Clinical Cancer Research Vol. 10, 2327-2335, April 2004
© 2004 American Association for Cancer Research
Single Ascending Dose Tolerability, Pharmacokinetic–Pharmacodynamic Study of Dihydropyrimidine Dehydrogenase Inhibitor Ro 09-4889
S. Eralp Bellibas1,
Indra Patel1,
Emmanuel Chamorey2,
Bettyna Brivet1,
Ernest D. Bush1,
Catherine Kircher1,
Stephane Nave1,
Ludger Banken1,
Nicole Renée2 and
Gérard Milano2
1 Department of Clinical Pharmacology, Hoffmann-La Roche Inc., Nutley, New Jersey, and 2 Centre Antoine Lacassagne, Oncopharmacology Laboratory, Nice, France
 |
ABSTRACT
|
|---|
Purpose: Ro 09-4889 was designed to enhance the anticancer efficacy of capecitabine (Xeloda) by generating a dihydropyrimidine dehydrogenase inhibitor (DPDi) 5-vinyluracil (5-VU) preferentially in tumor tissues. This study assessed the tolerance to Ro 09-4889 treatment, and related pharmacokinetic and pharmacodynamic data such as inhibition of DPD activity in peripheral blood mononuclear cells (PBMCs) and plasma uracil levels.
Experimental design: This was a single-center, double-blind, placebo-controlled, single-dose escalation study in 64 healthy male volunteers at 1-, 5-, 20-, 50-, 75-, 100-, and 200-mg oral dose of Ro 09-4889. Also, food effect was assessed separately in a group dosed with 20 mg of the compound.
Results: No serious adverse effects or significant laboratory and electrocardiogram abnormalities were observed during the study. Ro 09-4889 has a short elimination half-life (t1/2) of 0.5 h, followed by metabolites 5'-deoxy-5-vinyluridine (5'-DVUR), 5'-deoxy-5-vinylcytidine (5'-DVCR), and 5-VU with t1/2 of 1.3, 1.2, and 2 h, respectively. The major metabolite excreted in urine was 5-DVCR (45% of dose). The inhibition of PBMC DPD activity and the increase in plasma uracil were related to Ro 09-4889 dose. DPD inhibition versus dose and uracil AUC (area under the curve) versus dose were modeled using the Emax model with a baseline effect. The model-predicted ED50 value was 100 mg.
Conclusion: Single oral doses of Ro 09-4889 ranging from 1 to 200 mg were well tolerated. On the basis of these findings, a 10-to-30-mg dose range of Ro 09-4889 combined with capecitabine could be appropriate for further evaluation in cancer patients.
|
INTRODUCTION
|
|---|
The use of fluoropyrimidines in the therapy of solid tumors is now expanding through the clinical development of new oral formulations (1)
. Orally administered agents have several potential advantages over parenteral formulations, mainly because they are more convenient for patients and generate no morbidity inherent in the use of indwelling catheters and infusion pumps (2)
. Most so-called oral fluoropyrimidines include a dihydropyrimidine dehydrogenase (DPD) inhibitor (3)
. DPD is a ubiquitous enzyme that, at two levels at least, produces a marked variability in the pharmacological behavior of fluoropyrimidines. The first level concerns pharmacokinetics, because DPD controls the first step in 5-fluorouracil (5-FU) liver catabolism and DPD-deficient patients have been shown to be prone to develop more or less severe 5-FU-related toxicity (4)
. The second level relates to pharmacodynamics, because 5-FU catabolism at the target level itself has been identified, from both experimental (5)
and clinical (6)
data, as a factor of resistance to the 5-FU antitumor response. Hence, pharmacological DPD inhibition is of clinical relevance because it optimizes 5-FU-based therapy by attenuating unpredictable 5-FU pharmacokinetic variability and suppressing a major factor of tumor resistance to 5-FU.
