-38 systemic exposures were approximately fourfold less than that observed in control animals. Consistent with the pharmacokinetic data, four to fivefold more CPT-11 was required to induce regressions in human Rh30 xenografts grown in esterase-deficient scid mice, as opposed to those grown in scid animals. Additionally, the route of elimination of CPT-11, SN-38, and SN-38 glucuronide (SN-38G) was principally in the bile. Conclusions: The pharmacokinetic profile for CPT-11 and its metabolites in the esterase-deficient mice more closely reflects that seen in humans. Hence, these mice may represent a more accurate model for antitumor studies with this drug and other agents metabolized by CEs. 相似文献
13.
Prevention of irinotecan-induced diarrhea by oral sodium bicarbonate and influence on pharmacokinetics 总被引:1,自引:0,他引:1
Tamura T Yasutake K Nishisaki H Nakashima T Horita K Hirohata S Ishii A Hamano K Aoyama N Shirasaka D Kamigaki T Kasuga M 《Oncology》2004,67(5-6):327-337
Alkalization of the intestinal tract by oral administration of sodium bicarbonate has been reported to be a promising method for preventing delayed diarrhea, a dose-limiting toxicity in patients receiving chemotherapy with irinotecan hydrochloride. However, it is feared that this method may adversely affect the pharmacokinetics of irinotecan by inhibiting its intestinal absorption and that of its active metabolites. We compared the pharmacokinetics and toxicity of irinotecan with and without oral alkalization in a cross-over study that enrolled 10 colorectal cancer patients. We found that alkalization did not decrease the blood levels of irinotecan and its active metabolite. In fact, the area under concentration versus time curves (AUCs) of irinotecan and 7-ethyl-10-hydroxycamptothecin glucuronide (SN-38G) were statistically equivalent both with and without oral alkalization. Also, the AUC of SN-38 with alkalization was statistically equivalent or larger than that without alkalization. Oral alkalization reduced the incidence of diarrhea and gastrointestinal symptoms, and these adverse effects were not worsened by long-term administration. These results suggest that oral alkalization can control diarrhea and gastrointestinal toxicity without decreasing the blood levels of irinotecan and its active metabolites, thus improving the tolerability of long-term chemotherapy without reducing efficacy. 相似文献
14.
Monica E Loghin Michael D Prados Patrick Wen Larry Junck Frank Lieberman Howard Fine Karen L Fink Minesh Metha John Kuhn Kathleen Lamborn Susan M Chang Timothy Cloughesy Lisa M DeAngelis Ian H Robins Kenneth D Aldape W K Alfred Yung 《Clinical cancer research》2007,13(23):7133-7138
PURPOSE: To determine the maximum tolerated dose of irinotecan when administrated with temozolomide every 28 days, in patients with recurrent malignant glioma who were also receiving CYP450 enzyme-inducing antiepileptic drugs (EIAED), and to characterize the pharmacokinetics of irinotecan and its metabolites. The study was also intended to assess whether temozolomide affects the conversion of irinotecan to SN-38. DESIGN: Patients with recurrent malignant glioma received a fixed dose of temozolomide (150 mg/m(2)) daily for 5 days from days 1 to 5 every 28 days, and an i.v. infusion of irinotecan on days 1 and 15 of each cycle. The starting dose of irinotecan was 350 mg/m(2), which was escalated to 550 mg/m(2) in 50-mg/m(2) increments. The plasma pharmacokinetics of irinotecan and its active metabolite, SN-38, were determined during the infusion of irinotecan on cycle 1, day 1. RESULTS: Thirty-three patients were enrolled into the study and treated. Thirty-one patients were evaluable for both tumor response and toxicity and two patients were evaluable for toxicity only. Common toxicities included neutropenia and thrombocytopenia, nausea, vomiting, and diarrhea. Dose-limiting toxicities were grade 3 diarrhea and nausea/vomiting. The maximum tolerated dose for irinotecan was determined to be 500 mg/m(2). CONCLUSIONS: The recommended phase II dose of irinotecan in combination with temozolomide for patients receiving EIAEDs is 500 mg/m(2), administrated every 15 days on a 28-day schedule. This study also confirmed that concomitant administration of EIAEDs increases irinotecan clearance and influences SN-38 disposition. No pharmacokinetic interaction was observed between temozolomide and irinotecan. 相似文献
15.
