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Phase I and Pharmacologic Study of Oral (PEG-1000) 9-Aminocamptothecin in Adult Patients With Solid Tumors

From the Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital, Rotterdam, the Netherlands; Department of Medical Oncology, University Hospital Nijmegen, Nijmegen, the Netherlands; and IDEC Pharmaceuticals Corp, San Diego, CA.

Address reprint requests to M.J.A. de Jonge, MD, Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital, Groene Hilledijk 301, 3075 EA Rotterdam, the Netherlands; email jonge{at}onch.azr.nl

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: 9-Amino-20(S)-camptothecin (9-AC) is a specific inhibitor of topoisomerase-I. Recently, a bioavailability of approximately 48% for the oral PEG-1000 formulation was reported. We conducted a phase I and pharmacokinetic study of the oral PEG-1000 formulation of 9-AC to define the maximum-tolerated dose, toxicity profiles, pharmacokinetic-dynamic relationships, and preliminary antitumor activity in patients with solid tumors.

PATIENTS AND METHODS: Patients were treated with oral (PEG-1000) 9-AC given once a day for 7 or 14 days at doses ranging from 0.25 to 1.1 mg/m²/d; cycles were repeated every 21 days. For pharmacokinetic analysis, plasma sampling was performed on days 1 and 6 or 8 of the first course using a validated high-performance liquid chromatographic assay.

RESULTS: Thirty patients were entered onto the study; three patients were not assessable for toxicity and response. Twenty-seven patients received a total of 89 courses. The dose-limiting toxicities (DLTs) were myelosuppression and diarrhea at a dose of 1.1 mg/m²/d for 14 days. Pharmacokinetics showed a substantial interpatient variation of the area under the plasma concentration-time curve (AUC) of 9-AC. The intrapatient variability was extremely small. A significant correlation was observed between the percentage decrease in WBC count and the AUC of 9-AC lactone (r² = 0.86). One partial response was noted in a patient with metastatic colorectal cancer.

CONCLUSION: DLTs in this phase I study of oral 9-AC daily for 14 days every 21 days were myelosuppression and diarrhea. The recommended dose for phase II studies is 0.84 mg/m²/d. In view of the substantial interpatient variability in AUC and the availability of a limited sampling model, a pharmacokinetic guided phase II study should be considered.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
9-AMINO-20(S)-CAMPTOTHECIN (9-AC, NSC 603071, IDEC-132) is a semisynthetic analog of camptothecin. Like camptothecin, 9-AC is a specific inhibitor of topoisomerase I. Topoisomerase I is a nuclear enzyme that can relax the torsional strain of supercoiled DNA, which is necessary for DNA replication, RNA transcription, and DNA recombination.¹ This is achieved by forming a covalent adduct between topoisomerase I and the DNA, termed "the cleavable complex." This catalytic intermediate involves single-strand breaks, which allow the DNA molecule to rotate around the intact DNA strand at the cleavage site and leads to relaxation of the DNA molecule. These enzyme-bridged breaks are then resealed by topoisomerase I. Camptothecin analogs stabilize the cleavable complex, thus preventing resealing of the topoisomerase I–mediated single-strand break. Cytotoxicity of camptothecin analogs is specific to the S phase of the cell cycle.

