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© 2003 American Society for Clinical Oncology Pharmacokinetics and Pharmacodynamics of Oral Etoposide in Children With Relapsed or Refractory Acute Lymphoblastic Leukemia
From the Departments of Pharmaceutical Sciences, Hematology/Oncology, and Biostatistics, St. Jude Children’s Research Hospital, and Colleges of Pharmacy and Medicine, The University of Tennessee, Memphis, TN; and College of Medicine, University of Missouri, Columbia, MO. Address reprint requests to Mary V. Relling, PharmD, Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, 332 North Lauderdale, Memphis, TN 38105; email: mary.relling{at}stjude.org.
Purpose: To study the pharmacokinetics and pharmacodynamics of once- versus twice-daily oral etoposide in children with relapsed or refractory acute lymphoblastic leukemia (ALL). Patients and Methods: Fifty-eight patients were randomly assigned to etoposide at 50 mg/m2/d with once- versus twice-daily doses for 22 days. On day 8, vincristine, asparaginase, and dexamethasone were started. Etoposide pharmacokinetics and pharmacodynamics were studied for 47, 28, and 26 patients on day 1, 8, and 22, respectively, of remission reinduction therapy.
Results: Of 48 patients with pharmacokinetic data, 42 (87.5%) achieved complete remission, three (6.3%) failed to achieve remission, and three (6.3%) died during induction. Median etoposide day 8 area under concentration-time curve (AUC) and cumulative AUC tended to be greater (P = .06 and P = .07, respectively) in patients (n = 23) who achieved complete remission (24 and 522 µmol/L • h, respectively) than in patients (n = 3) who did not (14 and 303 µmol/L • h, respectively). Three of eight patients with plasma concentrations exceeding 1.7 µM (1 µg/mL) for more than 8 hours daily, compared with one of 20 patients with concentrations exceeding 1.7 µM for Conclusion: A pharmacodynamic relationship exists between systemic etoposide exposure and response to therapy when oral etoposide is used as part of remission induction regimens for relapsed or refractory childhood ALL.
CHILDREN WITH relapsed or refractory acute lymphoblastic leukemia (ALL) have a poor prognosis. Remission reinduction success rates range from 60% to more than 90%, depending on immunophenotype, site of relapse, duration of first remission, and drug therapy;1–4 however, the probability of maintaining a second bone marrow remission is low. The epipodophyllotoxin etoposide has been used as a single agent or in combination with other chemotherapeutics for treatment of relapsed leukemias,5–10 as well as for other primary and relapsed malignancies in children.11–14 Prolonged smaller daily doses of intravenous etoposide have been shown to be clinically superior to a single intravenous bolus dose despite achievement of the same systemic exposure (ie, area under the concentration-time curve [AUC]).15 The increased effectiveness of chronic exposure may be associated with increased time of etoposide plasma concentrations above 1.7 µM, a concentration that is clearly cytotoxic in vitro (0.5 to 1 µM).16–18 Whether chronic daily oral etoposide as a single agent or in combination with other agents is superior to or as effective as intravenous etoposide in children with ALL is not known, and there is some concern that low doses may not achieve and maintain plasma concentrations above a putative cytotoxic threshold for a long enough duration to be effective. Furthermore, it has been suggested that the extent of oral absorption of etoposide is dose-dependent, with a greater percentage of drug being absorbed at lower absolute doses.19–21 Therefore, twice-daily oral administration might result in a higher etoposide AUC, but perhaps a lower time-above-a-threshold concentration, than would once-daily oral dosing. Phase I and II single-agent studies in children indicate that oral etoposide at 60 mg/m2/d for 21 days was tolerated.11,22 In addition, prolonged oral etoposide was tolerated even in combination with a wide spectrum of anticancer agents.13,23–25 These findings indicated that 50 mg/m2/d of etoposide, in combination with limited additional antineoplastic therapy, would be tolerated. We report on a study in children with relapsed or refractory ALL treated with oral etoposide at 50 mg/m2/d (given as once- or twice-daily doses) for 22 days as part of remission reinduction chemotherapy.