Younis IR Malone S Friedman HS Schaaf LJ Petros WP 《Cancer chemotherapy and pharmacology》2009,63(3):517-524
Background Enterohepatic recirculation of irinotecan and one of its metabolites, SN-38, has been observed in pharmacokinetic data sets
from previous studies. A mathematical model that can incorporate this phenomenon was developed to describe the pharmacokinetics
of irinotecan and its metabolites.
Patients and methods A total of 32 patients with recurrent malignant glioma were treated with weekly intravenous administration of irinotecan at
a dose of 125 mg/m2. Plasma concentrations of irinotecan and its three major metabolites were determined. Pharmacokinetic models were developed
and tested for simultaneous fit of parent drug and metabolites, including a recirculation component.
Results Rebound in the plasma concentration suggestive of enterohepatic recirculation at approximately 0.5–1 h post-infusion was observed
in most irinotecan plasma concentration profiles, and in some plasma profiles of the SN-38 metabolite. A multi-compartment
model containing a recirculation chain was developed to describe this process. The recirculation model was optimal in 22 of
the 32 patients compared to the traditional model without the recirculation component.
Conclusion A recirculation chain incorporated in a multi-compartment pharmacokinetic model of irinotecan and its metabolites appears
to improve characterization of this drug’s disposition in patients with glioma. 相似文献
16.
D F Kehrer W Yamamoto J Verweij M J de Jonge P de Bruijn A Sparreboom 《Clinical cancer research》2000,6(9):3451-3458
The active metabolite of irinotecan (CPT-11), 7-ethyl-10-hydroxycamptothecin (SN-38), is either formed through enzymatic cleavage of CPT-11 by carboxyl esterases (CEs) or through cytochrome P-450 3A-mediated oxidation to 7-ethyl-10-[4-(1-piperidino)-1-amino] carbonyloxycamptothecin (NPC) and a subsequent conversion by CE. In the liver, SN-38 is glucuronidated (SN-38G) by UGT1A1, which also conjugates bilirubin. Fourteen patients were treated with 350 mg/m2 CPT-11, and we performed pharmacokinetic analysis during a 500-h collection period. The half-life and area under the plasma concentration-time curve of SN-38 were 47+/-7.9 h and 2.0+/-0.79 microM x h, respectively, both representing a 2-fold increase as compared with earlier reported estimates (A. Sparreboom et al, Clin. Cancer Res., 4: 2747-2754, 1998). As an explanation for this phenomenon, we noted substantial formation of SN-38 from CPT-11 and NPC by plasma CE, consistent with the low circulating levels of NPC observed. In addition, transport studies in Caco-2 monolayers indicated that nonglucuronidated SN-38 could cross the membrane from apical to basolateral, indicating the potential for recirculation processes that can prolong circulation times. Interestingly, individual levels of fecal beta-glucuronidase, which is known to mediate SN-38G hydrolysis, were not related to any of the SN-38 kinetic parameters (r = 0.09; P = 0.26), suggesting that interindividual variation in this enzyme is unimportant in explaining SN-38 pharmacokinetic variability. We have also found, in contrast to earlier data, that SN-38G/SN-38 plasma concentration ratios decrease over time from approximately 7 (up to 50 h) to approximately 1 (at 500 h). This decrease could be explained by the fact that glucuronidation of SN-38 and bilirubin is increasingly competitive at lower drug levels. In addition, no evidence was found for SN-38G transport through the Caco-2 cells. Our findings indicate that until now the circulation time of SN-38 has been underestimated. This is of crucial importance to our understanding of the clinical action of CPT-11 and for future pharmacokinetic/pharmacodynamic relationships. 相似文献
17.
