Effect of Food on the Pharmacokinetic Behavior of the Potent Oral Taxane BMS-275183

Purpose: BMS-275183 is a potent oral paclitaxel analogue that previously showed promising activity. The goal of the present trial was to investigate whether food affects the pharmacokinetics of BMS-275183. Additionally, we evaluated its pharmacokinetic variability using flat-fixed dosing compared with dosing individualized by body surface area (BSA).

Patients and Methods: The patients were treated with 200 mg of BMS-275183 under fasting condition (A), after a standard low-fat meal (B), or after a high-fat meal (C). The patients were randomized to one of six treatment sequences (ABC, ACB, BAC, BCA, CAB, or CBA). The fourth (D) and consecutive weekly doses were normalized by BSA and consisted of 200 mg/m². Pharmacokinetic sampling was done up to 72 hours after the first four doses and analyzed with a validated liquid chromatography/mass spectrometry assay.

Results: A total of 31 patients were treated. Pharmacokinetic data were available for 26 patients (A and C), 24 patients (B), and 21 patients (D). Compared with administration under fasted conditions, a decrease of 39% and 63% in the maximal observed drug concentration was observed when BMS-275183 was administered after a low-fat and a high-fat meal, respectively. There was no change in systemic exposure as measured by the area under the plasma concentration versus time curve extrapolated to infinity (AUC_inf). No apparent relationship was observed between AUC_inf and BSA for either the 200 mg or the 200 mg/m² regimen. BMS-275183 was well tolerated with grade 3 and 4 toxicity in eight patients. One partial response was observed in a non–small cell lung cancer patient.

Conclusions: Food intake does not affect the pharmacologic exposure to BMS-275183. BMS-275183 can be given orally by flat dosing instead of BSA-normalized dosing.

BMS-275183 is a novel, orally administered taxane analogue that has shown considerable antitumor activity in non–small cell lung cancer and other tumor types, with an overall response rate of 24% in a recently conducted phase I trial (1). This drug is a C-4 methyl carbonate analogue of paclitaxel containing modifications to the side chain. Like paclitaxel, its mechanism of action involves the stabilization of microtubules (2). The oral bioavailability in humans is ∼24%, and there is no need for premedication to prevent hypersensitivity reactions (3). The main and dose-limiting toxicity of BMS-275183 in a phase I trial investigating a weekly dosing regimen was peripheral neuropathy, whereas other dose-limiting toxicities consisted of fatigue, diarrhea, and neutropenia and did not occur frequently on a weekly dosing schedule. Promising activity was observed in non–small cell lung cancer and prostate carcinoma (1).

Thus far, BMS-275183 has been administered to patients in a fasting state. The presence of food can alter gastric pH, gastric emptying, gastrointestinal motility, and bile secretion and may also affect the biotransformation of drugs in the gastrointestinal tract wall and liver. Therefore, knowledge of the effect of food intake on the pharmacokinetic parameters of BMS-275183 is needed. Another important issue that has been debated for chemotherapeutic agents is whether dosing based on body surface area (BSA) is clinically relevant and better than flat dosing (4). Several studies have indicated that flat-fixed dosing does not increase the interpatient variability of pharmacokinetic parameters compared with BSA-based dosing regimens for cisplatin (5), irinotecan (6), and oral topotecan (7). In particular, for an oral drug such as BMS-275183, flat-fixed dosing would be more practical and convenient than BSA-based dosing. The primary goal of the current phase I trial was to assess the effect of food on the pharmacokinetics of weekly BMS-275183 in patients with advanced solid tumors. The secondary objectives were to assess the safety and tolerability of BMS-75183, to describe any evidence of antitumor activity, and to evaluate the pharmacokinetic variability of BMS-275183 with flat-fixed dosing compared with BSA-normalized dosing.

