Clinical applications of the camptothecins.

The camptothecin topoisomerase I-targeting agents are new class of antitumor drugs with demonstrated clinical activity in human malignancies, such as colorectal cancer and ovarian cancer. Currently, irinotecan and topotecan are the most widely used camptothecin analogs in clinical use and clinical trials are ongoing to better characterize their spectra of clinical activity, to determine their optimal schedules of administration and to define their use in combination with other chemotherapeutic agents. Newer camptothecin analogs in clinical development, such as 9-aminocamptothecin, 9-nitrocamptothecin, GI147211 and DX-8951f, are also being studied to determine if they have improved toxicity and efficacy profiles compared with existing analogs. Other potential clinical applications include the use of camptothecin derivatives as radiation sensitizers or as antiviral agents. The successful development of the camptothecins as antitumor agents highlights the importance of topoisomerase I as a target for cancer chemotherapy.

Paclitaxel by 96-hour continuous infusion in combination with cisplatin: a phase I trial in patients with advanced lung cancer.

PURPOSE: To determine the maximum-tolerated dose (MTD) of paclitaxel administered by 96-hour continuous infusion in combination with cisplatin, to determine if the addition of granulocyte colony-stimulating factor (G-CSF) permits significant paclitaxel dose escalation, and to assess the toxicity and preliminary activity of this combination in patients with advanced lung cancer. PATIENTS AND METHODS: Fifty patients with untreated lung cancer were enrolled: 42 had advanced non-small-cell lung cancer (NSCLC) and eight had extensive-stage small-cell lung cancer (SCLC). Patients received paclitaxel doses of 100 to 180 mg/m2/96 hours and cisplatin doses of 60 to 80 mg/m2 as a single 30-minute bolus injection at the end of the paclitaxel infusion. RESULTS: Two of six patients experienced dose-limiting neutropenia at a dose of paclitaxel 140 mg/m2/96 hours and cisplatin 80 mg/m2. With G-CSF support, one of three patients experienced both dose-limiting mucositis and fatal neutropenic sepsis at a dose of paclitaxel 180 mg/m2/96 hours and cisplatin 80 mg/m2. Significant peripheral neuropathy developed in five patients and occurred after six or more cycles of therapy. Thirty-three of 42 patients with NSCLC had measurable disease; the objective response rate was 55%, with two complete responses and 16 partial responses. For all 42 patients with NSCLC, the median time to progression and median survival duration were 5 months and 10 months, respectively. The actuarial 1-year survival rate was 41%. Of eight SCLC patients, four responded to therapy, and the median survival duration for all SCLC patients was 11 months. CONCLUSION: The MTD without G-CSF is paclitaxel 120 mg/m2/96 hours and cisplatin 80 mg/m2, and the MTD with G-CSF is paclitaxel 160 mg/m2/96 hours and cisplatin 80 mg/m2. Infusional paclitaxel with cisplatin is well tolerated and active in patients with advanced NSCLC.

Phase I and pharmacokinetic trial of weekly oral fluorouracil given with eniluracil and low-dose leucovorin to patients with solid tumors.

