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Pharmacokinetics of Nelarabine and 9-Beta-D-Arabinofuranosyl Guanine in Pediatric and Adult Patients During a Phase I Study of Nelarabine for the Treatment of Refractory Hematologic Malignancies

From the Ohio Northern University, Ada, OH; M.D. Anderson Cancer Center, Houston, TX; Duke University, Durham, University of North Carolina, Chapel Hill, and Glaxo Wellcome Inc, Research Triangle Park, NC; and Boston University Medical Center, Boston, MA.

Address reprint requests to David F. Kisor, Ohio Northern University, College of Pharmacy, Ada, OH 45810; email d-kisor{at}onu.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To characterize the pharmacokinetics of nelarabine (506U78), the water-soluble prodrug of 9-beta-D-arabinofuranosyl guanine (ara-G), and ara-G in pediatric and adult patients with refractory hematologic malignancies. Ara-G is phosphorylated within leukemic cells to form ara-G triphosphate (ara-GTP), which acts to terminate DNA chain elongation, resulting in cell death.

PATIENTS AND METHODS: The pharmacokinetics of nelarabine and/or ara-G were evaluated in 71 patients (25 pediatric and 46 adult patients) on the first day of therapy. Blood was collected at specified times for the determination of plasma nelarabine and ara-G concentrations.

RESULTS: There were no statistically significant differences in the pharmacokinetics of nelarabine between any of the groups of patients. The harmonic mean half-life (t1/2) of nelarabine in pediatric and adult patients was 14.1 minutes and 16.5 minutes, respectively. The maximum concentrations (C_max) of ara-G occurred at or near the end of the nelarabine infusion. The C_max of ara-G ranged from 11.6 µmol/L to 308.7 µmol/L at nelarabine doses of 5 to 75 mg/kg and was linearly related to the nelarabine dose. No statistically significant differences were noted for the pharmacokinetic parameter estimates of ara-G between adult male and female patients. In children versus adults, the dose-normalized C_max, time of the C_max, and the steady-state volume of distribution of ara-G were similar. However, the clearance of ara-G was higher in pediatric patients (0.312 L·h^-1·kg^-1) as compared with adult patients (0.213 L·h^-1·kg^-1) (P < .001). The t1/2 of ara-G was shorter in pediatric patients as compared with adult patients (2.1 hours v 3.0 hours; P < .01).

CONCLUSION: Nelarabine is an effective prodrug of ara-G, allowing systemic concentrations of ara-G that result in clinical activity.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
NELARABINE (506U78) IS a prodrug of the deoxyguanosine (dGuo) analog 9-beta-D-arabinofuranosyl guanine (ara-G).¹ dGuo is readily catabolized by purine nucleoside phosphorylase (PNP). Clinically, PNP deficiency has been associated with T-cell lymphopenia.² Metabolically, patients with T-cell lymphopenia are unable to catabolize dGuo, which results in an increase in the plasma concentration of dGuo. There is a greater accumulation of the triphosphate of dGuo in T cells because of the inherently higher phosphorylation of dGuo in T cells as compared with B cells.³ This accumulation of dGuo triphosphate leads to cell death via inhibition of DNA synthesis.^4,5 Although T-cell specificity was observed with dGuo, the efficient catabolism of dGuo by PNP limited its use clinically.

Ara-G, like dGuo, has been shown to be toxic to T cells,^6,7 with greater accumulation and retention of ara-G triphosphate (ara-GTP) in T cells as compared with B cells.⁸ Ara-G has been used successfully to purge malignant T cells from murine and human bone marrow ex vivo.^9,10 However, ara-G, which was synthesized in 1964,¹¹ has not been used clinically because of its poor solubility properties and difficult synthesis.

The application of an enzymatic method of purine arabinonucleoside synthesis led to the development of compound nelarabine,¹² the 6-methoxy derivative of ara-G, which is 10 times more soluble than ara-G.¹ In vitro, in the presence of adenosine deaminase, nelarabine is demethoxylated to generate ara-G (Fig 1). As a consequence of the high specific activity of adenosine deaminase in the RBCs and other large body organs of cynomolgus monkeys, intravenous (IV) administration of nelarabine resulted in rapid demethoxylation to generate ara-G.¹ Conversion of nelarabine to ara-G is required to induce cytotoxicity, as adenosine deaminase inhibition blocks the formation of the active nucleoside analog (ara-G).¹

View larger version (11K): [in this window] [in a new window]   Fig 1. The chemical structures of nelarabine and ara-G (on conversion via adenosine deaminase).