Patient population. Adult patients with a histologically or cytologically confirmed diagnosis of a solid tumor not amenable to standard therapy were eligible for this trial. Eligibility included an Eastern Cooperative Oncology Group performance status of 0 or 1; a life expectancy of at least 3 mo; and adequate renal, liver, and bone marrow function, defined as serum creatinine <1.5 × the institutional upper limits of normal, bilirubin <1.5 × upper limits of normal, alanine aminotransferase <2.5 × upper limits of normal, and absolute neutrophil count >2.0 × 10⁹/L, and platelets >100 × 10⁹/L. Prior immunotherapy, radiotherapy, or chemotherapy (including taxanes) was allowed, provided that the treatment-free interval was at least 4 wk (6 wk for mitomycin C or nitrosoureas) and radiotherapy involved no more than 25% of the bone marrow–containing skeleton (pelvis and lumbar spine). Women of child-bearing potential had to have a negative serum or urine pregnancy test before entry into the study, and an adequate method of contraception had to be used. Disease had to be evaluable but was not required to be measurable. The exclusion criteria consisted of the presence of an uncontrolled or significant cardiovascular or pulmonary disease; a serious uncontrolled medical disorder or active infection; active brain metastases; superior vena cava syndrome or tumor obstruction of a vital organ; grade ≥2 neuropathy or a prior history of grade 3 neuropathy (according to the National Cancer Institute Common Toxicity Criteria version 3.0); inability to swallow capsules; known history of gastrointestinal disease, surgery, or malabsorption that could potentially affect the uptake of the study drug; concomitant medication known to inhibit or induce drug metabolism by interference with cytochrome P450 CYP3A4; concurrent chemotherapy; any psychiatric or other disorders, such as dementia, which would impair compliance; and prisoners or subjects compulsory detained for treatment of a psychiatric or physical illness. The protocol was approved by the ethics committees of the participating institutions, and all patients gave written informed consent before study entry.

Study design. A total of 24 to 30 patients were assigned to receive a weekly fixed dose of 200 mg BMS-275183 under fasting conditions (treatment A), after a standard low-fat breakfast (treatment B), and after a standard high-fat breakfast (treatment C). The patients were randomized to one of six treatment sequences (ABC, ACB, BAC, BCA, CAB, or CBA). The randomization took place according to a computer-generated randomization scheme prepared by a randomization coordinator within the Drug Supply Management of Bristol-Myers Squibb. Each treatment sequence cohort consisted of at least four patients. The single oral dose of 200 mg was equivalent to 115 mg/m² for the population average BSA of 1.73 m². The selection of this dose was based on previous clinical experience with this compound in which 200 mg/m² given on a weekly schedule was determined to be the maximal tolerated dose (1) and the safety consideration that food may increase the exposure to BMS-275183. The fourth and consecutive weekly doses were individualized on BSA. To offer the patients the best chance for potential therapeutic benefit, this dose consisted of 200 mg/m². One cycle consisted of 4 wk of treatment, and there was no interval between the cycles. Blood samples for pharmacokinetic monitoring were taken after the first four doses. Patients who did not complete the pharmacokinetic part of the trial had to be replaced.

Drug administration. The study drug was provided as 5- and 25-mg capsules containing BMS-275183 solubilized in polyethylene glycol 400/polyethylene glycol 1450 with Gelucire 44/14 as the excipient system at a loading level of 4% (w/w). In the individualized-dosing part of the trial, the calculated dose was rounded to the nearest 5 mg. The drug was administered 30 min after the start of a standard low-fat or high-fat breakfast, or in fasting condition. The patients ingested the capsules with ∼240 mL of water and the administration time was encouraged to be within 10 min. The patients fasted at least 10 h before starting breakfast or drug administration and remained fasting for 4 h post-dose. Standard low-fat and high-fat breakfasts were designed according to Food and Drug Administration guidelines (8). The standard low-fat breakfast consisted of 2 slices of toasted white bread, 1 teaspoon (4.75 g) of low-fat margarine, 1 tablespoon (14 g) of jelly, and 8 fl oz (236 mL) of skim milk (319 calories, 8.2 g fat, 49 g carbohydrates, 12.6 g protein). The standard high-fat breakfast consisted of 2 eggs fried in butter, 2 slices of toasted white bread, 1 tablespoon (14 g) of butter, 1 tablespoon (14 g) of jelly, 2 strips of bacon, 4 oz (113 g) of hash brown potatoes, and 8 fl oz (236 mL) of whole milk (945 calories, 54.6 g fat, 82.4 g carbohydrates, 32.1 g protein). No standard prophylactic medication for hypersensitivity reactions was given, nor were antiemetics prophylactically prescribed. The patients were planned to receive at least two cycles (8 wk), and the treatment was allowed to continue if this was considered to be in the best interest of the patient.