PURPOSE: Fluorouracil (5-FU) given as a weekly, high-dose 24-hour infusion is active and tolerable. We evaluated an oral regimen of eniluracil (which inactivates dihydropyrimidine dehydrogenase [DPD]), 5-FU, and leucovorin to simulate this schedule. PATIENTS AND METHODS: Patients received a single 24-hour infusion of 5-FU (2,300 mg/m(2) on day 2) with leucovorin (15 mg orally [PO] bid on days 1 through 3) to provide reference pharmacokinetic data. Two weeks later, patients began treatment with eniluracil (20 mg) and leucovorin (15 mg) (PO bid on days 1 through 3) and 5-FU (10 to 15 mg/m(2) PO bid on day 2). RESULTS: Dose-limiting toxicity (diarrhea, neutropenia, and fatigue) was seen with 5-FU 15 mg/m(2) PO bid on day 2 given weekly for either 6 of 8 weeks or 3 of 4 weeks, whereas five of seven patients tolerated 5-FU 10 mg/m(2) PO bid given weekly for 3 of 4 weeks. Eniluracil led to a 35-fold reduction in 5-FU clearance. Fluoro-beta-alanine, a 5-FU catabolite, was not detected in plasma during oral 5-FU-eniluracil therapy. DPD activity was markedly suppressed in all patients during eniluracil therapy; the inactivation persisted after the last eniluracil dose; percentages of baseline values were 1.8% on day 5, 4.5% on day 12, and 23.6% on day 19. CONCLUSION: The recommended oral dosage of 5-FU (10 mg/m(2) PO bid) given with eniluracil and leucovorin is approximately 115-fold lower than the reference dosage for 24-hour infusional 5-FU. This difference is greater than expected given the reduction in 5-FU clearance. DPD inactivation persisted for several weeks after completion of eniluracil therapy.

Pharmacodynamics and pharmacokinetics of a 72-hour infusion of 9-aminocamptothecin in adult cancer patients.

PURPOSE: To investigate the pharmacokinetics and pharmacodynamics of 9-aminocamptothecin (9-AC) infused over 72 hours at doses of 5 to 74 micrograms/m2/h. PATIENTS AND METHODS: 9-AC lactone and total (lactone plus carboxylate) plasma concentrations were measured in 44 patients with solid tumors using a high-performance liquid chromatography (HPLC) assay. Fifteen patients underwent extended pharmacokinetic sampling to determine the distribution and elimination kinetics of 9-AC. RESULTS: At steady-state, 8.7% +/- 4.7% (mean +/- SD) of the total drug circulated in plasma as the active 9-AC lactone. Clearance of 9-AC lactone was uniform (24.5 +/- 7.3 L/h/m2) over the entire dose range examined; however, total 9-AC clearance was nonlinear and increased at higher dose levels. In 15 patients treated at dose levels > or = 47 micrograms/m2/h, the volume of distribution at steady-state for 9-AC lactone was 195 +/- 114 L/m2 and for total 9-AC it was 23.6 +/- 10.6 L/m2. The elimination half-life was 4.47 +/- 0.53 hours for 9-AC lactone and 8.38 +/- 2.10 hours for total 9-AC. In pharmacodynamic studies, dose-limiting neutropenia correlated with steady-state lactone concentrations (Css) R2 = .77) and drug dose (R2 = .71). CONCLUSION: Plasma 9-AC concentrations rapidly declined to low levels following the end of a 72-hour infusion and the mean fraction of total 9-AC circulating in plasma as the active lactone was less than 10%. The pharmacokinetics of 9-AC may have a great impact on its clinical activity and should be considered in the design of future clinical trials of this topoisomerase I inhibitor.

Phase I and pharmacologic study of irinotecan administered as a 96-hour infusion weekly to adult cancer patients.

PURPOSE: We conducted a phase I and pharmacologic study of a weekly 96-hour infusion of irinotecan to determine the maximum-tolerated dose, define the toxicity profile, and characterize the clinical pharmacology of irinotecan and its metabolites. PATIENTS AND METHODS: In 26 adult patients with solid tumors, the duration and dose rate of infusion were escalated in new patients until toxicity was observed. RESULTS: In 11 patients who were treated with irinotecan at 12.5 mg/m(2)/d for 4 days weekly for 2 of 3 weeks, dose-limiting grade 3 diarrhea occurred in three patients and grade 3 thrombocytopenia occurred in two patients. The recommended phase II dose is 10 mg/m(2)/d for 4 days given weekly for 2 of 3 weeks. At this dose, the steady-state plasma concentration (Css) of total SN-38 (the active metabolite of irinotecan) was 6.42 +/- 1.10 nmol/L, and the Css of total irinotecan was 28.60 +/- 17.78 nmol/L. No patient experienced grade 3 or 4 neutropenia during any cycle. All other toxicities were mild to moderate. The systemic exposure to SN-38 relative to irinotecan was greater than anticipated, with a molar ratio of the area under the concentration curve (AUC) of SN-38 to irinotecan of 0.24 +/- 0.08. One objective response lasting 12 months in duration was observed in a patient with metastatic colon cancer. CONCLUSION: The recommended phase II dose of irinotecan of 10 mg/m(2)/d for 4 days weekly for 2 of 3 weeks was extremely well tolerated. Further efficacy testing of this pharmacologic strategy of administering intermittent low doses of irinotecan is warranted.