Unlike other camptothecin analogs (topotecan and irinotecan), 9-AC is poorly soluble in water. In preclinical studies, 9-AC demonstrated activity against human colon cancer, prostate cancer, breast cancer, non–small-cell lung cancer, and melanoma tumor xenografts.^1-5 Preclinical in vivo data suggested that duration of exposure to 9-AC above a certain threshold concentration (10 nmol/L = 3.6 ng/mL) and frequency of administration were essential for antitumor activity.^6,7 Therefore, initial phase I studies using the intravenous formulation of 9-AC focused on schedules with prolonged infusion duration of 24 to 72 hours.^8-12 Dose-limiting toxicities (DLTs) included neutropenia, thrombocytopenia, and diarrhea. A more convenient method for prolonged drug administration might be the use of an oral formulation. 9-AC can be administered orally as a colloid dispersion (CD) or as gelatine capsules in polyethylene glycol (PEG) 1000 (PEG-1000). Given orally to rodents and dogs, both the CD and PEG-1000 formulation of 9-AC retained the antitumor activity¹³ (data on file, Pharmacia & Upjohn, Milan, Italy). In dogs, the oral bioavailability of the CD formulation was 13% (range, 4.5% to 26%) compared with 10% for the PEG-1000 formulation. Recently, a phase I study of the CD formulation of 9-AC administered orally 5 days a week every 2 weeks was completed. Diarrhea was the DLT at a dose level of 0.2 mg/m².¹⁴

In the present report, we describe a phase I study of oral 9-AC using the PEG-1000 capsule formulation administered once a day for 7 to 14 days repeated every 21 days.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Selection
Patients with a histologically confirmed diagnosis of a malignant solid tumor refractory to standard forms of therapy were eligible. Other eligibility criteria included the following: age of 18 to 75 years; Eastern Cooperative Oncology Group performance status 2; estimated life expectancy of 12 weeks; no previous anticancer therapy for at least 4 weeks (6 weeks for nitrosourea or mitomycin); no previous therapy with other camptothecins and/or intensive ablative regimens; and adequate hematopoietic (absolute peripheral granulocyte count 2,000/µL and platelet count 100 x 10⁹/L), hepatic (bilirubin within normal limits, and serum AST, ALT, and alkaline phosphatase 2.5 times normal limit), and renal (serum creatinine concentration < 133µmol/L) function. Specific exclusion criteria included significant gastrointestinal dysfunction that could alter absorption or motility and chronic treatment with corticosteroids. Concomitant administration of H₂ antagonists, antacids, proton pump inhibitors, and nonsteroidal anti-inflammatory drugs were avoided. If such therapies were necessary, their time of administration was at least 3 hours after the intake of the study drug. All patients gave written informed consent before study entry.

Treatment and Dose Escalation
9-AC was supplied as hard gelatine capsules that contained 0.10, 0.25, or 1 mg of the active drug and PEG-1000 as excipient and were stored at room temperature. A detailed description of the constituents and preparation of the oral dosage form will be presented elsewhere. Capsules were taken once a day with a glass of water after overnight fasting at least 30 minutes before a milk-free, nonfat breakfast. Patients were treated on an outpatient basis. The daily dose of 9-AC was provided in separate boxes, with each daily dosing clearly identifiable by the patient. Patients were instructed to record their daily amount of capsules taken, the time of administration, and the timing in relation to breakfast. Compliance with the scheduled treatment was assessed at the end of each course by counting the used and returned capsules of 9-AC in relation to the record kept by the patient for the given cycle.

The starting dose of 9-AC, 0.25 mg/m² given orally once a day for 7 days, was one third of the maximum-tolerated dose (MTD) in dogs. The total oral dose was rounded off at 0.25 mg. Courses were to be repeated every 21 days. Because prolonged drug administration might be essential for antitumor activity of 9-AC, the duration of the therapy was first extended from 7 to 14 days at the second dose level. Further dose escalations were based on the prior dose level toxicity. If no toxicity (excluding alopecia, fatigue, nausea, and vomiting) was observed at the previous dose level, then a 50% dosage increment was allowed. However, if toxicity was observed, a dose escalation of 15% to 40% (which was determined by the worst significant toxicity) was prescribed. At least three patients were entered at each dose level. The MTD was defined as one dose level below the dose that induced DLTs during course 1, which were defined as National Cancer Institute common toxicity criteria (CTC) grade 4 granulocytopenia for at least 5 days or occurring during treatment, grade 4 thrombocytopenia, complicated grade 3 or 4 granulocytopenia, and/or nonhematologic toxicity grade 3 (grade 2 for neurotoxicity), excluding fatigue, nausea, and vomiting, in two of six patients.¹⁵ If grade 4 neutropenia or thrombocytopenia and/or grade 3 nonhematologic toxicity (grade 2 for neurotoxicity) occurred during treatment days, 9-AC administration was stopped immediately. Intrapatient dose escalation was not allowed. If a patient encountered DLT, the dose of 9-AC was decreased with one dose level at re-treatment. The treatment was resumed when the neutrophil count had recovered to 2,000/µL and the platelet count to 100 x 10⁹/L.

