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Pharmacokinetic Study of Single Doses of Oral Fludarabine Phosphate in Patients With "Low-Grade" Non-Hodgkin's Lymphoma and B-Cell Chronic Lymphocytic Leukemia

From the Imperial Cancer Research Fund Medical Oncology Unit, St Bartholomew's Hospital, London, Department of Haematology, Royal Bournemouth Hospital, Bournemouth, Department of Haematology, Taunton and Somerset Hospital, Taunton, and Department of Oncology, Queen Elizabeth Hospital, Birmingham, United Kingdom; and Pharmacokinetics Therapeutics and Clinical Development Oncology, Schering AG, Berlin, Germany.

Address reprint requests to James M. Foran, MD, Imperial Cancer Research Fund Medical Oncology Unit, Department of Medical Oncology, 45 Little Britain, 2nd Floor, St Bartholomew's Hospital, London, EC1A 7BE United Kingdom; email foran{at}icrf.icnet.uk

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: Fludarabine phosphate (F-AMP), a purine analog, requires daily intravenous administration. A pharmacokinetic study of an oral formulation (10 mg immediate-release tablet) was undertaken in patients with "low-grade" non-Hodgkin's lymphoma and B-cell chronic lymphocytic leukemia.

PATIENTS AND METHODS: Oral F-AMP was incorporated into the "conventional" treatment schedule. Single oral trial doses of 50, 70, and 90 mg of F-AMP were given on the first day of three cycles of treatment; a comparative 50-mg intravenous trial dose was given on the first day of the fourth cycle. Intravenous F-AMP (25 mg/m²) was given on days 2 to 5 at 4-week intervals. Pharmacokinetic samples taken after each trial dose were analyzed for plasma 2-fluoro-arabinofuranosyl-adenine (2F-ara-A) concentration (its main metabolite); area under the curve 0 to 24 hours (AUC(0-24h)) and maximum concentration (C_max) were calculated. Eighteen patients received all three oral trial doses, and bioavailability was determined in 15 patients who completed four courses of therapy.

RESULTS: Oral administration of F-AMP resulted in a dose-dependent increase in C_max and AUC(0-24h) of 2F-ara-A and achieved an AUC(0-24h) similar to intravenous administration, although at a lower C_max. The linear increase in mean AUC(0-24h) by factors of 1.36 ± 0.22 (mean ± SD) and 1.72 ± 0.31 corresponded well with the increase in oral dose from 50 to 70 mg (factor of 1.4) and 90 mg (factor of 1.8), respectively. Bioavailability (approximately 55%, with low intraindividual variation) and time to C_max were dose independent.

CONCLUSION: Oral doses of F-AMP can achieve an AUC(0-24h) of 2F-ara-A similar to intravenous administration, with dose-independent bioavailability. The tablet will greatly enhance the use of F-AMP in a palliative setting.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
FLUDARABINE PHOSPHATE (F-AMP), a purine analog antimetabolite, is a water-soluble, fluorinated derivative of vidarabine (ara-A) that is relatively resistant to adenosine deaminase. As reviewed by Adkins et al¹ and Plunkett et al,² it is rapidly metabolized after administration to 2-fluoro-arabinofuranosyl-adenine (2F-ara-A) by serum phosphatases, after which it is concentrated intracellularly and phosphorylated to its active metabolite, 2-fluoro-arabinofuranosyl-adenosine-triphosphate. Its mode of action is thought to be related to inhibition of DNA and RNA synthesis by termination of chain elongation after incorporation into DNA; it may also inhibit DNA and RNA polymerases. It has been shown to induce apoptosis of transformed cell lines in vitro.

F-AMP was first tested in patients with acute leukemia, with the drug administered by continuous intravenous infusion and at high doses (125 to 150 mg/m²/d for 5 to 7 days), resulting in severe and delayed neurotoxicity.^3,4 Later reintroduced into the treatment of recurrent B-cell chronic lymphocytic leukemia (B-CLL) at a lower dose (25 mg/m²/d for 5 days) and given approximately monthly, it was associated with relatively high overall response and complete response (CR) rates.⁵ Significant neurotoxicity has been rare at this dose and schedule. More recently, F-AMP has been evaluated in patients with previously treated "low-grade" B-cell non-Hodgkin's lymphoma (Lg-NHL; Kiel classification and National Cancer Institute working formulation),^6,7 with reported response rates of 31% to 61%.^8-11 In patients with newly diagnosed follicular lymphoma, the overall and CR rates are 65% and 37%, respectively.¹²