Effects of 9-aminocamptothecin on newly synthesized DNA in patient bone marrow samples.

9-Aminocamptothecin (9-AC) inhibited cell growth and DNA synthesis in HCT 116 human colon cancer cells in a concentration- and time-dependent manner. Interference with nascent DNA chain elongation was monitored using pH step alkaline elution. After a 3-day 9-AC exposure, 38% (10 nM) and 53% (50 nM) of the total [3H]DNA eluted with pH steps 11.3-11.7, compared to 9% in control cells. Effects on nascent DNA integrity were also evaluated by fixed elution with pH 12.1 buffer. After a 3-day exposure to 9-AC, 27% (10 nM) and 82.5% (50 nM) of the total [3H]DNA eluted relative to control. Paired bone marrow samples were then obtained in 10 patients before treatment and between 42 and 72 h of a continuous i. v. infusion of 9-AC (35-74 microgram/m2/h for 72 h). The mononuclear cells were incubated with [3H]dThd for 2 or 4 h, and then analyzed using either pH step or fixed pH alkaline elution, respectively. In seven patients receiving >/=47 microgram/m2/h 9-AC, 4% +/- 1.5% (mean +/- SE) of the total [3H]DNA eluted with pH steps /=59 microgram/m2/h 9-AC (n = 7). Since hematological toxicity is dose limiting on this 9-AC schedule, these cellular pharmacodynamic studies provide evidence of a DNA-directed cytotoxic effect of 9-AC in a sensitive host target tissue.

Severe neurotoxicity following 5-fluorouracil-based chemotherapy in a patient with dihydropyrimidine dehydrogenase deficiency.

Patients with decreased dihydropyrimidine dehydrogenase (DPD) activity are at increased risk for experiencing serious adverse reactions following 5-fluorouracil (5-FU)-based chemotherapy. Symptoms include severe and potentially life-threatening gastrointestinal toxicity, myelosuppression, and neurological toxicity. In the present study, we describe a 50-year-old Caucasian man who developed severe encephalopathy during his second cycle of 5-FU chemotherapy. The patient remained in a comatose state for 4 days but then showed dramatic improvement in his neurological status following continuous i.v. infusion of thymidine at 8 g/m2/day. Laboratory studies revealed the patient to be severely DPD deficient, as demonstrated by DPD enzyme activity from peripheral blood mononuclear cells being below the lower limit of the 95th percentile of a control population and by Western immunoblot analysis showing undetectable levels of DPD protein. Additional studies revealed a significant defect in pyrimidine catabolism with a 3.3- and 365-fold increase in the levels of uracil in plasma and urine, respectively, compared to normal subjects. Family studies suggest that the inheritance pattern of this syndrome is complex and most consistent with an autosomal recessive trait. This study demonstrates that cancer patients with DPD deficiency are at increased risk for developing severe neurological toxicity secondary to 5-FU chemotherapy, and that infusional thymidine should be considered as a potential rescue agent against this particular host toxicity.

High inter- and intrapatient variation in 5-fluorouracil plasma concentrations during a prolonged drug infusion.