Patients and Drug Administration Fifty-eight children with relapsed or refractory ALL were enrolled on the St. Jude Children’s Research Hospital R15 relapse protocol. The primary aims of the R15 study were to determine the toxicity and estimate the response rate of children with relapsed or refractory ALL to multiagent combination therapy, to determine the toxicities of daily oral etoposide during reinduction therapy, and to characterize and compare the pharmacokinetics of once- versus twice-daily oral etoposide in children with relapsed or refractory ALL. Of the 58 children enrolled, 48 had plasma samples available for pharmacokinetic and pharmacodynamic analysis, and they are the subject of this report. The study was approved by the institutional review board, and informed consent was obtained from the parent or guardian and (where appropriate) patients. All patients had a CSF examination before initiation of remission reinduction therapy to assign their CNS status: CNS 1 (no blasts), CNS 2 (< 5 WBC/µL with blasts identifiable on cytospin), or CNS 3 (  5 WBC/µL with blasts).26,27 Patients were randomly assigned to receive oral etoposide 50 mg/m2/d, administered as the intravenous (IV) formulation diluted in saline,28 once or twice daily for the first 22 days. Additional remission reinduction therapy with weekly vincristine (1.5 mg/m2 IV), three times per week Escherichia coli asparaginase (Elspar, Merck, West Point, PA; 10,000 U/m2 per dose intramuscularly [IM]), and daily dexamethasone (8 mg/m2/d orally) therapy started on day 8 (Fig 1 ). Intrathecal injections of methotrexate, hydrocortisone, and cytarabine were also administered during reinduction on the basis of the patient’s CNS status: patients with CNS 1 received intrathecal injections on days 8 and 22, and those with CNS 2 or CNS 3 received weekly intrathecal injections (Fig 1). On days 1, 8, and 22, blood (3 mL) was obtained before and 0.17, 0.5, 1, 2, 5, and 8 hours after the dose of etoposide. The plasma was stored at -70°C until the samples were analyzed in duplicate by high-performance liquid chromatography with electrochemical detection.29
Pharmacokinetic Analysis Etoposide pharmacokinetics were studied on days 1, 8, and 22 in 47, 28, and 26 patients, respectively. Although etoposide disposition after IV dosing is well described by a first-order two-compartment model, and fitting a two-compartment model to these data gives reasonable parameter estimates (data not shown), we have herein reported parameters using a first-order one-compartment structural model with oral absorption. The model was fit to etoposide plasma concentration versus time data using a two-stage Bayesian approach30 and a nonlinear mixed effects modeling approach to estimate pharmacokinetic parameters. Model fitting for the two-stage approach was implemented in ADAPTII (University of Southern California, Los Angeles, CA).31 First, 36 data-rich data sets (12 patients from each course) including six or more points per course were fit using a maximum likelihood fitting algorithm. Initial parameter estimates (elimination constant, ke = 0.35 hours-1; volume of central compartment, VC = 3.0 L/m2; absorption rate constant, ka = 0.75 hours-1; and absorption lag time,  = 0.17 hours) were drawn from previously published data.12 Bioavailability was not directly measured and was fixed at 50% on the basis of prior published data;12,32,33 it should be noted that this will result in higher-than-actual variation being assigned to other estimated parameters. The above criteria were used to estimate population parameter medians on the basis of the 36 data-rich data sets. The median estimated population parameters (coefficient of variation [CV%]) were ke = 0.25 hours-1 (106%), VC = 5.58 L/m2 (67%), ka = 1.70 hours-1 (145%), and = 0.13 hours (68%). These data were then used as the starting parameter estimates and variances and as the prior population means to estimate parameters for all 101 data sets, including the 36 data-rich sets using a Bayesian fitting algorithm. All data sets had at least three data points. Amount of drug in the