Capecitabine (Xeloda) was rationally synthesized to be efficiently absorbed from the gastrointestinal tract as a prodrug and to be converted to 5-FU through the action of thymidine phosphorylase (TP) and preferentially in tumors by exploiting the high activity of TP in malignant tissue (7)
. The compound Ro 09-4889 was designed to optimize the anticancer efficacy of capecitabine by generating a DPD inhibitor, 5'-vinyluracil (5-VU), preferentially in tumors (Fig. 1)
. Hence, Ro 09-4889 follows an identical pathway of enzymatic activation to capecitabine. It is converted by esterases abundant in human liver to 5'-deoxy-5-vinylcytidine (5'-DVCR), then to 5'-deoxy-5-vinyluridine (5'-DVUR) by cytidine deaminase, and then to 5-vinyluracil (5-VU), the active metabolite, by TP (Fig. 2)
. 5-VU inhibits DPD by both mechanism-based inhibition and classically defined competitive inhibition, thereby blocking the catabolism of 5-FU (data in file). Therefore, by combining Ro 09-4889 with capecitabine, it can be anticipated that a higher exposure of 5-FU in tumors could be achieved, thus optimizing efficacy without a detrimental increase in toxicity. This study investigated the tolerability, safety, pharmacokinetics, and pharmacodynamics of a single oral intake of Ro 09-4889 in healthy volunteers. As regards the pharmacodynamics, the impact of drug administration on peripheral blood mononuclear cell (PBMC) DPD activity was taken into consideration as well as the plasma levels of uracil, a natural substrate of DPD. The information obtained from this study will be useful in optimizing study designs (dose range, dosage frequency, and duration of dosing) for subsequent Phase I safety/efficacy studies in cancer subjects.
View larger version (37K):
[in this window]
[in a new window]
[Download PPT slide]
|
Fig. 2. Enzymatic activation of Ro 09-4889. (A'), esterase; (A), carboxylesterase; (B), cytidine deaminase (Cyt deaminase); (C), thymidine phosphorylase (dThdPase); DPD, dihydropyrimidine dehydrogenase; DPDi, DPD inhibitor; 5-FU, 5-fluorouracil; FUH2, dihydro-5-fluorouracil.
|
|
|
MATERIALS AND METHODS
|
|---|
Overall Study Design
This was a Phase 1, single-center, double-blind, placebo-controlled, single ascending dose study. Sixty-four male volunteers were allocated among the seven different dosage groups (1, 5, 20, 50, 75, 100, and 200 mg) in which study medication was administered within 15 min of eating a 94-calorie standard breakfast and one overnight fasted group (20 mg). Within each dosage group, two subjects were randomly assigned to receive placebo. Subjects were admitted to the investigational site the evening before study drug administration and baseline assessments were performed.
The type of adverse event, date of onset, date of resolution, treatment for the adverse event, and outcome were based on information volunteered by or elicited from the subject, or from observations made by the investigator or staff. The investigator evaluated the intensity of each adverse event, related to the dose tested, and whether or not the event was serious. An adverse event was considered to be serious if it clearly presented, or could be expected to present, a threat to the well-being of the subject. Investigators were required to report serious adverse events to the sponsor within 1 working day.
Pharmacokinetic Parameters
Plasma and urine concentrations of Ro 09-4889 and its three metabolites (5'-DVUR, 5'-DVCR, and 5-VU) were measured at the time points indicated in Table 1
.
The plasma pharmacokinetic parameters were estimated using WinNonlin Professional (Version 3.0, Pharsight Corporation, Mountain View, CA) based on model-independent techniques according to the Roche internal "Guideline for calculation and analysis of noncompartmental pharmacokinetic parameters" issued in February 1998.
The cumulative amount of Ro 09-4889 and its three metabolites excreted in urine was calculated at 6, 12, 24, 36, and 48 h postdose.