The purpose of the study was to examine inter- and intrapatient variation in 5-fluorouracil (5-FU) plasma concentrations in adult cancer patients receiving a 3-day drug infusion. Fourteen patients received 1266 mg/m2 N-(phosphonacetyl)-L-aspartate (PALA) infused i.v. over 15 min on day 1, followed immediately by a loading dose of 500 mg/m2 calcium leucovorin over 30 min. Then a prolonged infusion of leucovorin at 500 mg/m2/day and 5-FU at 1750 mg/m2/day was administered as either a constant rate or as a circadian infusion over 72 h. During constant rate infusions, 5-FU concentrations within individuals varied by 1.7-fold, but no uniform time of peak or trough concentration was observed. Transformation of these data by setting the time of peak to 0 h and by expressing concentrations as the percentage of the 24-h mean value revealed a nonrandom distribution of the time from peak to trough with a median time of 12 h (P = 0.027). These transformed data were also successfully fit to a circadian cosinor function (P < 0.001). During multiple constant rate 5-FU infusions, the intrapatient variability was high; the times of peak 5-FU concentration occurred at the same approximate sampling time 43% of the time, and troughs coincided 17% of the time. No difference in clinical toxicity was observed when matched constant rate and circadian infusions of 5-FU were compared. High inter- and intrapatient variability exists in 5-FU plasma concentrations in adult cancer patients during constant rate infusions with no evidence of a consistent circadian rhythm in untransformed data.

Phase II trial of paclitaxel by 96-hour continuous infusion in combination with cisplatin for patients with advanced non-small cell lung cancer.

Our purpose was to determine the antitumor efficacy and safety profile of the combination of paclitaxel administered by 96-h continuous i.v. infusion followed by bolus cisplatin in patients with untreated advanced non-small cell lung cancer (NSCLC). Fifty-eight patients with untreated advanced or recurrent NSCLC were enrolled between October 1995 and December 1998. The median patient age was 60 years (age range, 34-75 years). Twenty-four patients were female. The majority of patients (n = 52) had an Eastern Cooperative Oncology Group performance status of 0/1. Twelve patients had stage IIIB NSCLC, 43 had stage IV disease, and 3 had recurrent disease after prior resection. Seven patients had received cranial irradiation for brain metastases, and 5 patients had received bone irradiation before enrollment. Patients were treated with paclitaxel (120 mg/m2/96 h) by continuous i.v. infusion followed by cisplatin (80 mg/m2) on day 5. Therapy was administered every 3 weeks as tolerated until disease progression or a maximum of six cycles. A total of 264 cycles of therapy were administered. Twenty-nine patients received all six cycles. Forty-six patients had measurable disease, with 20 patients achieving a partial response, and no complete responses were seen (overall response rate, 43%; 95% confidence interval, 29-60%). The median progression-free survival was 5.5 months. At a median potential follow-up of 27.2 months, the median survival for all 58 enrolled patients was 8.5 months, and the actuarial 1-year survival was 37% (95% confidence interval, 25.9-50.5%). This is the most extensive evaluation of prolonged continuous infusional paclitaxel in patients with advanced-stage cancer. In contrast to predictions from in vitro cytotoxicity models, the regimen does not appear to be obviously superior to shorter infusion times in the clinical setting. Additional trials of this regimen in patients with NSCLC are therefore of low priority.

A Phase I study of raltitrexed, an antifolate thymidylate synthase inhibitor, in adult patients with advanced solid tumors.