central compartment (ICc) was estimated for each day 8 and day 22 data set to account for the possibility of residual plasma levels of etoposide from the previous dose. The AUC from 0 to 24 hours was calculated from simulated concentrations using each individual set of estimated pharmacokinetic parameters. The steady-state AUC predicted from the day 1 pharmacokinetic parameters (day 1 SS AUC) was also estimated using day 1 pharmacokinetic parameters to simulate AUC at steady-state dosing. Apparent oral clearance was calculated using the equation ke x Vc. The time that etoposide plasma concentrations were more than 1.7 µM was estimated for each patient using his or her estimated pharmacokinetic parameters to simulate plasma concentration data at 10-minute intervals for 24 hours. The same structural model was used for nonlinear mixed effects modeling as implemented in NONMEM V (University of California at San Francisco, San Francisco, CA). Age at relapse, weight, sex, race, day of therapy, timing of etoposide relative to dexamethasone, concurrent fluconazole (n = 5 courses), concurrent barbiturates (n = 18 courses), concurrent narcotics (n = 26 courses), serum bilirubin, serum albumin, and once-daily versus twice-daily dosing were considered as possible covariates of etoposide disposition. Covariates were considered significant if the change in the objective function (-2 log likelihood) decreased significantly (> 3.84) compared with the base model and if the covariate parameter estimates were significantly different than zero.
Statistical Analysis Bonferroni’s correction was applied to the toxicity, effect, and outcome analyses for day 8 AUC and for the time etoposide concentrations were more than 1.7 µM on day 8, to account for multiple testing. Dichotomization of patients with AUCs above and below 40 µmol/L • h was based on visual inspection of the data. We12 and others11,34 have shown the 1.7 µM (1 µg/mL) threshold to be a relevant concentration for etoposide effects in vivo. All P values reported are two sided, and all analyses were performed in SAS 6.12 (SAS Institute, Cary NC), with exact tests conducted using Proc StatXact or in LogXact-4 Version 4.0.2 (Cytel, Cambridge, MA).
Toxicity Criteria
Etoposide pharmacokinetic parameters were estimated from 101 courses in 48 patients. Forty-one of these patients had B-lineage, five patients had T-lineage, and two patients were not classified for immunophenotype. Three patients had t(12;21) (TEL-AML), five patients had t(9;22) (BCR-ABL), two patients had t(4;11) (MLL-AF4), and one patient had t(1;19) (E2A-PBX1). Additional patient characteristics are listed in Table 1 .
Pharmacokinetics and pharmacodynamics differed little between once-daily and twice-daily etoposide dosing (Table 2 ; Fig 2). The day 1 AUC, day 1 SS AUC, and day 8 AUC did not differ in once-daily versus twice-daily dosing regimens (P = .55, P = .78, and P = .86, respectively); however the day 22 AUC trended lower with once-daily versus twice-daily dosing (P = .046) (Table 2). There was no difference in the duration for which etoposide plasma concentrations were more than 1.7 µM on day 1, 8, or 22 between once-daily and twice-daily dosing (P = .02, P = 0.94, and P = 0.39, respectively), after adjusting for multiple tests. Severe infections were similarly frequent in the once-daily (eight of 22 patients) versus the twice-daily (11 of 26 patients) treatment groups.
As expected, the day 8 AUC was higher than the day 1 AUC (P < .001), partly because by day 8, patients were at steady-state (Table 2  ). However, even when the day 1 AUC was extrapolated to steady-state (day 1 SS), it was still lower than the measured day 8 AUC (P < .001). Median predose concentrations on days 8 and 22 were comparable at 0.23 and 0.24 µM, respectively. Although there is limited power of the pharmacokinetic model to unambiguously distinguish ka from ke, flip-flop kinetics (ka < ke) appeared to be present in 43 of 101 courses. The Tmax in the patients displaying flip-flop kinetics was a median of 2.4 hours compared with a median of 1.4 hours for the remaining patients.