Treatment Assessment
Before initiating therapy, a complete medical history was taken and a physical examination was performed. A complete blood cell (CBC) count, including WBC differential, and serum biochemistry, which involved sodium, potassium, calcium, phosphorus, urea, creatinine, total protein, albumin, total bilirubin, alkaline phosphatase, AST, ALT, gamma-glutamyltransferase, glucose, and uric acid, were performed, as were urinalysis, ECG, and chest x-ray. Weekly evaluations included history, physical examination, toxicity assessment according to the CTC criteria, and serum chemistry. CBC count was determined twice weekly. Tumor evaluation was performed after every two courses according to the World Health Organization (WHO) criteria for response. Patients were taken off protocol at the onset of disease progression.

Sample Collection and Drug Analysis
For pharmacokinetic analysis, 10 blood samples (~ 4 mL) were obtained from an indwelling intravenous canula and collected in vials containing lithium heparin as anticoagulant. The samples were taken immediately before dosing and at 20 and 40 minutes and 1, 2, 3, 5, 7.5, 11, and 24 hours after administration of the drug on days 1 and 6 (7-day schedule) or days 1 and 8 (14-day schedule) of the first course. All samples were centrifuged immediately after sampling and the plasma supernatant was snap-frozen at -20°C to prevent degradation of the 9-AC lactone form. Concentrations of 9-AC lactone and 9-AC total (ie, lactone plus carboxylate) drug forms in plasma were determined according to a validated reversed-phase high-performance liquid chromatographic (HPLC) assay with fluorescence detection, described in detail elsewhere.¹⁶ The lower limits of quantitation were 50 pg/mL for 9-AC lactone and 100 pg/mL for 9-AC total using 1-mL and 0.25-mL volumes, respectively, for sample clean-up and analysis. The percentage deviation from nominal values and the intra- and interassay variability were always less than 10%.

Pharmacokinetic and Pharmacodynamic Data Analysis
The plasma concentration-time curves were analyzed using the pharmacokinetic software package Siphar (Version 4.0, SIMED, Creteil, France) by determination of slopes and intercepts of the plotted curves with multiexponential functions. Initial parameter estimates were obtained by an automated peeling-algorithm procedure, with an integrated numerical algorithm based on the Powell method to minimize any objective function by the following criteria:

where n is the number of observations, Y_oi and Y_ci are Y observed and calculated values, respectively, for the i-th observation, and _yi is the standard deviation for the i-th observation. The statistical best fit was determined by application of i, Akaike's information criterion with the ² test to discriminate between models, and ii, the coefficient of correlation, defined as the ratio of the standard deviation computed using the variance-covariance matrix and the parameter value. Both weighted least squares and extended least squares methods were evaluated to estimate model parameters minimizing the sum of squared differences between experimental and computed values and the log-likelihood function. The drug disposition half-lives (t_1/2) and the area under the plasma concentration-time curve (AUC) were determined on the basis of the best fitted curves, whereas the peak plasma concentration (C_max) and the time to the peak plasma concentration (T_max) were determined graphically. The observation of multiple peaks in the kinetic profile of 9-AC total¹⁷ limited application of conventional compartmental analysis. Therefore, the AUC of 9-AC total was estimated using the experimental values (trapezoidal rule) with extrapolation to infinity using the terminal elimination rate constant, defined as the slope of the final three to four data points of the log-linear concentration-time plot.