High-dose,single-agent irinotecan as first-line therapy in the treatment of metastatic colorectal cancer 总被引:4,自引:0,他引:4
Ychou M Raoul JL Desseigne F Borel C Caroli-Bosc FX Jacob JH Seitz JF Kramar A Hua A Lefebvre P Couteau C Merrouche Y 《Cancer chemotherapy and pharmacology》2002,50(5):383-391
PURPOSE: The efficacy and safety of single-agent, high-dose irinotecan (CPT-11, Campto) 500 mg/m(2) every 3 weeks were investigated as first-line treatment for advanced colorectal cancer (CRC). PATIENTS AND METHODS: Patients were enrolled into the study to receive a first cycle of therapy with irinotecan at a dose of 350 mg/m(2) every 3 weeks, which could be escalated to 500 mg/m(2) for the second and subsequent cycles depending on toxicity. Efficacy, safety and pharmacokinetics were determined in the intent to treat (ITT) population and the high-dose population (i.e. patients who had received at least three cycles of irinotecan, the second and third at 500 mg/m(2)). RESULTS: Of 49 patients enrolled into the study (ITT population), 31 (63%) received at least three cycles of treatment with cycles 2 and 3 at an irinotecan dose of 500 mg/m(2) (the high-dose population). The response rates (RR) for the ITT and high-dose populations were 24.5% and 35.5%, respectively. The main grade 3/4 toxicities per cycle in the ITT and high-dose populations were neutropenia 22% and 17%, febrile neutropenia 5% and 3%, and diarrhoea 12% and 7%, respectively. The pharmacokinetics of irinotecan and its metabolite SN-38 were investigated in 31 patients in cycle 1 and 22 patients in cycle 2. Irinotecan clearance and SN-38 exposure were not sufficiently correlated with toxicity in cycle 1 to identify patients for dose increase in subsequent cycles. The exposure to irinotecan and SN-38 increased in proportion to dose from 350 to 500 mg/m(2). CONCLUSION: These results suggest that high-dose irinotecan can be safely administered as first-line monotherapy to approximately two-thirds of patients who present with advanced CRC following a selective first cycle. 相似文献
18.
Kato A Ueyama J Abe F Hotta K Tsukiyama I Oshima T Kondo F Saito H Hasegawa T 《Anticancer research》2011,31(9):2915-2922
The present study has investigated the effect of panipenem, a widely used antibiotic, on the pharmacokinetics of an active metabolite of irinotecan (CPT-11), 7-ethyl-10-hydroxy-camptothecin (SN-38) and SN-38 glucuronide (SN-38G) produced by uridine-diphosphate glucuronosyltransferase (UGT) 1A isoform-mediated glucuronidation in rats. Rats received a 1 h infusion with panipenem at a loading dose of 10 mg/kg and a maintenance dose of 15 mg/min/kg once a day for 5 days. When the effect of pretreatment with panipenem on glucuronidation activities of substrates for hepatic UGT1A isoforms was investigated using substrates 4-methylumbelliferone (4MU), estradiol and SN-38, the rate of 4MU glucuronide formation was significantly increased, but that of estradiol glucuronide formation was unchanged. However, the rate of SN-38G formation showed a tendency to increase. One hour after the final infusion of panipenem or saline, SN-38 (2 mg/kg) was administered intravenously in rats with or without bile duct cannulation. Pretreatment with panipenem had no effect on the plasma concentration-time curves and biliary excretion of SN-38 and SN-38G in rats with and without bile duct cannulation. There were also no significant differences in the relative extent of glucuronidation of SN-38 to SN-38G (AUC(2 h, SN-38G)/AUC(2 h, SN-38)) between panipenem-treated and untreated rats. These findings suggest that pretreatment with panipenem does not alter the pharmacokinetics of SN-38 and SN-38G, suggesting the possibility that panipenem can be used safely for cancer patients undergoing irinotecan chemotherapy. 相似文献
19.