There was no significant difference in oral clearance of etoposide whether it was estimated by the two-stage approach (mean, 40.6 mL/min/m2; median 35.1, mL/min/m2) or by nonlinear mixed effects modeling (mean, 33.8 mL/min/m2). Nonlinear mixed effects modeling indicated that there was substantial interpatient (CV, 35%) and intrapatient (CV, 41%) variability in oral clearance. No patient characteristics were identified as significant covariates of oral clearance except day of therapy. The objective function was reduced by 17.2 (P < .001) when day of therapy was added to the nonlinear mixed effects model. Clearances on days 8 and 22 were 13.8 and 10.5 mL/min/m2 lower (P < .001 and P < .002, respectively) than the clearance on day 1, as suggested by the two-stage analysis (Table 2
We explored whether the duration of etoposide plasma concentrations more than 1.7 µM on day 8 and day 8 AUC were predictors of toxicity (number of days of etoposide, vincristine, asparaginase, or dexamethasone dosing, grade 3 or 4 infection; Table 3
Of 48 analyzable patients, 42 (87.5%) patients achieved complete remission, three (6.3%) patients did not achieve remission, and three (6.3%) additional patients died during induction therapy. The median day 8 AUC and median cumulative AUC (day 8 AUC times total number of etoposide doses) were 24 and 522 µmol/L • h, respectively, in the 23 evaluable patients who achieved complete remission, compared with 14 and 303 µmol/L • h, respectively (P = .06 and P = .07, respectively) among the three patients who remained alive but did not achieve a complete remission (Fig 4 ). Considering only the patients with bone marrow involvement at relapse, 31 of 36 (86%) achieved a complete remission, with median day 8 and cumulative AUCs of 22 and 491 µmol/L • h, respectively, in the evaluable patients (n = 16) who achieved remission, and 14 and 312 µmol/L • h, respectively, in the evaluable patients (n = 2) who did not achieve complete remission (P = .26 and P = .26, respectively). In the patients with isolated CNS relapse, six of seven (86%) achieved a complete remission, with median day 8 and cumulative AUCs of 35 and 772 µmol/L • h, respectively, in the patients (n = 6) who achieved remission and 13 and 288 µmol/L • h, respectively, in the one patient who did not achieve complete remission.
Steady-state plasma etoposide concentration35,36 and etoposide AUC35 have been related to antitumor response in patients with solid tumors. At present, there are no data establishing a pharmacodynamic relationship between etoposide plasma concentration or AUC and response to therapy in children with relapsed ALL. Furthermore, data relating etoposide pharmacokinetic parameters and response to therapy are scarce in any patient group. In our study, day 8 and cumulative AUC tended to be higher for patients who achieved a complete remission versus those who remained alive but did not achieve a complete remission. Although the low number of patients who experienced treatment failure limits the statistical power, these results are consistent with a pharmacodynamic relationship between systemic exposure to etoposide and response to therapy among children with relapsed or refractory ALL.