The method for quantifying of Ro 09-4889, 5'-DVUR, 5'-DVCR, and 5-VU in human plasma was validated, from 1 to 1000 ng/ml for Ro 09-4889, 5'-DVUR, and 5'-DVCR, and from 2 to 1000 ng/ml for 5-VU. The analysis procedure is briefly summarized as follows: 200 µl of acidified sodium fluoride/potassium oxalate human plasma samples were fortified with internal standards. The samples were extracted by solid-phase-extraction with Oasis cartridges from Waters Corporation. The reconstituted extract solution was injected into a triple quadrupole liquid chromatography/tandem mass spectrometry (MS/MS) system for separation and detection by positive and negative electrospray ionization. High-performance liquid chromatography separation was performed on a 100 x 2 mm 5 mcm Phenomenex Columbus C18 column with water and methanol containing ammonium acetate as mobile phase. Detection was conducted in selective reaction monitoring mode on the MS/MS instrument.
The method used to quantify Ro 09-4889, 5'-DVUR, 5'-DVCR, and 5-VU in human urine was validated, from 2 to 1000 ng/ml for Ro 09-4889, 5'-DVCR, and 5-VU and from 5 to 1000 ng/ml for 5-DVUR. The analysis procedure is briefly summarized as follows: 200 µl urine samples were fortified with internal standards. The samples were extracted by solid-phase-extraction with Oasis HLB cartridges from Waters Corporation. The reconstituted extract solution was injected into a triple quadrupole liquid chromatography/MS/MS system for separation and detection by positive and negative electrospray ionization. High-performance liquid chromatography separation and detection were performed using the identical method as for the plasma samples.
Assay Performance
Performance of the assay during sample analysis was determined from the results of the quality control samples and back-calculated concentrations of calibration standards. Precision for the human plasma standards and quality control samples (as measured by the percentage coefficient of variation) ranged from 5.4 to 9.3% for Ro 09-4889, from 3.9 to 10.2% for 5'-DVUR, from 4.4 to 10.4% for 5'-DVCR, and from 5.2 to 9.4% for 5-VU. Accuracy for the human plasma standards and quality control samples (as measured by the percentage relative error) ranged from –3.0 to 6.4% for Ro 09-4889, from –6.8 to 6.0% for 5'-DVUR, from –4.4 to 3.6% for 5'-DVCR, and from –4.5 to 3.8% for 5-VU.
Precision for the human urine standards and quality control samples (as measured by the percentage coefficient of variation) ranged from 3.4 to 7.2% for Ro 09-4889, from 4.6 to 9.6% for 5'-DVUR, from 4.5 to 11.1% for 5'-DVCR, and from 3.8 to 9.3% for 5-VU. Accuracy for the human urine standards and quality control samples (as measured by the percentage relative error) ranged from –5.0 to 2.8% for Ro 09-4889, from –5.8 to 2.0% for 5'-DVUR, from –8.7 to 6.0% for 5'-DVCR, and from –3.0 to 4.0% for 5-VU.
PD Parameters
PD parameters were DPD inhibition in PBMCs, plasma uracil levels, and urine uracil levels.
Predicted pharmacodynamic (PD) parameters were modeled based on an Emax model with a baseline effect E0 using WinNonlin Professional (Version 3.0, Pharsight Corporation, Mountain View, CA).
DPD Activity in PBMCs.
DPD activity in PBMCs was measured at the time points indicated in Table 1
. DPD activity was measured using a radio-enzymatic method, described previously (8)
. The following PD parameters were determined: lowest level (minimal) of DPD enzyme activity (Emin), DPD Emin (%) is the minimal DPD activity expressed as the percentage of the individual baseline value; time of minimal DPD activity (Tmin); and DPD activity recovery time (T90R = time to 90% recovery) is the time DPD takes to recover to 90% of the baseline activity.
Plasma Uracil Levels.
Plasma uracil levels were measured at the time points indicated in Table 1
and the following PD parameters were determined from the plasma uracil concentration-time data: maximum plasma uracil concentration (Cmax) and area under the plasma uracil concentration-time curve from time zero to 48 h (AUC48 h).