The purpose of this study was to perform a Phase I trial of raltitrexed, a selective inhibitor of thymidylate synthase, and to determine the pharmacokinetic and toxicity profiles as a function of raltitrexed dose. Fifty patients with advanced solid tumors and good performance status were treated with raltitrexed as a 15-min i.v. infusion every 3 weeks, at doses escalating from 0.6 to 4.5 mg/m2. Asthenia, neutropenia, and hepatic toxicity were the most common dose-limiting toxicities in this largely pretreated patient population, but they occurred during the initial cycle in only one of nine patients treated with 4.0 mg/m2 and in two of nine patients treated with 4.5 mg/m2. Only 2 of 13 patients treated with 3.5 mg/m2 ultimately experienced unacceptable toxicity after three and seven cycles, compared with 42 and 56% of patients receiving 4.0 and 4.5 mg/m2 after medians of three and two cycles, respectively. The maximum raltitrexed plasma concentration and the area under the plasma concentration-time curve increased in proportion to dose. Raltitrexed clearance was independent of dose and was associated with the estimated creatinine clearance. Asthenia, neutropenia, and hepatic transaminitis were dose-related and tended to occur more frequently when patients received three or more cycles of therapy. A 3-week treatment interval was feasible in the majority of patients at all doses. Although 4.0 mg/m2 appeared to be a safe starting dose in this pretreated patient population, about half who received two or more courses ultimately experienced dose-limiting toxicity. A dose of 3.5 mg/m2 was well tolerated in most patients.

Respiratory syncytial virus infections on an adult medical ward.

Eleven cases of respiratory syncytial virus (RSV) infection occurred in acutely ill hospitalized adults over a 7-week period. Nosocomial illness was suspected in two patients. Because RSV can cause serious infections in immunocompromised adults with the potential for nosocomial spread, the following recommendations are indicated: (1) during the winter months, early recognition and diagnosis of RSV infections both in hospital staff and in patients should be encouraged; (2) infected hospital personnel should avoid patient contact when possible; (3) during outbreaks, careful attention must be paid to hand washing and gloving; and (4) a high level of vigilance for RSV infection should be maintained on units with immunocompromised patients. Increased awareness of the potential risks of RSV infection is needed on adult medical units.

An overview of topoisomerase I-targeting agents.

The camptothecins are a new class of antitumor agents that target topoisomerase I. Irinotecan and topotecan are the most widely used camptothecin analogs in clinical practice, with documented clinical activity in colorectal and ovarian cancer. Ongoing clinical trials with these agents are further characterizing their spectra of clinical activity and determining their optimal schedule of administration in combination with other anticancer agents. Newer camptothecin analogs in clinical development, such as 9-aminocamptothecin, 9-nitrocamptothecin, GI1147211, and DX-8951f, are also being studied to determine if they have improved toxicity and efficacy profiles compared with existing analogs. The successful development of the camptothecins as antitumor agents demonstrates the importance of topoisomerase 1 as a target for cancer chemotherapy.

Antifolates in clinical development.

Many novel antifolate compounds with unique pharmacologic properties are currently in clinical development. These newer antifolates differ from methotrexate, the most widely used and studied drug in this class, in terms of their lipid solubility and cellular transport affinity, their level of polyglutamation, and their specificity for inhibiting folate-dependent enzymes, such as dihydrofolate reductase, thymidylate synthase, or glycinamide ribonucleotide formyltransferase. The current status (ie, mechanism of action, clinical response rates, and toxicity) of some of the newer antifolate compounds presently in clinical testing, including edatrexate, piritrexim, raltritrexed, LY 231514, AG337, AG331, 1843U89, ZD 9331, and lometrexol, is reviewed.

Correlation between ribosomal RNA production and RNA-directed fluoropyrimidine cytotoxicity.