Patient evaluation. Pretreatment evaluation was done within 2 wk of study entry and included a complete history and physical examination (including vital signs and assessment of body weight and performance status), urinalysis (including a pregnancy test in women of child-bearing potential), tumor assessment, chest X-ray, 12-lead electrocardiogram, a full blood count, serum chemistries (including sodium, potassium, chloride, phosphorus, magnesium, calcium, blood urea nitrogen, creatinine, glucose, albumin, alkaline phosphatase, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, γ-glutamyltransferase, and total bilirubin), and the determination of tumor markers when known to be elevated. In women of child-bearing potential, a pregnancy test was repeated every two cycles. During the first course, physical examination, urinalysis, full blood counts, and serum chemistries were repeated weekly. From the second course onward, full blood counts were done weekly, whereas physical examination, urinalysis, and serum chemistries were done before each course. Toxicity was assessed continuously from the first drug administration through at least 30 d after treatment discontinuation or until drug-related toxicities had resolved or were deemed irreversible. Side effects were graded according to the National Cancer Institute Common Toxicity Criteria version 3.0. Electrocardiograms to monitor the potential prolongation of the QTc interval by BMS-275183 were repeated 1, 2, 6, and 24 h after drug administration in the first cycle and when patients went off the study.

Response criteria. The response to therapy was assessed every other cycle by X-ray, computerized tomography scan, magnetic resonance imaging scan, or physical examination (the same technique was required to assess the same lesion). Tumor markers were only supportive and not used for response assessment. The tumor response was measured according to the Response Evaluation Criteria in Solid Tumors criteria (9). The response duration was calculated from the first documentation of response until the first objective signs of progressive disease. All patients who received BMS-275183 were considered evaluable for response, except for patients without measurable disease at baseline who did not progress or achieve a complete response and patients who did not have tumor reassessment for reasons other than drug toxicity, early death, or progression.

Blood sampling and pharmacokinetic analysis. Pharmacokinetic monitoring was done after all the drug administrations of cycle 1. Blood samples of 5 mL each were collected in potassium EDTA (K₃EDTA) Vacutainers (Becton Dickinson) up to 72 h after drug administration (time points: 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 24, 48, and 72 h). The tube was placed on ice for 10 to 30 min and centrifuged for 5 min at 2,000 × g at 0°C to 4°C; the plasma was separated and stored at −20°C until analysis. The BMS-275183 concentration was determined with the use of a validated liquid chromatography/mass spectrometer (assay range, 0.1-20 ng/mL) as described previously (1).

Pharmacokinetic profiles were evaluated by noncompartmental analysis with the software package Kinetica version 4.2 (InnaPhase Corporation). The elimination half-life (t_1/2) was assessed from the elimination rate constant, estimated by the linear regression of the terminal phase of the semilogarithmic concentration versus time curve. The area under the plasma concentration versus time curve (AUC) was estimated by the linear-logarithmic trapezoidal method up to the last measured concentration time point and extrapolated to infinity (AUC_inf). The maximal observed drug concentration (C_max) and the time to maximal observed drug concentration (T_max) were obtained directly from experimental data.

Statistical analysis. The number of patients was not based on statistical power considerations. However, the data from 24 subjects were expected to provide ∼90% confidence that the point estimate for the ratio of population geometric means of either a low-fat or a high-fat meal to fasted condition was within 33% of the true value of C_max and within 29% of the true value of AUC_(0-T). These calculations assumed that C_max and AUC were log-normally distributed with intrasubject variations of 0.57 for log (C_max) and 0.50 for log (AUC), based on data from a previous study.⁴

Descriptive statistics were used for baseline characteristics, safety assessment, and pharmacokinetic parameters (C_max, T_max, AUC_inf, AUC_(0-T), t_1/2). The software package SAS (version 8.2 for Unix) was used for statistical analysis. ANOVA was used to estimate intrasubject variability in AUC_inf.

To assess the effect of food on pharmacokinetic parameters of BMS-275183 following oral administration, ANOVA was done on log (C_max), log (AUC_(0-T)), and log (AUC_inf). The factors in each group were sequence group, subject within sequence, period, and treatment. Point estimates and 90% confidence intervals for means and differences between means on the log-scale were exponentiated to obtain estimates for geometric means and ratios of geometric means on the original scale. Following the U.S. Food and Drug Administration guidance on food-effect bioavailability and fed studies (10), the absence of an effect of food on pharmacokinetic parameters would be concluded if the 90% confidence intervals for the ratio of population geometric means were contained within 80% and 125%. No adjustments were made for multiplicity.