The method for quantifying uracil in human plasma was validated, from 10 to 3000 ng/ml for uracil (and 5 to 3000 ng/ml for 5-FU). The analysis procedure is briefly summarized as follows: 200 µl of acidified sodium fluoride/potassium oxalate human plasma samples were fortified with internal standards. Acetonitrile was added to precipitate the proteins. Supernatant resulting from the protein precipitation was evaporated to dryness and reconstituted in water. The reconstituted solution was injected into a triple quadrupole liquid chromatography/MS/MS system for separation and detection by negative electrospray ionization. High-performance liquid chromatography separation was performed on a 150 x 2 mm 5 µm Zorbax Bonus-RP column with water and methanol containing ammonium acetate as mobile phase. Detection was conducted in selective reaction monitoring mode on the MS/MS instrument.
Urine Uracil Levels.
Urine uracil and creatinine levels were measured at the time points indicated in Table 1
. The cumulative amount of uracil excreted at 6, 12, 24, 36, and 48 h postdose was calculated.
The method for quantifying uracil in human urine was validated, from 50 to 10,000 ng/ml. Interassay precision ranged (as measured by the percentage coefficient of variation) from 2.9 to 8.5% for blood and from 2.0 to 14.2% for urine uracil assays. Overall accuracy (percentage relative error) ranged from –2.0 to 7.5% for blood and from –5.6 to 6.0% for urine uracil assays.
The analysis procedure is briefly summarized as follows: 200 µl of urine samples were fortified with internal standards. Acetonitrile was added to precipitate the proteins. Supernatant resulting from the protein precipitation was evaporated to dryness and reconstituted in water. The reconstituted solution was injected to triple quadrupole liquid chromatography/MS/MS system for separation and detection by negative electrospray ionization. High-performance liquid chromatography separation and detection were performed as for the plasma samples.
|
Statistical Analyses
|
|---|
All pharmacokinetic and PD parameters were subjected to descriptive analysis including arithmetic means, SDs, geometric means, coefficients of variation, and ranges.
Pharmacokinetic-PD relationships were explored by examining the behavior of plasma and urine uracil level and DPD inhibition in lymphocytes as a function of plasma exposure of Ro 09-4889 and/or 5-VU.
Predicted AUC as a function of Ro 09-4889 dose were modeled with sigmoid Emax model with a baseline effect using the following:
where Emax is the maximal effect, E0 is the baseline effect, EC50 is the drug concentration producing 50% of Emax, and the exponential constant 
controls the slope of the sigmoid-shape curve.
|
RESULTS
|
|---|
Safety Data
The overall incidence of adverse events was similar among dosage groups. The most frequent adverse event was headache, which was reported by 25% of placebo-treated subjects and 27% of Ro 09-4889-treated subjects. No adverse event demonstrated a dose relationship. A summary of adverse events by dosage group is presented in Table 2
. Adverse events in each dosage group were mild or moderate in severity. No significant biological and electrocardiogram abnormalities were reported.
PK Data
Mean data and pharmacokinetic (PK) profiles for Ro 09-4889 and three metabolites obtained in the 75-mg, 100-mg, and 200-mg study groups are presented in Table 3
and Fig. 3
. The main circulating species was 5'-DVUR followed by 5'-DVCR and 5-VU.
View larger version (32K):
[in this window]
[in a new window]
[Download PPT slide]
|
Fig. 3. Logarithmic and linear pharmacokinetic profiles for Ro 09-4889 and three metabolites obtained in 75-mg (top), 100-mg (middle) and 200-mg (bottom) study groups. 5'-DVCR, 5'-deoxy-5-vinylcytidine; 5'-DVUR, 5'-deoxy-5-vinyluridine; 5'-VU, 5-vinyluracil.
|
|
Cmax for Ro 09-4889 increased dose-dependently ranging from 1.51 to 42.9 ng/ml with tmax ranging from 1.2 to 2.0 h. Ro 09-4889 and the three metabolites were quickly eliminated. Mean values of t1/2 for Ro 09-4889, 5'-DVCR, 5'-DVUR, and 5-VU were 0.5 h, 1.2 h, 1.3 h, and 2 h, respectively.
For the final metabolite with pharmacological efficacy, 5-VU, food caused a 32% decrease in Cmax with values of 13.32 ± 5.67 ng/ml and 8.94 ± 3.07 ng/ml in fasted and fed groups, respectively (Table 4)
. The intersubject variability in the PK parameters was similar in the 20-mg dosage fed and fasted subjects.