Thompson PA Gupta M Rosner GL Yu A Barrett J Bomgaars L Bernstein ML Blaney SM Mondick J 《Cancer chemotherapy and pharmacology》2008,62(6):1027-1037
Objective To develop a population pharmacokinetic model of irinotecan and its major metabolites in children with cancer and to identify
covariates that predict variability in disposition.
Methods A population pharmacokinetic model was developed using plasma concentration data from 82 patients participating in a multicenter
Pediatric Oncology Group (POG) single agent phase II clinical trial. Patients between 1 and 21 years of age with solid tumors
refractory to standard therapy received irinotecan, 50 mg/m2, as a 60-min intravenous infusion for 5 consecutive days every 3 weeks. Blood samples were collected and analyzed for irinotecan
and three metabolites (SN-38, SN-38G, and APC). The population model was developed with NONMEM. Clearance and volume were
scaled allometrically using corrected body weight. Exponential error models were used to describe the interindividual variance
in pharmacokinetic parameters, and the residual error was described with a proportional model. Significant covariate effects
were identified graphically using S-PLUS and were added to the base-model. The final model was evaluated by simulating data
from two other POG trials.
Results The best structural model for irinotecan and its metabolites consisted of six-compartments: two compartments for irinotecan
and SN-38, and one each for APC and SN-38G. Age and bilirubin were found to be significant covariates affecting SN-38 clearance.
SN-38 clearance was greater in patients less than 10 years of age and lower in patients with a total serum bilirubin >0.6 mg/dL.
Simulations revealed that the model was able to predict drug and metabolite exposure (AUC) for patients receiving the same
or similar doses (30–65 mg/m2) of irinotecan.
Conclusions This population model accurately describes the pharmacokinetics of irinotecan and its primary metabolites. The model, which
includes age and bilirubin as covariate effects on SN-38 clearance, is the first population model to describe the pharmacokinetics
of irinotecan and its major metabolites in children.
Supported in part by: NICHD 5 U10 HD037242-09, NIH M01 RR000188-43, NCI U01 CA57745, NCI U10 CA98453, NCRR M01 RR00188-37,
The Mitchell Ross Children’s Cancer Fund, Pharmacia/Upjohn. 相似文献
20.
Czejka M Kiss A Koessner C Terkola R Ettlinger D Schueller J 《Anticancer research》2011,31(10):3573-3578
Biotransformation of irinotecan (CPT-11) into its pharmacologic active metabolite SN-38 was investigated in patients treated for advanced colorectal cancer. A dose of 180 mg/m(2) CPT-11 was administered to 6 patients by 60 min hepatic intra-arterial infusion (HAI) via a surgically implanted Port-a-Cath? system. Blood samples were collected from 0 to 360 min after start of HAI, and CPT-11 plus metabolites were analysed by a selective reversed phase HPLC method. The objective of this study was to evaluate the extent to which SN-38 is generated after HAI of irinotecan given at a low dose of 180 mg/m(2). In a second investigation, CPT-11 was administered via conventional intravenous infusion (dose 180 mg/m(2), 60 min infusion time, 11 patients) and CPT-11 plus metabolites were quantified using identical analytical procedure. Compared to i.v. infusion, the pharmacokinetics of CPT-11 and SN-38 were altered by HAI. The mean c(max) of CPT-11 after HAI was reduced by 37%, whereas the mean c(max) of SN-38 increased by 60%. HAI resulted in a desired, increased metabolic conversion of CPT-11 into SN-38 and might improve the regional availability of the pharmacologic active metabolite SN-38 at the site of tumor. Plasma concentrations of the metabolites SN-38 glucuronide and APC remained unaffected by the route of administration. 相似文献