To assess the effect of BSA on the apparent oral clearance of BMS-275183 when this compound was given as a fixed versus BSA-normalized dose, scatter plots and linear regressions of apparent oral clearance versus BSA for the fasted fixed-dose regimen and the fasted mg/m²-dose regimen were reviewed.

Patients and treatment. Between November 2003 and December 2004, 32 patients were enrolled at one site in the United States and one site in the Netherlands. Among the 32 patients enrolled, 31 were treated and 1 patient did not receive any study medication for reasons not related to the study drug. The patient characteristics of all the treated patients are summarized in Table 1. In summary, the study population was well balanced for gender, ranged in age from 33 to 74 years, and had mainly an Eastern Cooperative Oncology Group performance status of 1 at baseline (87%). There was a large subgroup of non–small cell lung cancer patients (58%), and a majority of patients (84%) had received at least two chemotherapy regimens. All treated patients were included in the safety and efficacy analysis. Pharmacokinetic data were available from 26 patients, and 5 patients were excluded from statistical pharmacokinetic analysis because of missing exposure data. The median number of courses of BMS-275183 administered was 1 (range, 1-11 courses).

Effect of food on pharmacokinetic parameters of BMS-275183. The patients were randomized to receive weekly doses of 200 mg BMS-275183 on each of three different occasions: after a fast of 10 hours (A), 30 minutes after a standard low-fat breakfast (B), and 30 minutes after a standard high-fat breakfast (C). Complete pharmacokinetic data were available for 26 patients on treatments A and C, and for 24 patients on treatment B. Table 2 summarizes all the pharmacokinetic parameters. We observed a relatively high interpatient variability of 66% to 81% for AUC_inf, depending on the treatment arm. As presented in Table 3, C_max decreased significantly by 39% after a low-fat breakfast (B) compared with fasting conditions (A). However, overall exposure as measured by AUC_inf and AUC_(0-T) was similar, and the 90% confidence intervals were entirely contained within the “no effect” interval of 80% to 125% specified in the guidance on food-effect bioavailability and fed studies from the U.S. Food and Drug Administration. After a high-fat breakfast (C), a similar pattern was observed: C_max decreased significantly by 63% compared with that under fasting conditions, whereas AUC_inf and AUC_(0-T) did not show substantial changes. The median T_max in fasting conditions was 1.0 hour but delayed to 1.5 and 2.0 hours after a low-fat and a high-fat breakfast, respectively (Table 2). The carryover effect was not statistically significant (data not shown). These results indicate that food does not affect the exposure to BMS-275183.

Flat-fixed versus BSA-based dosing. A secondary objective of the trial was to investigate whether individualized dosing based on BSA gives less pharmacokinetic variability when compared with flat-fixed dosing. A total of 21 patients completed pharmacokinetic blood sampling after a fixed dose of 200 mg as well as after an individualized dose of 200 mg/m². Although the interpatient variability decreased from 84% to 66% when dosing was based on BSA instead of on a fixed dose, the linear regressions of apparent oral clearance versus BSA for both the fasted fixed-dose regimen (R = 0.054) and the fasted mg/m²-dose regimen (R = 0.123) failed to show evidence of a correlation between apparent oral clearance and BSA (Fig. 1). These results suggest no advantage in administering BMS-275183 based on BSA.

Adverse events induced by BMS-275183.Table 4 summarizes the drug-related adverse events. Overall, the most frequent treatment-related adverse events were fatigue (52%), diarrhea (42%), nausea (42%), and alopecia (36%). In addition, a total of 8 (26%) patients were reported to have sensory and/or motor neuropathy. Severe hematologic toxicity did not occur frequently: grade 3 or 4 neutropenia was observed in 3 (10%) patients, grade 3 or 4 thrombocytopenia in 2 (6%) patients, and grade 3 or 4 anemia in 2 (6%) patients. In total, 5 patients discontinued treatment because of a drug-related adverse event, consisting of grade 3 sensory neuropathy in course 5 (n = 1), grade 3 muscular weakness in course 2 (n = 1), grade 2 peripheral neuropathy in course 11 (n = 1), grade 2 mucosal inflammation and grade 1 sensory neuropathy in course 1 (n = 1), and grade 2 sensory neuropathy in course 2 (n = 1). Electrocardiogram monitoring showed a mean QTc interval of 0.419 second at baseline, which did not change significantly after dosing (mean QTc intervals after 1, 2, 6, and 24 hours were 0.411, 0.416, 0.418, and 0.422 second, respectively). These results suggest that BMS-275183 does not have any effects on cardiac rhythm.