The major metabolite excreted in urine was 5'-DVCR, which represented almost one-half of the administered dose (Table 5)
. Recovery ratios (percentage of Ro 09-4889 dose recovered in urine) in the 200-mg dosage group at 48 h for Ro 09-4889, 5'-DVUR, 5'-DVCR, and 5-VU were 0.34, 2.39, 45.4, and 1.86%, respectively. These ratios were consistent with those seen in other dosage groups.
PD Data
DPD Inhibition in PBMCs.
DPD inhibition in PBMCs by time and dosage group is shown in Fig. 4A
. A sustained DPD inhibitory effect was not seen in either the 1-mg or 5-mg dosage groups. The 20-mg dosage group had a 70% decrease in basal DPD activity at 
4 h postdose; DPD activity returned to 50 and 70% of the basal level at 24 and 48 h postdose, respectively. The 50-, 75-, and 100-mg dosage groups decreased basal DPD activity 80–90% reaching a minimum DPD activity at 7 h postdose.
View larger version (26K):
[in this window]
[in a new window]
[Download PPT slide]
|
Fig. 4. A, inhibition of dihydropyrimidine dehydrogenase (DPD) activity in lymphocytes. Data represent average DPD activity at specific time points per dosage group. B, mean plasma uracil levels; Conc., concentration. Data represent average plasma uracil levels at specific time points per dosage group. C, mean urine uracil levels. Data represent average uracil amounts excreted by urine per dosage group. Time points are shown as midpoints of 6-h-long urine collecting intervals.
|
|
Mean Emin, tmin, and t90R are summarized in Table 6
. With the exception of the 50-mg and 100-mg dosage groups, the time when DPD recovered to 90% of the baseline activity (T90R) was dose dependent and ranged from 35 to 300 h.
Uracil Levels.
Mean plasma uracil levels to 48 h postdose are summarized by dosage group in Fig. 4B
. Both the mean maximum plasma uracil concentrations (Cmax) and the AUC48 h values were dose dependent ranging from 15 to 300 ng/ml and 676 to 4833 ng·h/ml (Table 6)
. Tmax was 8 h for all dosage groups. Mean urine uracil levels to 48 h postdose are summarized by dosage group in Fig. 4C
. Mean urine concentration of uracil was dose dependent. DPD inhibition in PBMCs showed a nonlinear correlation with plasma uracil exposure with an R2 value of 0.82 as shown in Fig. 5
.
View larger version (17K):
[in this window]
[in a new window]
[Download PPT slide]
|
Fig. 5. Dihydropyrimidine dehydrogenase (DPD) Emin levels versus plasma uracil AUC48 h values. Emin, lowest level (minimal) of DPD enzyme activity; AUC48 h, area under the curve from time zero to 48 h.
|
|
PK/PD Modeling Results.
Observed and predicted DPD Emin values by Ro 09-4889 dose are shown in Fig. 6A
. The 20-mg dosage group is marked with an arrow because 20 mg was believed to be a threshold value for nonsystemic DPD inhibition. Ro 09-4889 at a dosage level higher than 20 mg may result in losing the tumor-selective action of capecitabine because of increased 5-FU in both tumor tissues and plasma. Consequently, a 20-mg dose of Ro 09-4889 was considered to be the tumor-selective DPD inhibitor dose.
Observed and predicted plasma uracil AUCfrom baseline to 48 h postdose are shown in Fig. 6B
. The predicted Ro 09-4889 dose is 100 mg for ED50.