Higher levels of plasma etoposide may be indicative of better outcome but may also be associated with a greater level of toxicity. Studies of oral etoposide in children11,12 and in adults34 with various relapsed malignancies found that toxicity was related to AUC or to the time that plasma concentrations were more than 1.7 µM. In this study, inability to complete all 22 days of etoposide therapy tended to be more common in patients with more than 8 hours per day of etoposide plasma concentrations more than 1.7 µM than among those with Random assignment of patients to either once-daily or twice-daily dosing allowed the investigation of dose dependence of oral absorption of etoposide. Previous reports demonstrated that a greater percentage of drug was absorbed at lower absolute doses (eg, 100 v 600 mg)19–21 using etoposide capsules. However, such capsules do not allow precise dosing in children. Whether there is dose-dependent absorption with the IV preparation of etoposide given orally, which permits adequate accuracy for pediatric dosing, had not been previously evaluated. We observed no schedule-dependent differences in AUCs at day 1 or 8 or in time above 1.7 µM at day 1, 8, or 22 with once-daily versus twice-daily dosing. At day 22, however, AUC tended to be lower (P = .046) with once-daily versus twice-daily dosing. One might speculate that by day 22, concurrent therapy with vincristine and dexamethasone saturates enzymes involved in absorption and metabolism and, therefore, affects once-daily more than twice-daily dosing at day 22 but not at day 8. Toxicity did not differ between the two dosing regimens. In any case, the clear dose-dependent absorption seen with higher oral etoposide doses19–21 was not observed in our study. Our data indicate that there is no meaningful pharmacokinetic or pharmacodynamic advantage for twice-daily versus once-daily dosing at a dosing level of 50 mg/m2/d in children. Etoposide pharmacokinetic parameters were estimated by fitting a first-order one-compartment structural model to plasma concentration versus time data. The median estimated oral clearance, volume of distribution, and absorption rate constant are similar to previously reported estimates of these parameters in children with either IV32,33,37–39 or oral12,32,33 administration of etoposide. A substantial number of patient courses were characterized by apparently prolonged absorption (as indicated by flip-flop kinetics). This is consistent with prior findings in children with solid tumors,12 and the reason underlying this finding remains unknown. There was notable interpatient and intrapatient variation in the estimated parameters; however, the data were well fit in all cases using the pharmacokinetic model above, and there was less intrapatient variability between days 8 and 22 than there was between days 1 and 8. Because etoposide40 and many of the concurrent medications41 taken by patients in this study are substrates, inducers, or inhibitors of CYP3A and P-glycoprotein, and these proteins are thought to contribute to wide intrapatient and interpatient variability in metabolism and excretion of affected drug substrates, it is not surprising that oral etoposide in this context would be associated with substantial interpatient and intrapatient variability. In addition, the decrease in the leukemic burden over the first 21 days of remission induction therapy may affect regulatory cytokine levels and perhaps hepatic leukemic burden, which have previously been associated with changes in hepatic drug metabolism among children with ALL.42 These data indicate that comparable exposure to etoposide could be achieved with either once- or twice-daily dosing and that both toxicity and failure to achieve remission were related to systemic etoposide exposure in children with relapsed or refractory ALL.
We thank our clinical staff; research nurses Sheri Ring, Lisa Walters, Margaret Edwards, Terri Kuehner, and Paula Condy; and the patients and their parents for their participation. We also thank Jean Cai, Ted Kim, Sara Kassm, Michael Hancock, Yinmei Zhou, Mark Wilkinson, and Nancy Kornegay for technical, statistical, and computer assistance.
Ching-Hon Pui is the American Cancer Society F.M. Kirby Clinical Research Professor. Supported by grants CA21765, CA51001, and CA23944 from the National Institutes of Health, Department of Health and Human Services, Bethesda, MD; by a Center of Excellence grant from the state of Tennessee; and by American Lebanese Syrian Associated Charities (ALSAC).