Pharmacokinetic/pharmacodynamic relationships between 9-AC kinetic parameters and hematologic toxicity associated with drug administration were evaluated using the Siphar and NCSS (Number Cruncher Statistical Systems Version 5.0, NCSS, Kaysville, UT) computer programs. Within individual patients, myelosuppression was described as the continuous variable, consisting of percentage decrease in WBC count, absolute neutrophil count, and platelet count, and CTC myelotoxicity grade as the discrete variable. The relative hematologic toxicity was defined as:

Only the first course of each patient was taken into consideration to avoid potentially confounding bias due to cumulative toxicity. All data were fitted to a sigmoidal maximum effect (E_max) model based on the modified Hill equation, as follows:

In this equation, E₀ is the minimum reduction possible, fixed at a value of 0, E_max is the maximum response, fixed at 100 (continuous variables) or 4 (discrete variable), KP is the pharmacokinetic parameter of interest, KP₅₀ the value of the pharmacokinetic parameter predicted to result in half of the maximum response, and is the Hill constant describing the sigmoidicity of the curve. Models were evaluated for goodness of fit by minimization of sums of the squared residuals and by reduction of the estimated coefficient of variation for fitted parameters. Significance of the relationships was assessed by construction of contingency tables with subsequent ² analysis.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
A total of 30 patients were entered onto the study. Patient characteristics are listed in Table 1. All patients were eligible, but three patients were considered not assessable for toxicity and response because they were taken off protocol at their own request before completing the first course without any notable toxicity at that time. Therefore, 27 patients were assessable for toxicity and response. The majority of the patients were either asymptomatic or had only mild symptoms. All patients except two had received prior chemotherapy and/or radiotherapy. The most common tumor type was colorectal cancer. The total number of assessable courses was 89. The median number of courses per patient was two (range, one to 10). Dose levels studied were 0.25 mg/m²/d for 7 days and 0.25, 0.40, 0.60, 0.84, 1.0, and 1.1 mg/m²/d for 14 days. Two treatment cycles had to be discontinued early because of toxicity; one patient treated at a dose of 0.60 mg/m²/d for 14 days experienced grade 3 fatigue during his second cycle and discontinued therapy after 10 days. In a second patient, treated at 1.1 mg/m²/d for 14 days, therapy was discontinued after 10 days during the first cycle because of grade 4 neutropenia and thrombocytopenia.

Hematologic Toxicity
A combination of thrombocytopenia and neutropenia complicated by fever was the DLT of 9-AC at a dose of 1.1 mg/m²/d with this schedule. Dose reduction to 1.0 mg/m²/d also resulted in DLT. Overall, the hematologic toxicity was relatively mild (Table 2), with neutropenia occurring mainly in the second and third week and thrombocytopenia in the third week after the start of treatment (Fig 1). Grade 3 to 4 neutropenia was observed in 10 of 89 courses (11%). It was complicated by neutropenic fever in four patients. Thrombocytopenia was mild, being grade 3 to 4 in only 6% of the cycles, all in conjunction with neutropenia. Despite the limited severity of myelosuppression, treatment had to be delayed in 23% of the courses due to prolonged myelosuppression. One patient was taken off study because of persisting leukocytopenia after 2 weeks of treatment delay. Two patients required dose reductions after experiencing DLT. A marked inhibition of erythropoiesis was observed. The percentage of patients requiring erythrocyte transfusions was 55% during 22 of 89 courses.

View larger version (17K): [in this window] [in a new window]   Fig 1. Median absolute neutrophil count (; left y-axis) and platelet count (; right axis) as a function of the time posttreatment in patients experiencing grade 4 myelotoxicity.