|
DISCUSSION
|
|---|
The combined use of a DPD inhibitor with an oral fluoropyrimidine offers several potential pharmacological advantages mainly on account of the less unpredictable variability in 5-FU pharmacokinetics and the elimination of a cellular factor of tumoral resistance. For instance, it has been shown that, after the administration of the DPD inhibitor eniluracil in association with oral 5-FU, the clearance of 5-FU was essentially predictable on the basis of the individual value of the estimated creatinine clearance (9)
. On the other hand, previous experimental data have shown that 5-FU-resistant tumoral cells exhibiting high DPD activity recovered drug sensitivity after the application of a specific DPD inhibitor (10)
. Interestingly, the combined use of the DPD inhibitor prodrug Ro 09-4889 and the 5-FU prodrug, capecitabine, could offer additional potential benefits. This is explained by the fact that both the 5-FU production from capecitabine and the delivery of the DPD inhibitor 5-VU are strictly dependent on TP activity, which is known to be overexpressed in malignant tissue (11
, 12)
. Therefore, it is reasonable to anticipate that, because of the higher TP activity in tumors, a more intense exposure of 5-FU in malignant cells will be achieved by combining Ro 09-4889 and capecitabine (continuous production from deoxy-5-fluorouridine and less degradation by DPD), thereby optimizing the efficacy without a detrimental increase in the drug-related toxicity. This tumoral selectivity conferred by capecitabine is illustrated by a recent clinical study by Schüller et al. (13)
in which colorectal cancer patients received capecitabine 2.5 g/m2/day for 5–7 days before surgical resection of the primary tumor and for hepatic metastases. 5-FU concentrations in primary tumor were on average 3.2-fold higher than in adjacent healthy tissue and, importantly, 21-fold higher than in plasma.
The presence of 5-FU can impact on DPD activity (14
, 15)
. Thus, in theory, after the administration of a drug combination with a DPD inhibitor and a fluoropyrimidine, it can be difficult to distinguish between the PD effects attributable to DPD inhibition and those resulting from 5-FU itself. It was thus judged preferable to perform a separate Phase I study of the DPD inhibitor prodrug Ro 09-4889 to examine the specific pharmacological consequences on DPD activity and on other relevant biochemical variables. The present study indicates that single oral doses of Ro 09-4889 varying from 1 mg to 200 mg were safe and well tolerated by healthy male volunteers. No serious adverse events or premature withdrawals because of adverse events were reported. The overall incidence of minor adverse events was similar in placebo-treated and Ro-4889-treated subjects, and no adverse events showed a Ro 09-4889 dose relationship. In addition, no clinically significant laboratory, vital sign, or electrocardiogram abnormalities were reported.
From the PK part of the study, it appears that the circulating levels of 5-VU (final metabolite and DPD inhibitor) were particularly low. This suggests that a systemic DPD inhibition is improbable and DPD inhibition through 5-VU will preferentially occur in tissues expressing TP. It was found that food caused a 32% decrease in the Cmax value of 5-VU. Thus, food is likely to raise a problem for the combination of Ro 09-4889 with capecitabine because the latter is recommended to be taken with food (16)
.
The impact of Ro 09-4889 on DPD activity was examined in PBMCs, although the liver is the main site for 5-FU clearance. Nevertheless, a previous study has shown the existence of a satisfactory correlation between DPD activity in PBMCs and normal hepatic tissue of identical subjects (17)
. However, the relevance of liver DPD inhibition is limited in the case of a capecitabine–Ro 09-4889 combination because capecitabine generates relatively low 5-FU circulating concentrations (18)
. The inhibition of DPD activity and the increase in plasma uracil were related to Ro 09-4889 dosage. Plasma uracil thus appears to be a reliable surrogate marker of pharmacological DPD inhibition. Similar conclusions concerning uracil levels and DPD inhibition were reported in recent studies (9