1. Rivera GK, Hudson MM, Liu Q, et al: Effectiveness of intensified rotational combination chemotherapy for late hematologic relapse of childhood acute lymphoblastic leukemia. Blood 88:831–837, 1996 2. Gaynon PS, Qu RP, Chappell RJ, et al: Survival after relapse in childhood acute lymphoblastic leukemia: Impact of site and time to first relapse—the Children’s Cancer Group Experience. Cancer 82:1387–1395, 1998[CrossRef][Medline]
3. Sadowitz PD, Smith SD, Shuster J, et al: Treatment of late bone marrow relapse in children with acute lymphoblastic leukemia: A Pediatric Oncology Group study. Blood 81:602–609, 1993
4. Beyermann B, Agthe AG, Adams HP, et al: Clinical features and outcome of children with first marrow relapse of acute lymphoblastic leukemia expressing BCR-ABL fusion transcripts. BFM Relapse Study Group. Blood 87:1532–1538, 1996
5. Ribeiro RC, Rivera GK, Hudson M, et al: An intensive re-treatment protocol for children with an isolated CNS relapse of acute lymphoblastic leukemia. J Clin Oncol 13:333–338, 1995 6. Crooks GM, Sato JK: Ifosfamide and etoposide in recurrent childhood acute lymphoblastic leukemia. J Pediatr Hematol Oncol 17:34–38, 1995[Medline] 7. Belasco JB, Goldwein JW, Simms S, et al: Hypofractionated moderate dose radiation, intrathecal chemotherapy, and repetitive reinduction/reconsolidation systemic therapy for central nervous system relapse of acute lymphoblastic leukemia in children. Med Pediatr Oncol 34:125–131, 2000[CrossRef][Medline] 8. Leahey AM, Bunin NJ, Belasco JB, et al: Novel multiagent chemotherapy for bone marrow relapse of pediatric acute lymphoblastic leukemia. Med Pediatr Oncol 34:313–318, 2000[CrossRef][Medline] 9. Bernstein ML, Abshire TC, Pollock BH, et al: Idarubicin and cytosine arabinoside reinduction therapy for children with multiple recurrent or refractory acute lymphoblastic leukemia: A Pediatric Oncology Group study. J Pediatr Hematol Oncol 19:68–72, 1997[CrossRef][Medline]
10. Abromowitch M, Bowman WP, Ochs J, et al: Etoposide (VP-16) with prednisone and vincristine for the treatment of refractory acute lymphoblastic leukemia. J Clin Oncol 3:789–792, 1985 11. Davidson A, Gowing R, Lowis S, et al: Phase II study of 21 day schedule oral etoposide in children. New Agents Group of the United Kingdom Children’s Cancer Study Group (UKCCSG). Eur J Cancer 33:1816–1822, 1997[Medline] 12. Sonnichsen DS, Ribeiro RC, Luo X, et al: Pharmacokinetics and pharmacodynamics of 21-day continuous oral etoposide in pediatric patients with solid tumors. Clin Pharmacol Ther 58:99–107, 1995[CrossRef][Medline] 13. Wolff JE, Molenkamp G, Westphal S, et al: Oral trofosfamide and etoposide in pediatric patients with glioblastoma multiforme. Cancer 89:2131–2137, 2000[CrossRef][Medline]
14. Kushner BH, Kramer K, Cheung NK: Oral etoposide for refractory and relapsed neuroblastoma. J Clin Oncol 17:3221–3225, 1999 15. Slevin ML, Clark PI, Joel SP, et al: A randomized trial to evaluate the effect of schedule on the activity of etoposide in small-cell lung cancer. J Clin Oncol 7:1333–1340, 1989[Abstract]
16. Minami H, Ando Y, Sakai S, et al: Clinical and pharmacologic analysis of hyperfractionated daily oral etoposide. J Clin Oncol 13:191–199, 1995 17. Bailey-Wood R, Dallimore CM, Littlewood TJ, et al: The effect of etoposide on human CFU-GM. Br J Cancer 52:613–617, 1985[Medline] 18. D’Incalci M, Erba E, Vaghi M, et al: In vitro cytotoxicity of VP 16 on primary tumor and metastasis of Lewis lung carcinoma. Eur J Cancer Clin Oncol 18:377–380, 1982[CrossRef][Medline] 19. Harvey VJ, Slevin ML, Joel SP, et al: The effect of dose on the bioavailability of oral etoposide. Cancer Chemother Pharmacol 16:178–181, 1986[Medline] 20. Slevin ML, Joel SP, Whomsley R, et al: The effect of dose on the bioavailability of oral etoposide: Confirmation of a clinically relevant observation. Cancer Chemother Pharmacol 24:329–331, 1989[CrossRef][Medline]