The relationship between cytotoxicity and fluoropyrimidine effects on the production of mature cytoplasmic 28S and 18S ribosomal RNA was studied in S-180 cells for the fluoropyrimidines: 5-fluorouracil (FUra), 5-fluorouridine (FUrd), 5-fluorodeoxyuridine (FdUrd), and 5'-deoxy-5-fluorouridine (5'-dFUrd). After a 6-hr drug exposure, the total cytotoxicity in the absence of added thymidine (dThd) was determined by soft-agar cloning and resulted in LC90 (lethal concentration to 90% of cells) values of 0.6 microM FdUrd, 0.7 microM FUrd, 5.3 microM FUra and 93 microM 5'-dFUrd. The RNA-directed (dThd-nonreversible) cytotoxicity was assessed by cloning the cells in the presence of 10 microM dThd. This resulted in an altered order of potency and increased LC90 values to 5.5 microM FUrd, 20 microM FUra, 265 microM FdUrd and 870 microM 5'-dFUrd. The production of mature cytoplasmic rRNA was determined by measuring the amount of [3H]cytidine incorporated into the 28S and 18S rANA species following their separation by agarose gel electrophoresis, compared with the level of [3H]cytidine incorporated into the nuclear rRNA. When all four fluoropyrimidines were compared together, the degree of inhibition of cytoplasmic rRNA production was poorly predictive of the total cytotoxicity in the absence of dThd (correlation coefficient, r = 0.77). FdUrd, in particular, had a very minor effect on rRNA production even at very toxic drug concentrations. When toxicity was assessed in the presence of dThd, however, there was a strong and significant correlation between rRNA production and RNA-directed cytotoxicity (r = 0.95, P less than 0.001), for all the fluoropyrimidines tested, including FdUrd. Thus, when the inhibition of thymidylate formation was eliminated as a site of drug action and only RNA-directed cytotoxicity was assessed, the impaired production of cytoplasmic rRNA was strongly associated with cytotoxicity. These results demonstrate that the inhibition of mature cytoplasmic rRNA production may be an important common mechanism of RNA-directed cytotoxicity for all the fluoropyrimidines, and not limited to FUrd or FUra.

Pulmonary infiltrates associated with sulindac therapy.

Pulmonary infiltrates, cough, dyspnea, and fever developed in a 62-year-old woman with chronic degenerative arthritis who had been receiving sulindac therapy for six months. Her pulmonary signs and symptoms resolved upon withholding the drug. Inadvertent rechallenge resulted in rapid recurrence of respiratory symptoms and pulmonary infiltrates. This constellation of clinical findings provides strong evidence of isolated pulmonary reactions as a complication of sulindac therapy.

The clinical development of 9-aminocamptothecin.

9-Aminocamptothecin (9-AC) is a topoisomerase I-targeting agent first synthesized by Wani and Wall in 1986. Because of its potent in vitro effects and promising preclinical activity in colorectal cancer animal models, it was designated a high-priority compound for further drug development by the NCI. In 1993, 9-AC first entered clinical trials as a 72-hour intravenous (i.v.) infusion. Predictable myelosuppression was the major dose-limiting toxicity, and pharmacokinetic studies showed a relatively short plasma half-life and unstable lactone ring. Unfortunately, phase II studies using this schedule showed minimal or no activity in tumors such as colorectal and lung cancer. Modest activity was observed in ovarian cancer and in refractory lymphomas. Efforts to improve systemic drug exposure by utilizing alternative schedules of administration of 9-AC such as prolonged, continuous intravenous infusions have also been tested. However, phase II studies of 120-hour weekly infusions of 9-AC have not shown improved activity against solid tumors such as colorectal cancer. More recently, a daily times 5 days i.v. administration schedule has been tested. Currently, further development of intravenously administered 9-AC for the treatment of colorectal cancer is not promising. Thus, topotecan and irinotecan remain the only two successfully developed topoisomerase I-targeting drugs in the United States. This experience with 9-AC raises important questions regarding how to best select new topoisomerase I-targeting drugs for future clinical development.

Inter- and intraindividual variation in dihydropyrimidine dehydrogenase activity in peripheral blood mononuclear cells.