At present, F-AMP is available only as an intravenous formulation. An oral formulation (10-mg immediate-release tablet) has recently been developed, on the assumption that tablets are easier and cheaper to administer than intravenous injections. Therefore, a pharmacokinetic trial was performed after single oral doses of F-AMP in patients with previously treated B-CLL or Lg-NHL undergoing treatment with intravenous F-AMP. The results form the basis of this article.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
A prospective, open-label, three-way randomized cross-over trial was performed at four centers in the United Kingdom. The primary aim was to investigate single-dose pharmacokinetics after oral administration of 50, 70, and 90 mg of F-AMP, with particular interest in the dose dependence of 2F-ara-A, its main plasma metabolite. The secondary pharmacokinetic aim was to calculate the systemic availability of 2F-ara-A after oral administration of F-AMP compared with that after a 50-mg intravenous dose. Response rates and the safety profile of the combination of 1 day of oral F-AMP followed by 4 days of intravenous F-AMP were noted. The trial was approved by the ethics committee at each participating institution. Informed, written consent was obtained from each patient.

The study design is outlined in Table 1. Oral F-AMP was incorporated into the "conventional" 5-day schedule of intravenous treatment. Patients received F-AMP in 5-day cycles at 4-week intervals. The first day of the first four cycles constituted the "trial dose." For the first three cycles, patients received 50, 70, or 90 mg of oral F-AMP after an overnight fast in random order, in the form of 10-mg tablets. On the first day of the fourth cycle, patients received a 50-mg intravenous trial dose of F-AMP, given by 30-minute infusion. Blood samples for analysis of 2F-ara-A were collected after each trial dose. For the remaining 4 days of each treatment cycle, patients received intravenous F-AMP at the standard daily dose (25 mg/m²). Any remaining treatment cycles (ie, five or more) involved the standard intravenous dose (25 mg/m²/d on days 1 to 5) without pharmacokinetic sampling. The F-AMP was provided by Schering Health Care Limited (Burgess Hill, West Sussex, United Kingdom).

The intent was for patients to receive four cycles of F-AMP unless progression of B-CLL or NHL was documented or the patient was withdrawn for toxicity. Formal evaluation of response was performed at that time; patients with evidence of response could receive up to eight cycles. Patients with progressive lymphoma at any point were immediately withdrawn from the protocol.

Patients with previously treated B-CLL or Lg-NHL (Kiel classification and National Cancer Institute working formulation)^6,7 and a World Health Organization performance status of 0, 1, or 2 were eligible. The intent was for 18 patients to receive each of the first three cycles to evaluate the dose dependence of orally administered F-AMP; patients who dropped out before receiving all three oral doses were replaced. In total, 27 patients were treated; their clinical characteristics are listed in Table 2. Of note, most patients (22) had previously received chlorambucil on at least one occasion, five patients had previously been treated with intravenous F-AMP, and two patients had previously been treated with cladribine.

Standard definitions of response were applied for patients with Lg-NHL (for patients with B-CLL, responses were defined according to International Workshop on Chronic Lymphocytic Leukemia criteria¹³). CR was defined as disappearance of all signs of disease by physical examination, radiologic examination, and bone marrow trephine biopsy, with a normal peripheral blood count; partial response (PR) was defined as regression of all measurable and assessable disease by more than 50% (by cross-sectional area), without the appearance of any new manifestations; stable disease was defined as regression of less than 50% in assessable sites of disease or progression of existing lesions by less than 25%; and progressive disease was defined as increase in existing disease by more than 25% or the appearance of any new manifestations of lymphoma.

Pharmacokinetic Sampling and Assay
Heparinized blood samples (5 mL) were drawn through a peripheral venous cannula up to 24 hours after each trial dose at the following times: time 0 (baseline predose); 15, 30, 40, 50, 60, and 90 minutes; and 2, 3, 4, 6, 8, 10, and 24 hours. Plasma was promptly separated and stored at -20°C. 2F-ara-A plasma concentration was measured using a validated high-performance liquid chromatography method with fluorescence detection after derivatization with chloracetaldehyde, according to the method described by Kemena et al.¹⁴ Pharmacokinetic parameters were calculated by means of the validated software TOPFIT (version 2.1ß, Thomae, Gödecke, Schering), using a noncompartmental approach.