Efficacy results. Of the 31 patients treated in this study, 1 patient with non–small cell lung cancer had a partial response (duration, 3.5 months). This patient was previously treated with carboplatin-docetaxel and gefitinib and had a partial response on the taxane-containing treatment regimen. In addition, 2 patients had a long-lasting stable disease as best clinical response while on BMS-275183 therapy: 1 patient with prostate carcinoma (6 months) and 1 patient with a mucinous carcinoma of the appendix (10 months).

In the present clinical study, we have shown that the oral taxane BMS-275183 can be administered without restrictions with respect to food intake. This is an important finding and increases the convenience and possibilities of application of this novel drug. In addition, our trial provides evidence for a fixed dosing of BMS-275183 instead of the more commonly used BSA-based dosing. This finding is in contrast to i.v. paclitaxel, for which it was shown that drug disposition is significantly related to BSA (11). This difference is possibly due to an association of i.v. administered paclitaxel in circulation with Cremophor EL micelles, of which the distribution is linked to total blood volume and, thus, BSA (11). For BMS-275183 capsules, no Cremophor EL is used.

BMS-275183 was relatively well tolerated in this trial, with 8 of 31 patients experiencing grade 3 or 4 toxicity, including only 1 case of grade 3 neurotoxicity. In our previous trial with a weekly dosing regimen of BMS-275183, we observed a 13% incidence of grade 3 neuropathy, which was its main dose-limiting toxicity (1). In the present study, patients were treated with a relatively low dose during the first course to anticipate a potential increased absorption by food intake. This lower dose may explain the apparent better tolerability observed in the present trial. A third phase I trial with BMS-275183 was conducted, investigating a twice-weekly dosing regimen (12). From this latter study, it was concluded that BMS-275183 is preferably given in a twice-weekly schedule.

The relatively high interpatient variability for BMS-275183 observed in this trial is not unprecedented and was also found in our previous studies (1, 12). This may be due to variation in the absorption of the drug, combined with individual differences in metabolism. BMS-275183 is metabolized by cytochrome P450 CYP3A4 and is a substrate for MDR-1 and MRP-1, but not for BCRP (13). Concomitant interacting medication and genetic polymorphisms may contribute to the observed high interpatient variability. The concomitant use of CYP3A4-modifying drugs was prohibited in the current trial, but drugs modifying MDR-1 and MRP-1 were not excluded, nor were studies undertaken to investigate the effect of genetic polymorphisms on the absorption metabolism of BMS-275183. We do not expect, however, that these factors will significantly influence the results of our study on the effect of food on the pharmacokinetic behavior of BMS-275183 because individual patients were studied in both fasting and fed conditions. Future trials may address this important issue.

In the current trial, we observed one partial response in a non–small cell lung cancer patient. This confirms our previous finding that BMS-275183 is active in this tumor type. However, in our previous trials, we observed higher overall response rates of 24% (weekly administration) and 13% (twice-weekly dosing regimen), with most responses in non–small cell lung cancer and prostate carcinoma (1, 12). Although there were hints of activity of BMS-275183 in taxane-resistant tumors in a previously conducted phase I trial (1), most responses were observed in taxane-naïve or taxane-responsive patients (1, 12). In the present trial, many patients were pretreated with a taxane (13% with paclitaxel and 58% with docetaxel). This may explain the relatively low response rate observed in the present study.

In summary, BMS-275183 is a potent novel taxane analogue that can be administered orally without food restrictions. There is no advantage of BSA-normalized dosing over flat-fixed dosing of BMS-275183.

P.M. LoRusso has received grants from Amgen, Array BioPharma, Ariad, AstraZeneca, Boeringer Ingelheim, Bristol-Myers Squibb, Endocyte, Exelixis, Genentech, GlaxoSmithKline, ImClone, Merck, Nereus, Novartis, Pfizer, Roche, Sanofi Aventis, and Ziopharm; is on the speakers' bureau of Aventis, Genentech, and GlaxoSmithKline; and is a consultant for Takeda, AstraZeneca, Pfizer, and Genentech.