The purpose of this report is to describe the pharmacokinetics of nelarabine and ara-G in patients with refractory hematologic malignancies who were receiving nelarabine as a 1-hour infusion daily for 5 consecutive days. The pharmacokinetics of the prodrug and/or ara-G, including the clearance (CL) and steady-state volume of distribution (V_ss), were characterized in 78 of the 93 patients from this study. The mean and median maximum plasma concentration (C_max) and t1/2 of nelarabine and ara-G for 24 patients have previously been reported.¹⁴ In the present report, specific attention was given to potential differences in the pharmacokinetics of these compounds based on age, sex, and diagnoses.

	PATIENTS AND METHODS

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Ninety-three patients with refractory hematologic malignancies were enrolled from April 1994 through February 1997 in this phase I, multicenter, open-label, dose escalation study of nelarabine. This study was approved by the institutional review boards at Duke University Medical Center, Durham, NC, the University of North Carolina Medical Center, Chapel Hill, NC, the Dana-Farber Cancer Institute, Boston, MA, and M.D. Anderson Cancer Center, Houston, TX. All patients received information and gave written informed consent to participate in the study. Seventy-eight of these patients participated in the pharmacokinetics portion of this study (Table 1). Patients at M.D. Anderson Cancer Center signed a separate consent form to participate in the clinical pharmacology studies.

Drug
Nelarabine clinical trial material (study drug) was obtained from Burroughs Wellcome Co (now Glaxo Wellcome, Inc, Research Triangle Park, NC) as a lyophilized powder in 200-mg vials. At the time of administration, the powder was diluted with 25 mL of 0.45% sodium chloride to provide a concentration of 8 mg/mL. The clinical trial material averaged 100.27% ± 1.25% of the labeled strength of nelarabine.

Treatment Protocol
In each patient, an indwelling IV catheter was placed in a peripheral or central vein for IV fluid and study drug administration. A second catheter was placed in a peripheral vein for blood sample collection. Patients received nelarabine at 5 mg/kg (n = 9; five pediatric and four adult patients), 10 mg/kg (n = 5; two pediatric and three adult patients), 20 mg/kg (n = 9; four pediatric and five adult patients), 25 mg/kg (n = 1; an adult), 31 mg/kg (n = 12; all adults), 39 mg/kg (n = 8; all pediatric patients), 40 mg/kg (n = 33; four pediatric and 29 adult patients), 60 mg/kg (n = 15; 10 pediatric and five adult patients), or 75 mg/kg (n = 1; a pediatric patient), infused over 0.75 to 2 hours daily for 5 consecutive days. Ninety-one percent (610 of 669) of the infusions were administered over 1 hour. The 31-mg/kg and 39-mg/kg dose levels represent an equivalent 1.2-g/m² dose level in adult and pediatric patients, respectively. The 1.2-g/m² dose level was initially identified as the common maximum-tolerated dose. One adult patient received a dose of 25 mg/kg (1 g/m²) before the maximum-tolerated dose was identified. Where clinically indicated, the 5-day course of therapy was repeated every 21 to 28 days.

Chemicals
Deoxycoformycin was obtained from the National Cancer Institute, Bethesda, MD, and was placed in each blood collection tube (see below). For high-pressure liquid chromatography analysis, nelarabine and ara-G were obtained from Glaxo Wellcome, Inc, and R.I. Chemicals, Inc (Orange, CA), respectively. All other chemicals were reagent grade.