The primary parameters for determining the dose dependence of 2F-ara-A in the 18 patients who received each of the three oral trial doses were the area under the plasma concentration-time curve, measured for 24 hours after the administration of each day-1 trial dose (AUC(0-24h)), and the maximum plasma concentration (C_max) after each trial dose. Intraindividual comparisons of the AUC(0-24h) were used to calculate the bioavailability of the three oral trial doses compared with that of the 50-mg intravenous trial dose in 15 patients who completed four courses of therapy. In previous trials, the terminal half-life of orally administered F-AMP was approximately 22 to 29 hours.^15-17 The necessity for daily intravenous dosing inherent in the trial design (ie, 24 hours after the oral trial dose) precluded an accurate estimate of half-life in this study. Therefore, the duration of half-maximum plasma levels has been calculated instead.

Statistical Methods
Descriptive statistics (number, arithmetic mean, geometric mean, SD, and coefficient of variation [CV]) were calculated for all pharmacokinetic parameters separately for the three oral trial doses and the intravenous trial dose. Tests for dose linearity and dose dependence were performed using general linear modeling techniques, including terms for dose, sequence, period, and deviation from linearity.¹⁸

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Pharmacokinetics
In total, 23, 21, and 26 patients received the 50-, 70-, and 90-mg oral trial doses, respectively; 18 patients received all three oral trial doses, and 15 patients received all four trial doses (ie, three oral and one intravenous). Measurement of 2F-ara-A plasma concentration demonstrated a clear dose-dependent increase in the C_max and the AUC(0-24h) with increasing doses of oral F-AMP (Fig 1 and Table 3). In patients who received all three oral trial doses (n = 18), there was a linear increase in the mean AUC(0-24h) by factors of 1.36 ± 0.22 (mean ± SD) and 1.72 ± 0.31, which corresponded well with the increase in dose by factors of 1.40 (70 mg) and 1.80 (90 mg) (Fig 2). The AUC(0-24h) attained after the 90-mg oral dose of F-AMP was similar to that attained after the 50-mg intravenous dose, but at a substantially lower C_max. The C_max after the 90-mg oral dose was similar to that seen at 30 to 60 minutes after the termination of the intravenous (50-mg) infusion.

View larger version (14K): [in this window] [in a new window]   Fig 1. Mean plasma concentration-time profiles after doses of 50 mg (|s4), 70 mg (), and 90 mg (|a9) of F-AMP administered orally (n = 18) and 50 mg () of F-AMP administered intravenously (n = 15). For clarity, the SD is noted only on the 90-mg oral curve.

View larger version (25K): [in this window] [in a new window]   Fig 2. Plasma 2F-ara-A AUC(0-24h) ratio after doses of 50, 70, and 90 mg of F-AMP administered orally (n = 18). The bold lines represent the mean AUC ratio (|B5) and the dose factor (|B).

2F-ara-A was detected in plasma by 15 to 30 minutes in each patient after each oral dose, with the exception of a single patient after the 70-mg dose, in whom it was detected at 50 minutes. The time to C_max was independent of the oral dose, occurring at 1.1 to 1.2 hours after administration of oral F-AMP. In the 15 patients who received all four trial doses, the systemic availability of oral F-AMP was calculated using the AUC(0-24h) on an intraindividual basis compared with the intravenous trial dose. The mean bioavailability was approximately 55% and was independent of dose (56%, 54%, and 54% after the 50-, 70-, and 90-mg oral trial doses, respectively) (Table 3). The overall bioavailability demonstrated low intraindividual variation (Fig 3).

View larger version (21K): [in this window] [in a new window]   Fig 3. Intraindividual comparison of 2F-ara-A bioavailability after oral administration of 50, 70, and 90 mg of F-AMP compared with a 50-mg intravenous dose (n = 15). Mean bioavailability is represented by the bold line.

Toxicity
A total of 98 cycles of F-AMP was given to 27 patients; most toxicity was related to myelosuppression or infection. There were 28 and 13 episodes of World Health Organization grade 3 or 4 granulocytopenia and thrombocytopenia, respectively. Of 27 episodes of infection, only four were grade 3 or 4. Three patients developed grade 3 nausea/vomiting and diarrhea, and two others developed grade 3 alopecia. There was no instance of grade 3 or 4 neuropathy. The oral component of treatment was not associated with any particular toxicity in this cohort.

Nine patients with Lg-NHL were withdrawn early (ie, before receiving the first three cycles of F-AMP) for the following reasons: progressive disease (n = 2); death (n = 1); and "adverse events" (n = 6). The latter included the following: thrombocytopenia (n = 2); rapid progression of disease while receiving the first course of F-AMP, requiring the addition of intravenous cyclophosphamide (n = 1; inassessable for response); fever and abnormal liver function tests (n = 1); chest pain (n = 1); and edema/anasarca (n = 1).