Nonhematologic Toxicity
One patient treated at a 9-AC dose of 1.0 mg/m²/d experienced grade 4 diarrhea. Grade 1 to 2 diarrhea was observed in 25 of 89 courses (28%) and seemed to be dose-related (Table 3). The median day of onset of the diarrhea was day 12 (range, 1 to 23 days). Diarrhea lasted for a median duration of 3 days (range, 1 to 23 days) and was self-limiting in most patients. Two patients who required treatment for diarrhea responded to a low-dose loperamide regimen. Mild to moderate (CTC grade 1 to 2) nausea and vomiting occurred in 48% and 36% of courses, respectively. Antiemetic therapy consisting of low-dose metoclopramide (20 mg tid) was sufficient in most patients. Other side effects were alopecia (30%), mucositis (9%), and fatigue (56%). The latter was partly associated with anemia, as symptoms subjectively reduced after transfusion.

Pharmacokinetics and Dynamics
Full kinetic data were obtained on days 1 and 6 (7-day schedule) or 8 (14-day schedule) from 29 patients after the administration of 9-AC. Pharmacokinetics could not be determined in three courses as a result of limited sample availability or significant chromatographic interference in the drug assay by an unknown compound.

The plasma concentration-time profiles of 9-AC were similar for all patients studied, with a representative example shown in Fig 2. The absorption of 9-AC lactone after oral drug administration was associated with a lag time of 0.302 ± 0.063 hours (mean ± SD; n = 29) and maximum peak drug levels at 1.05 ± 0.149 hours. The conversion of 9-AC lactone into the ring-opened carboxylate species in plasma could be demonstrated from the first sample acquired and peaked at 2.50 ± 0.68 hours after dosing. Eventually, the 9-AC carboxylate accounted for 90.9% ± 3.32% of 9-AC total concentrations, indicating a clear predominant interconversion of lactone to carboxylate. In the majority of patients, concentrations of 9-AC lactone and 9-AC carboxylate, calculated as the difference between total drug and intact lactone, were still above the lower limit of quantitation of our HPLC assay (50 pg/mL) before administration of the drug on the second day. However, the kinetic data and recorded AUC values for the following days of administration were similar to those achieved on the first day in the same patient (Table 4). The resulting intrapatient variability, expressed as the coefficient of variation, in AUC and peak drug levels was extremely small and averaged 8.67% for 9-AC lactone and 10.9% for 9-AC carboxylate. The interpatient variability in the observed pharmacokinetics was large, with coefficients of variation in AUC values as high as 89.5% for 9-AC lactone and 99.0% for 9-AC carboxylate. Elimination of 9-AC from the central plasma compartment was characterized by decay in an apparent triexponential manner based on conventional compartmental modeling using weighted least squares analysis with a weighting factor of 1/Y. The estimated terminal elimination half-life was relatively constant in all subjects, exhibiting mean values of 6.83 ± 2.51 hours for 9-AC lactone and 7.56 ± 1.73 hours for 9-AC carboxylate, and was not dependent on the dose of 9-AC.

View larger version (12K): [in this window] [in a new window]   Fig 2. Representative plasma concentration-time profiles of 9-AC lactone (, ) and 9-AC total (•, ) measured on day 1 (, ) and day 8 (, •) of the first treatment course in a single patient after oral administration of 9-AC at a dose level of 0.84 mg/m2 daily for 14 days.

Sigmoidal maximum effect modeling of pharmacokinetic and hematologic toxicity data revealed that the AUC of 9-AC lactone was significantly correlated (P < .001) with the percentage decrease in WBC (coefficient of correlation [r²] = 0.86; Fig 3A) and the worst observed myelotoxicity grade according to CTC criteria (r² = 0.93; Fig 3B). In the latter case, the cut-off AUC value associated with development of any myelotoxicity of grade 2 or worse was 17.3 ng · h/mL, using the Hill equation and data shown in Fig 3B. Significant correlations were also observed between the AUC of 9-AC lactone and the percentage decrease in neutrophil count (r² = 0.66) and platelet count (r² = 0.83). Pharmacokinetic/pharmacodynamic correlations based on linear and nonsigmoidal maximum effect models were less predictive, as were models based on 9-AC carboxylate or 9-AC total kinetics (data not shown).