Biologic Fluid Sample Collection
In 71 patients, blood samples were collected at baseline, before the first infusion of nelarabine (day 1 of the 5-day course), at 15, 30, and 45 minutes during the infusion (24 patients), at the end of the infusion, and at 15, 30, and 45 minutes and 1, 2, 3, 4, 6, and, in some patients, 23 hours after the end of the infusion. Four patients had samples collected on day 2, one patient had samples collected on day 4, and two patients had samples collected on day 5. The blood sampling schedule for these patients was similar to the schedule for patients from whom blood was sampled on day 1. Six of the 78 patients had blood samples collected for the determination of nelarabine and ara-G concentrations on at least two occasions during the first course or the first and a subsequent course of therapy with nelarabine. Each blood sample was collected in a purple-top (EDTA) or green-top (lithium/sodium heparin) tube containing 2.5 µmol/L deoxycoformycin per mL of blood (50 µL/tube for blood samples from pediatric patients and 175 µL/tube for blood samples from adult patients) to prevent further conversion of nelarabine to ara-G after collection of the blood samples. After collection, each blood sample was placed on wet ice and centrifuged, and the plasma was frozen. For samples from Duke University Medical Center, the University of North Carolina Medical Center, and the Dana-Farber Cancer Institute, the frozen plasma was shipped to Glaxo Wellcome for determination of nelarabine and ara-G concentrations. Blood samples from patients at the M.D. Anderson Cancer Center were assayed at that institution in the Department of Clinical Investigation.

Detection and Quantification of nelarabine and Ara-G
Plasma samples sent to Glaxo Wellcome were analyzed for the presence of nelarabine and ara-G using high-pressure liquid chromatography with ultraviolet detection (254 nm). The nelarabine and ara-G assays were linear over the concentration ranges of 0.336 µmol/L to 134.4 µmol/L and 0.353 µmol/L to 141.2 µmol/L (0.1 µg/mL to 40 µg/mL), respectively. Samples with concentrations above the validation range were diluted and then reanalyzed. The intraday and interday coefficients of variation of the assay for nelarabine and ara-G were less than 10%. Plasma samples from patients at the M.D. Anderson Cancer Center were analyzed using reverse-phase high-pressure liquid chromatography with ultraviolet detection, as previously described.¹⁴

Pharmacokinetic Analysis and Calculations
For pharmacokinetic analysis of individual patient data, the labeled strength of nelarabine was assumed to be 100%. Pharmacokinetic analyses were performed using noncompartmental methods. Assuming total conversion of nelarabine to ara-G, the dose of ara-G was calculated as the dose of nelarabine multiplied by the ratio of the molecular weight of ara-G to the molecular weight of nelarabine. The noncompartmental calculations were performed using WinNonlin version 1.1 (Statistical Consultants Inc, Apex, NC). In this analysis, the observed C_max and the time of the maximum concentration were the observed values from the plasma concentration–time profiles. The terminal elimination rate constant (z) was estimated with WinNonlin 1.1 using linear regression of the ln (concentration)-versus-time data. The t1/2 was then calculated as ln(2)/z. The pharmacokinetic analyses for nelarabine and ara-G included calculation of the area under the plasma concentration–time curve from time 0 until the time of the last measurable plasma concentration, the area under the plasma concentration–time curve from time 0 to infinite time (AUC₀), and the plasma CL. Plasma CL estimates were obtained by use of the entire AUC₀, such that

The V_ss for nelarabine and ara-G was calculated using noncompartmental methods, as described by Gibaldi and Perrier.¹⁶

Statistical Analysis of Pharmacokinetic Parameter Values
Statistical analyses were performed using Microsoft Excel 97 for Windows (Microsoft Corporation, Seattle, WA). Dose proportionality was examined by plotting the dose-normalized C_max and AUC₀ for nelarabine and ara-G versus the nelarabine dose. Pharmacokinetic parameter estimates for pediatric patients were compared with estimates in adult patients using Student’s t test for unpaired samples with the assumption of unequal variances. Before Student’s t test was run, the data were ln-transformed if they were not normally distributed. Pharmacokinetic estimates were also compared between male and female patients using Student’s t test for unpaired samples with the assumption of unequal variances. Estimates of creatinine CL were made for pediatric and adult patients using the relationships described by Schwartz et al¹⁷ and Cockroft and Gault,¹⁸ respectively. Geometric regression analysis was used to examine the relationship between the estimated creatinine CL and the CL of ara-G.^19,20