, 19)
. One can question the need to achieve a complete inhibition of DPD activity. Significant DPD activity is present in intestinal mucosa and hematological cells (20)
. It is thus conceivable that the presence of DPD in these 5-FU-targeted tissues plays a detoxifying role and may limit the cytotoxic impact of 5-FU. Consequently, complete DPD inhibition could be detrimental to the drug therapeutic index. This view is strengthened by recent experimental data showing that the transduction of DPD gene attenuates 5-FU cytotoxicity on murine hematopoietic progenitor cells (21)
. Bearing this in mind, one can recommend a Ro 09-4889 dose of 20 mg because, in the present study, it has been shown to lead to DPD Emin levels 80% while producing a minimal increase in plasma uracil levels. More specific and sophisticated pharmacological studies are needed to check whether a 20-mg dose is also sufficient to significantly decrease DPD activity in tumor tissue. At the dose of 20 mg of Ro 09-4889, the average time needed for DPD to recover 90% of the baseline activity was close to 90 h (Table 6)
. Because of the profound and prolonged inhibition of DPD activity induced by eniluracil, and given the fact that Grem et al. (9)
highlighted the occurrence of fatal toxicities (notified by CTEP) in patients rechallenged with 5-FU 4 and 5 weeks after eniluracil, a wash-out period of 2 months was recommended for eniluracil. The present data argue in favor of a much shorter and more clinically manageable 1-week wash-out period when using a Ro 09-4889 dose in the proposed 10–30 mg range. We previously reported on a population study showing that DPD activity was a mean 15% lower in women than in men (22)
. To limit the factors of variability, only male subjects were recruited for participation in this study. However, this slight difference in DPD activity does not suggest the need for different Ro 09-4889 dosages in women. The pharmacological and clinical observations reported in the present study may be useful for future development of Ro 09-4889 given in combination with capecitabine. Hattori et al. (23)
recently reported encouraging preliminary preclinical data on human lung carcinoma xenografts with more than additive growth inhibition resulting from the combination capecitabine–Ro 09-4889. Because the activation pathways for Ro 09-4889 are the same as those for capecitabine, it is anticipated that forthcoming clinical investigations with the drug combination will have to explore the possibility of PK interactions between the two drugs.
|
FOOTNOTES
|
|---|
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Requests for reprints: Gérard Milano, Oncopharmacology Unit, Centre Antoine Lacassagne, 33, Avenue de Valombrose, 06189 Nice Cedex 2, France. Phone: 33-(4)-92-03-15-53; Fax: 33-(4)-93-81-71-31; E-mail: gerard.milano{at}nice.fnclcc.fr
Received 9/25/03;
revised 11/27/03;
accepted 12/23/03.
|
REFERENCES
|
|---|
- Tebbutt NC, Cattell E, Midgley R, Cunningham D, Kerr D. Systemic treatment of colorectal cancer. Eur J Cancer, 38: 1000-15, 2002.
- DeMario MD, Ratain MJ. Oral chemotherapy: rationale and future directions. J Clin Oncol, 16: 3362-5, 1999.
- De Bono JS, Twelves CJ. The oral fluorinated pyrimidines. Investig New Drugs, 19: 41-59, 2001.[CrossRef][Medline]
- Milano G, Etienne MC, Pierrefite V, Barberi-Heyob M, Deporte-Fety R, Renée N. Dihydropyrimidine dehydrogenase deficiency and fluorouracil-related toxicity. Br J Cancer, 79: 627-30, 1999.[CrossRef][Medline]
- Beck A, Etienne MC, Cheradame S, et al Wide range for optimal concentration of folinic acid in fluorouracil modulation. Experimental data on human tumor cell lines. Eur J Cancer, 30: 1522-6, 1994.[CrossRef]
- Etienne MC, Cheradame S, Fischel JL, et al Response to fluorouracil therapy in cancer patients: the role of tumoral dihydropyrimidine dehydrogenase activity. J Clin Oncol, 13: 1656-62, 1995.[Abstract/Free Full Text]
- Miwa M, Ura M, Nishida M, et al Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumors by enzymes concentrated in human liver and cancer tissue. Eur J Cancer, 34: 1274-81, 1998.