Response to Therapy
Two patients with Lg-NHL were withdrawn from the study before any assessment of response; five others achieved CR, and four achieved PR. The overall response rate (CR plus PR) for the 18 assessable patients with Lg-NHL, therefore, was 50%. Five patients with B-CLL responded to therapy, although none achieved CR; the overall response rate in this group was 71% (five of seven).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Although F-AMP has significant activity as a single agent in Lg-NHL and B-CLL, its use is hampered by the need for daily intravenous administration. This study is the first to demonstrate that single oral doses of F-AMP given as 10-mg immediate-release tablets result in a clear dose-dependent systemic exposure to 2F-ara-A (its main plasma metabolite) and that oral dosing can achieve a similar AUC(0-24h) to intravenous dosing. Furthermore, it has shown a dose-independent systemic availability (approximately 55%). Accumulation from cycle to cycle was not seen. In the management of patients with incurable disease with a long natural history, an equivalent and reliable oral formulation of F-AMP could significantly improve the feasibility of therapy.

Bioavailability ranged from 30% to 80% between patients, although a low intraindividual variation in bioavailability was seen after the three oral doses (Fig 3). The latter finding suggests that the differences between patients may be related more to the individual metabolism of F-AMP than to the absorption characteristics of the oral (tablet) preparation. Additionally, interpatient variability in AUC(0-24h) after each oral dose was 29% to 33% (CV), similar to that seen after intravenous dosing (CV, 27%), again suggesting that the oral preparation contributes little to the existing pharmacokinetic variability between patients. Coupled with the predictable intraindividual bioavailability after oral F-AMP, this variation in AUC(0-24h) suggests that the interindividual variation in oral bioavailability is not likely to present a new or significant problem in clinical use.

The data in this study are consistent with those of previous reports of aqueous F-AMP (ie, drinking the intravenous solution), with a similar bioavailability (range, 57% to 77%) and similar absorption characteristics and peak plasma concentrations.^15-17 On the basis of these earlier data and an interim analysis of the relationship of dose to plasma 2F-ara-A concentration in this study, a multicenter phase II trial of oral F-AMP has been conducted in patients with previously treated B-CLL, at a dose of 40 mg/m²/d for 5 days, given every 4 weeks (approximately equivalent to 25 mg/m² intravenously). A study of its absorption after a standard breakfast (National Cancer Institute) is also in progress.

Although an AUC(0-24h) similar to that seen with intravenous administration of F-AMP can be achieved with oral dosing, the C_max was substantially lower with the oral formulation. Although granulocytopenia has been reported to correlate with the AUC,¹⁹ it is possible that some toxicity (especially neurologic) could be avoided with oral dosing if these effects are related to the C_max rather than the AUC. Demonstration of this effect, and of equivalent efficacy at a lower C_max, must await the results of an ongoing phase II trial.

Most toxicity in this trial was related to myelosuppression and infection; this is similar to that seen with the intravenous formulation. Although no particular toxicity was noted with the oral dose, the number of patients treated was small and systemic exposure to the oral formulation was limited to the first day of the first three cycles (ie, three doses in total); therefore, most effects would be expected to be the result of intravenous treatment. Similarly, the response rate mirrors that seen with intravenous F-AMP^5,8-11; again, the number of patients treated was small, with limited exposure to the oral formulation. Equivalent activity and toxicity of single-agent oral F-AMP await confirmation.

Intravenous F-AMP in combination with either mitoxantrone^20,21 or cyclophosphamide^22,23 has demonstrated high response rates and complete remission rates in patients with Lg-NHL; indeed, these combinations may be more effective than F-AMP as a single agent.²⁴ An equivalent oral formulation of F-AMP, possibly combined with an oral alkylating agent and/or anthracycline (eg, idarubicin), could make such combination therapy easier and cheaper to deliver to outpatients.

In conclusion, single oral doses of F-AMP demonstrated predictable systemic exposure and a dose-independent bioavailability. Confirmation of equivalent single-agent efficacy and toxicity must await the results of phase II trials under way at present. The documentation of equivalence will be of particular importance if F-AMP is to be used as a component of palliative therapy, the avoidance of intravenous medication being a substantial advantage.

	ACKNOWLEDGMENTS

 
We gratefully acknowledge the help of Simon Joel for critical review of the manuscript. We also acknowledge the patients who participated in the trial, the nursing and medical staff who cared for the patients, the physicians who referred them, and the pharmacists at the participating institutions.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted October 5, 1998; accepted January 4, 1999.

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