	RESULTS

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Systemic Pharmacokinetics of Nelarabine
During the infusion, nelarabine accumulated, with the C_max of nelarabine generally occurring at the end of the infusion. The end-of-infusion concentration was typically slightly higher than the concentration at 45 minutes, indicating that nelarabine was reaching its steady-state concentration (Fig 2A). The C_max increased linearly with the nelarabine dose (Fig 3A). The slopes of the plots of dose-normalized C_max and AUC₀ of nelarabine versus the nelarabine dose were not statistically significantly different from zero (P = .1 and P = .38, respectively), which suggests that nelarabine was dose proportional. After the end of the nelarabine infusion, the concentrations of nelarabine declined with time in a monoexponential fashion. Nelarabine pharmacokinetic parameter estimates were made in only 64 of the 78 patients. Incomplete concentration-versus-time data prevented pharmacokinetic parameter estimation in the remaining 14 patients. The pharmacokinetic parameter estimates for nelarabine after the first infusion (day 1) of nelarabine in pediatric and adult patients are presented in Table 2A. Very large SDs were observed for the CL, V_ss, and t1/2 of nelarabine in both pediatric and adult patients. The coefficients of variation (%) for CL, V_ss, and t1/2 in pediatric and adult patients were 138.2% and 143.6%, 135.3% and 138.2%, and 131.7% and 34.8%, respectively. The harmonic mean t1/2 of nelarabine in pediatric and adult patients was 14.1 minutes and 16.5 minutes, respectively. With respect to the pharmacokinetics of nelarabine, no statistically significant differences were seen between adult male and female patients (Table 2B), nor were there apparent differences in nelarabine pharmacokinetic parameter estimates between patients with different diagnoses (data not shown).

View larger version (14K): [in this window] [in a new window]   Fig 2. Plasma concentration-versus-time data for (A) nelarabine and (B) ara-G during a 60-minute infusion of nelarabine in five adult patients.

View larger version (15K): [in this window] [in a new window]   Fig 3. Relationship between (A) nelarabine Cmax and (B) ara-G Cmax and nelarabine dose. The Cmax of nelarabine and ara-G increased linearly with the nelarabine dose.

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View larger version (13K): [in this window] [in a new window]   Fig 4. Plasma concentration-versus-time data for ara-G in a pediatric and adult patient at the 40-mg/kg dose level. The solid lines represent the "fitted" slope for each concentration-versus-time data set.

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Finally, pharmacokinetic data were compared in patients with different diagnoses to determine whether leukemia/lymphoma pathophysiology affected the disposition of ara-G. Pharmacokinetic estimates of ara-G between patients with different diagnoses were similar (Table 4). Although the number of patients for each diagnosis is small, comparison of the pharmacokinetic data indicates that leukemia type did not clearly distinguish ara-G disposition. Similarly, patients with lymphoma had similar plasma ara-G dispositions.

View larger version (23K): [in this window] [in a new window]   Fig 5. Relationship between estimated creatinine CL and ara-G CL. Each point represents an individual patient. The solid line represents the "fitted" slope determined using geometric regression (P < .0001). Here, ara-G CL = (2.01 · CLcr) + 1.31.

Intrapatient Variability
To determine whether there were differences in ara-G pharmacokinetics between days and courses, within patients, pharmacokinetic estimates for ara-G from patients who had blood sampled on at least two occasions were compared (Table 5). Within individual patients, pharmacokinetic estimates for ara-G were similar from day to day. Although the C_max and AUC₀ were proportional to the different doses administered to one patient (patient no. 47), the CL and V_ss were similar (Table 5).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

0

0

As with nelarabine, the concentrations of ara-G declined with time in a monoexponential fashion after the end of the infusion. The C_max and AUC₀ of ara-G increased in proportion to the administered nelarabine dose. The linear increase in ara-G with increasing nelarabine dose was a result of nelarabine concentrations being well below the Km of nelarabine for adenosine deaminase. There was much less variability in the C_max of ara-G, as evidenced by the 23% and 26.7% coefficients of variation in the dose-normalized C_max values for pediatric and adult patients, respectively. Comparison of the systemic pharmacokinetics of nelarabine and ara-G, with respect to diagnosis, demonstrated that neither the C_max nor AUC₀ were dependent on the diagnosis (data not shown for nelarabine; ara-G data are presented in Table 4). This was in contrast to the cellular pharmacokinetics of ara-GTP, which depended on diagnosis.¹⁴

Determination of the relationship between the C_max of ara-G and the nelarabine dose suggests that the ara-G C_max depended on the nelarabine dose (Fig 3, r² = .75, P < .00001). Also, as shown previously, there is a relationship between ara-G C_max, at different doses of nelarabine, and cellular accumulation of ara-GTP.¹⁴ These data suggest that the cellular nucleoside kinases are not saturated at the concentrations of ara-G achieved at the dose levels used in this study. This is consistent with the observation that the ara-G C_max range observed in this study (11.6 µmol/L to 308.7 µmol/L) was well below the Km of ara-G for deoxycytidine kinase (900 µmol/L).^1,21 Also, in addition to deoxycytidine kinase, dGuo kinase has been shown to phosphorylate ara-G with greater affinity (Km 7 µmol/L).^22-24 Therefore, while phosphorylation of ara-G by dGuo kinase may be saturated, deoxycytidine kinase may have the capacity to efficiently phosphorylate higher plasma concentrations of ara-G.