- Harris BE, Song R, Soong S, Diasio RB. Relationship between dihydropyrimidine dehydrogenase activity and plasma 5-fluorouracil levels with evidence for circadian variation of enzyme activity and plasma drug levels in cancer patients receiving 5-fluorouracil by protracted continuous infusion. Cancer Res, 50: 197-201, 1990.[Abstract/Free Full Text]
- Grem JL, Harold N, Shapiro J, et al Phase I and pharmacokinetic trial of weekly oral fluorouracil given with eniluracil and low-dose leucovorin to patients with solid tumors. J Clin Oncol, 18: 3952-63, 2000.[Abstract/Free Full Text]
- Fischel JL, Etienne MC, Spector T, Formento P, Renée N, Milano G. Dihydropyrimidine dehydrogenase: a tumoral target for fluorouracil modulation. Experimental data. Clin Cancer Res, 1: 991-6, 1995.[Abstract]
- Takebayashi Y, Yamada K, Ohmoto Y, et al The correlation of thymidine phosphorylase activity with the expression of interleukin 1
, interferon and interferon in human colorectal carcinoma. Cancer Lett, 95: 57-62, 1995.[CrossRef][Medline]
- O’Brien TS, Cranston D, Fuggle S, Bicknell R, Harris AL. Different angiogenic pathways characterize superficial and invasive bladder cancer. Cancer Res, 55: 510-3, 1995.[Abstract/Free Full Text]
- Schüller J, Cassidy J, Dumont E, et al Preferential activation of capecitabine in tumor following oral administration in colorectal cancer patients. Cancer Chemother Pharmacol, 45: 291-7, 2000.[CrossRef][Medline]
- Fleming R, Milano G, Thyss A, et al Correlation between dihydropyrimidine dehydrogenase activity in peripheral mononuclear cells and systemic clearance of fluorouracil in cancer patients. Cancer Res, 52: 2899-902, 1992.[Abstract/Free Full Text]
- McLeod HL, Sludden J, Hardy SC, Lock RE, Hawksworth GM, Cassidy J. Autoregulation of 5-fluorouracil metabolism. Eur J Cancer, 34: 1623-7, 1998.
- Reigner B, Verweij J, Dirix L, et al Effect of food on the pharmacokinetics of capecitabine and its metabolites following oral administration in cancer patients. Clin Cancer Res, 4: 941-8, 1998.[Abstract]
- Chazal M, Etienne MC, Renée N, Bourgeon A, Richelme H, Milano G. Link between dihydropyrimidine dehydrogenase activity in peripheral blood mononuclear cells and liver. Clin Cancer Res, 2: 507-10, 1996.[Abstract]
- Poole C, Gardiner J, Twelves C, et al Effect of renal impairment on the pharmacokinetics and tolerability of capecitabine (Xeloda) in cancer patients. Cancer Chemother Pharmacol, 49: 225-34, 2002.[CrossRef][Medline]
- Keith B, Guo XD, Zentko S, et al Impact of two weekly schedules of oral eniluracil given with fluorouracil and leucovorin on the duration of dihydropyrimidine dehydrogenase inhibition. Clin Cancer Res, 8: 1045-50, 2002.[Abstract/Free Full Text]
- Naguib FNM, El Kouni MH, Cha S. Enzymes of uracil catabolism in normal and neoplastic human tissues. Cancer Res, 45: 5405-12, 1985.[Abstract/Free Full Text]
- Takebe N, Zhao SC, Ural AU, et al Retroviral transduction of human dihydropyrimidine dehydrogenase cDNA confers resistance to 5-fluorouracil in murine hematopoietic progenitor cells and human CD34+-enriched peripheral blood progenitor cells. Cancer Gene Ther, 8: 966-73, 2001.[CrossRef][Medline]
- Etienne MC, Lagrange JL, Dassonville O, et al Population study of dihydropyrimidine dehydrogenase in cancer patients. J Clin Oncol, 12: 2248-53, 1994.[Abstract/Free Full Text]
- Hattori K, Kohchi Y, Oikawa N, et al Design and synthesis of the tumor-activated prodrug of dihydropyrimidine dehydrogenase (DPD) inhibitor, RO0094889 for combination therapy with capecitabine. Bioorg Med Chem Lett, 13: 867-72, 2003.[CrossRef][Medline]
Top
ABSTRACT
INTRODUCTION
, the observed values; line (curve), the model-predicted relationship between Ro 09-4889 dose and DPD Emin levels as a percentage of baseline. Arrow, the 20-mg dose. B, Mean uracil AUC48 h (area under the plasma uracil concentration-time curve from time zero to 48 h).