View larger version (11K): [in this window] [in a new window]   Fig 3. Correlation between the AUC of 9-AC lactone and the percentage decrease in WBC count at (A) nadir of the first treatment course or (B) the worst observed myelotoxicity grade. The lines represent the fitting of the data to a sigmoidal maximum effect model.

Responses
One partial response that lasted for 28 weeks was observed at a dose of 1.0 mg/m²/d for 14 days in a patient with metastatic colorectal cancer involving the liver. Disease stabilization lasting for a median of 28 weeks (range, 21 to 50 weeks) was noted in six patients who had colorectal cancer (two patients), breast cancer, ovarian cancer, bile duct cancer, and cancer of the appendix (one patient each).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Topoisomerase I inhibitors are a class of drugs with a broad antitumor activity, and they form an important addition to the presently available classes of agents. 9-AC is a semisynthetic analog of the parent topoisomerase I inhibitor, camptothecin. In preclinical studies, 9-AC demonstrated activity against several human tumor cell lines and xenografts. In vitro experiments and in vivo studies with human xenografts revealed a better antitumor effect with prolonged exposure to topoisomerase I inhibitors.^2-3,18-22 Therefore, initial phase I studies using the intravenous formulation of 9-AC focused on schedules with prolonged infusion duration. The availability of an oral formulation of 9-AC for clinical use would enable a more convenient method of prolonged drug administration and provide the opportunity for cost-effective outpatient therapy. Recently, the bioavailability of 9-AC formulated as gelatine capsules in PEG-1000 was explored after oral administration using 9-AC at a dose of 1.5 mg/m².¹⁷ After oral delivery, 9-AC is rapidly absorbed with an overall bioavailability (F) of 48.6% ± 17.6% (range, 24.5% to 80.4%), indicating significant systemic exposure to the drug. This compares favorable with the oral bioavailability of topotecan (F = 30.0%),²³ GI147211 (F = 11.3%),²⁴ and irinotecan (F = 12% to 21%),²⁵ which may be an advantage with potential pharmacodynamic importance.

The DLT of the oral administration (PEG-1000) of 9-AC given for 14 days every 3 weeks was a combination of thrombocytopenia, febrile neutropenia, and diarrhea. Overall, the hematologic toxicity was relatively mild. Grade 3 to 4 hematologic toxicity was observed in 11.2% of the courses and consisted of neutropenia that occurred in conjunction with grade 3 to 4 thrombocytopenia in five of 10 courses. Despite the mild myelosuppression, treatment had to be delayed in 23% of the cycles due to prolonged myelosuppression. In contrast, after oral administration of topotecan in different schedules, treatment had to be delayed due to slow recovery from myelosuppression in only 0% to 7% of the cycles.^26,27 However, oral administration of 9-nitrocamptothecin also resulted in prolonged myelosuppression, requiring treatment delay in 12% to 25% of cycles.²⁸ Anemia is a well-documented side effect of treatment with topoisomerase I inhibitors, especially of topotecan.^26,27,29-31 In our present study, anemia CTC grade 2 occurred in 16.8% of the cycles despite RBC transfusions.

Diarrhea is also a well-known side effect of camptothecin and its derivatives. However, the types of diarrhea seem to differ. Irinotecan administered intravenously induces an acute as well as a delayed type of diarrhea. The acute diarrhea seems to be related to a release of vasoactive compounds, whereas the delayed type of diarrhea is related to the degree of glucuronidation of the irinotecan metabolite SN-38 in the bile. Oral administration of 20-S-camptothecin,³² 9-nitrocamptothecin,²⁸ topotecan,^26,27 and 9-AC in the CD formulation¹⁴ induced diarrhea in 24% to 54% of the cycles. Especially prolonged oral administration (21 days) of topotecan resulted in severe diarrhea in 22% of cycles, which could not be controlled with loperamide. In our present study, grade 1 to 2 diarrhea was observed in 28% and grade 3 to 4 in 2% of the cycles. In most patients, diarrhea consisted only of several loose stools and did not require any therapy. Local intestinal effects of camptothecin and its derivatives seem to be responsible for the diarrhea. However, the exact mechanism is yet unknown. Other nonhematologic toxicities were mainly mild.