In most patients, blood sampling to determine plasma ara-G concentrations ended at 7 hours. This resulted in approximately 18% of the AUC₀ being extrapolated. However, the concentration-versus-time profile in patients with blood samples collected beyond 18 hours (n = 16) was linear, suggesting that the "fitted" elimination slopes for data sets from patients with sampling out to 7 hours yielded legitimate values.

The CL of ara-G was higher in pediatric patients as compared with adult patients. Although the reason for this is not entirely clear, it may be attributed to age-related differences in renal function. Plotting the CL of ara-G against the estimated creatinine CL identified a positive relationship between these variables, which suggests that ara-G CL is related to renal function (Fig 5). A similar finding was seen with fludarabine when the CL of fludarabine was compared with the serum creatinine value.²⁵ With a creatinine CL estimate of zero, as in a functionally anephric patient, the CL of ara-G is estimated to be 1.31 mL·min^-1·kg^-1. A comparison of this value with the total CL estimates for ara-G in pediatric and adult patients suggests that the nonrenal CL of ara-G is 25% to 36% of the total CL and that the renal CL represents 64% to 75% of the total CL. However, the r² value revealed that creatinine CL explained only 25% of the variability in the ara-G CL. Currently, urine samples from patients in subsequent phase I studies are being analyzed to more clearly define the relationship between ara-G CL and renal function. The higher CL of ara-G in pediatric patients was responsible for the shorter t1/2 of ara-G in this group, as the volume of distribution of ara-G was similar in pediatric and adult patients.

The plasma t1/2 of ara-G is relatively long, ie, 2.1 hours and 3 hours in pediatric and adult patients, respectively. Thus, at the maximum-tolerated dose in pediatric and adult patients, 39 mg/kg and 31 mg/kg, respectively (a common 1.2-g/m² dose), concentrations of ara-G remained above 10 µmol/L for more than 8 hours. Earlier, in vitro studies showed that a concentration of 10 µmol/L would support linear accumulation of ara-GTP by primary leukemic cells.²⁴ In fact, clinical responses have been reported with the lowest dose used in this study, ie, 5 mg/kg, indicating that plasma ara-G concentrations in the range of 15 to 30 µmol/L will support accumulation of ara-GTP in leukemic blasts.¹³ These pharmacokinetic characteristics are favorable compared with other purine analogs and may lean toward the use of nelarabine in the treatment of indolent leukemias, where other nucleoside analogs have been used successfully. However, clinical investigation is needed to examine this potential.

In conclusion, nelarabine is an effective prodrug of ara-G, with approximately 94% of an administered dose being converted to ara-G by the end of a 1-hour infusion. The pharmacokinetics of nelarabine vary in pediatric and adult patients but seem to be linear over the dose range of 5 mg/kg to 75mg/kg. The pharmacokinetics of ara-G are also linear over the nelarabine dose range of 5 mg/kg to 75 mg/kg. The CL of ara-G is higher in pediatric patients as compared with adult patients and may to be related to renal function; however, more data are needed to better explain the relationship between ara-G CL and renal function. The pharmacokinetics of nelarabine and ara-G were similar in male and female adult patients. Diagnosis of a particular hematologic malignancy does not distinguish the pharmacokinetics of nelarabine or ara-G from estimates obtained in patients with other diagnoses.

	ACKNOWLEDGMENTS

 
Supported in part by grants no. CA32839 and CA57629 from the National Cancer Institute, Department of Health and Human Services, Bethesda, MD.

The investigators thank Claudia Breuckner, Billie Nowak, Mary Ayres, and Min Du for their expert technical assistance and Stephen Weller and Gertrude Elion for critically reviewing the manuscript.

	NOTES

 
This work is dedicated to the memory of Gertrude B. Elion, mentor, colleague, and friend.

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Submitted August 13, 1999; accepted October 19, 1999.

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