PURPOSE: The activity of dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme in fluorouracil catabolism, has been reported to vary according to time of day. We wished to determine whether peak and trough DPD activities occurred at uniform times in six subjects, whether individual patterns fit a discernible profile, and whether such patterns were consistent and reproducible over time. METHODS: Mononuclear cells were isolated from peripheral blood at 3-h intervals over a 24-h period on three different dates over a 6-month period. DPD activity was determined by incubating cellular lysates with [3H]FUra and measuring [3H]dihydrofluorouracil formation over time. RESULTS: When the data were averaged by study date for each subject, the median value for the average DPD activity (11.0 pmol/min per 10(6) cells) was significantly different from both the median peak (21.1 pmol/min per 10(6) cells, P = 0.004) and median trough activities (4.0 pmol/min per 10(6) cells, P = 0.002). Within the six subjects, the average DPD activity for the three study dates differed by a median of 2.4-fold (range 1.2- to 4.8-fold). The time at which peak and trough DPD activities occurred varied between subjects: 8 of the 17 peaks (47%) occurred between 10:00 p.m. and 6:00 a.m., 6 (35%) occurred between 8:00 a.m. and 3:00 p.m., and 3 (18%) occurred between 5:00 p.m. and 8:15 p.m. Thus, the time of day when the peak occurred was essentially randomly distributed over the 24-h period of observation (P = 0.68). Ten (59%) of the trough DPD activities occurred between 7:00 a.m. and 3:00 p.m. The median interval between the peak and trough was 6.5 h. The data were also expressed as percent of the mean for each individual's 24-h sampling period, and reordered as time from peak rather than as the actual time of day. When the combined data for all cycles was considered, the trough occurred 6-9 h after the peak, and the DPD levels subsequent to the peak did not display merely random variation (P = 0.0055). CONCLUSIONS: DPD activity levels and the times at which peak and trough DPD activities occurred varied both between and within subjects. If fluctuations in DPD activity influence the tolerability of fixed-rate infusions of FUra, these data suggest that a single variable-rate infusion regimen may not be suitable for all patients nor for a given individual treated over several months.

Human plasma carboxylesterase and butyrylcholinesterase enzyme activity: correlations with SN-38 pharmacokinetics during a prolonged infusion of irinotecan.

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.

Pharmacokinetics and pharmacodynamic effects of 5-fluorouracil given as a one-hour intravenous infusion.

PURPOSE: Clinical toxicity associated with 5-fluorouracil (5-FU) is related to the area under the plasma concentration-time curve (AUC). Recently, short-term infusions of 5-FU given over 30 or 60 min have been substituted for conventional "bolus" 5-FU given over 3-5 min in randomized clinical trials, but there are only limited pharmacokinetic data for these altered infusion durations. We therefore wished to determine the pharmacokinetics and toxicity associated with 5-FU given as a 1-h intravenous (i.v.) infusion. METHODS: A group of 22 adults with advanced gastrointestinal tract cancers and no prior systemic chemotherapy for advanced disease received interferon alpha-2a (5 MU/m2 s.c., days 1-7), leucovorin (500 mg/m2 i.v. over 30 min, days 2-6) and 5-FU (370 mg/m2 i.v. over 1 h, days 2-6). The doses of 5-FU and interferon-alpha were adjusted according to individual tolerance. The pharmacokinetics and clinical toxicity were retrospectively compared with patients receiving the same regimen under the same treatment guidelines except that 5-FU was given over 5 min. RESULTS: The regimen was well tolerated, and 41% of the patients tolerated 5-FU dose escalations to 425-560 mg/m2 per day. Grade 3 or worse diarrhea and fatigue ultimately occurred in 14% of the patients each. Granulocytopenia, mucositis, and diarrhea appeared to be appreciably milder in the present trial compared with our prior phase II experience in colorectal cancer. The peak 5-FU plasma levels and AUC with 370 mg/m2 5-FU given over 1 h were 7.3-fold and 2.4-fold lower than previously measured in 31 patients who received 5-FU over 5 min. CONCLUSION: Increasing the length of 5-FU infusion to 1 h seemed to substantially reduce the clinical toxicity with this modulated 5-FU regimen, likely due to markedly lower peak 5-FU plasma levels and AUC. Changes in the duration of a short infusion of 5-FU clearly affects the clinical toxicity, but raises the concern of a potentially adverse impact on its antitumor activity. These results suggest the importance of including precise guidelines concerning the time over which 5-FU is given in clinical trials. Having a specified duration of 5-FU infusion is also important if 5-FU dose escalation is considered.