In the present study, 9-AC demonstrated linear and dose-independent pharmacokinetics over the dose range studied, with the AUC increasing from 8.18 ± 3.84 to 48.9 ± 26.8 ng · h/mL. Interpatient variability in the concentrations of 9-AC at each of the sample time points as well as in the AUC was large, with values for the coefficient of variation as high as 99%. In contrast, intrapatient variability in AUC and peak drug levels was extremely small (coefficient of variation < 10%), indicating that repeated exposure to 9-AC does not result in drug accumulation or alteration of the kinetic profile. These findings are inconsistent with the data reported by Mani et al.¹⁴ In their phase I study of a CD formulation of 9-AC administered orally, dose escalation was discontinued because of poor bioavailability and apparent saturable absorption of the drug. The difference in bioavailability may be related to differences in absorption of the two formulations of 9-AC. However, the significant degree of interpatient variability in the pharmacokinetics of 9-AC limits the power to detect a linear dose-AUC relationship, especially when only a limited number of patients are studied.

Sigmoidal maximum effect modeling of the pharmacokinetic and pharmacodynamic data of the present study revealed a significant correlation of the AUC of 9-AC lactone with the percentage decrease in leukocyte (r = 0.86), granulocyte (r = 0.66), and platelet count (r = 0.83). Recently, a limited-sampling model was developed for reliable and accurate prediction of the systemic exposure to 9-AC after oral drug administration.³³ By measuring 9-AC plasma concentrations at 3 hours and 11 hours after drug dosing, AUCs of total 9-AC and 9-AC lactone could be predicted. Because the determination of the lactone and lactone-plus-carboxylate forms of 9-AC in plasma was simplified by using a reversed-phase HPLC,¹⁶ application of the proposed model in clinical routine has become possible. This may enable us to optimize the treatment for any given patient. After determination of the target AUC, treatment can be adjusted on the basis of individual pharmacokinetic characteristics.

Topoisomerase I inhibitors are S-phase–specific drugs. In preclinical studies, a better antitumor effect was noted after prolonged exposure to the active lactone form of 9-AC above a threshold concentration of 10 nmol/L (3.6 ng/mL).^6,7 In previous studies of the intravenous administration of 9-AC, only in the schedule studying the 24-hour infusion of 9-AC once weekly for 4 weeks every 5 weeks, the concentration of 9-AC lactone at steady state reached this threshold value at the recommended dose for phase II studies of 1.65 mg/m²/wk.¹¹ In our present study, concentrations of 9-AC lactone 10 nmol/L were achieved for several hours on every treatment day (days 1 to 14) at the dose level of 0.84 mg/m²/d.

In the present study using the PEG-1000 formulation of 9-AC administered orally for 14 days every 3 weeks, one partial response was observed in a patient with metastatic colorectal cancer. In another six patients, disease stabilization was achieved. Whether this schedule is the most optimal must be investigated. Other phase I studies exploring different schedules should be performed.

In conclusion, in this phase I study with oral administration of 9-AC (PEG-1000) given once a day for 14 days repeated every 3 weeks, the DLTs were myelosuppression and diarrhea. The recommended dose for phase II studies is 0.84 mg/m²/d. However, in view of the substantial interpatient variation in AUC and the availability of a limited sampling model, a pharmacokinetically guided phase II study should be considered.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted September 4, 1998; accepted March 11, 1999.

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