21. Hande KR, Krozely MG, Greco FA, et al: Bioavailability of low-dose oral etoposide. J Clin Oncol 11:374–377, 1993 22. Mathew P, Ribeiro RC, Sonnichsen D, et al: Phase I study of oral etoposide in children with refractory solid tumors. J Clin Oncol 12:1452–1457, 1994[Abstract]
23. Bremnes RM, Sundstrom S, Vilsvik J, et al: Multicenter phase II trial of paclitaxel, cisplatin, and etoposide with concurrent radiation for limited-stage small-cell lung cancer. J Clin Oncol 19:3532–3538, 2001
24. Glisson B, Scott C, Komaki R, et al: Cisplatin, ifosfamide, oral etoposide, and concurrent accelerated hyperfractionated thoracic radiation for patients with limited small-cell lung carcinoma: Results of Radiation Therapy Oncology Group Trial 93-12. J Clin Oncol 18:2990–2995, 2000 25. Mok TS, Zee B, Chan AT, et al: A phase II study of gemcitabine plus oral etoposide in the treatment of patients with advanced nonsmall cell lung carcinoma. Cancer 89:543–550, 2000[CrossRef][Medline]
26. Mahmoud HH, Rivera GK, Hancock ML, et al: Low leukocyte counts with blast cells in cerebrospinal fluid of children with newly diagnosed acute lymphoblastic leukemia. N Engl J Med 329:314–319, 1993
27. Gajjar A, Harrison PL, Sandlund JT, et al: Traumatic lumbar puncture at diagnosis adversely affects outcome in childhood acute lymphoblastic leukemia. Blood 96:3381–3384, 2000 28. McLeod HL, Relling MV: Stability of etoposide solution for oral use. Am J Hosp Pharm 49:2784–2785, 1992[Medline] 29. Cai X, Woo MH, Edick MJ, et al: Simultaneous quantitation of etoposide and its catechol metabolite in human plasma using high-performance liquid chromatography with electrochemical detection. J Chromatogr B A Biomed Sci Appl 728:241–250, 1999 30. Steimer JL, Mallet A, Golmard JL, et al: Alternative approaches to estimation of population pharmacokinetic parameters: Comparison with the nonlinear mixed-effect model. Drug Metab Rev 15:265–292, 1984[Medline] 31. D’Argenio DZ, Schumitzky A: A program package for simulation and parameter estimation in pharmacokinetic systems. Comput Programs Biomed 9:115–134, 1979[CrossRef][Medline] 32. Pinkerton CR, Dick G, Aherne GW: 24-hour plasma etoposide profile after oral and intravenous administration in children. Eur J Cancer 29A:1479–1481, 1993[Medline] 33. Chen CL, Rawwas J, Sorrell A, et al: Bioavailability and pharmacokinetic features of etoposide in childhood acute lymphoblastic leukemia patients. Leuk Lymphoma 42:317–327, 2001[Medline] 34. van der Gaast A, Vlastuin M, Kok TC, et al: What is the optimal dose and duration of treatment with etoposide? II. Comparative pharmacokinetic study of three schedules: 1 x 100 mg, 2 x 50 mg, and 4 x 25 mg of oral etoposide daily for 21 days. Semin Oncol 19:8–12, 1992[Medline] 35. Desoize B, Marechal F, Cattan A: Clinical pharmacokinetics of etoposide during 120 hours continuous infusions in solid tumours. Br J Cancer 62:840–841, 1990[Medline] 36. Kunitoh H, Watanabe K: Phase I/II and pharmacologic study of long-term continuous infusion etoposide combined with cisplatin in patients with advanced non-small-cell lung cancer. J Clin Oncol 12:83–89, 1994[Abstract] 37. Evans WE, Sinkule JA, Crom WR, et al: Pharmacokinetics of Teniposide (VM26) and etoposide (VP16-213) in children with cancer. Cancer Chemother Pharmacol 7:147–150, 1982[Medline]
38. Rodman JH, Murry DJ, Madden T, et al: Altered etoposide pharmacokinetics and time to engraftment in pediatric patients undergoing autologous bone marrow transplantation. J Clin Oncol 12:2390–2397, 1994 39. Relling MV, McLeod HL, Bowman LC, et al: Etoposide pharmacokinetics and pharmacodynamics after acute and chronic exposure to cisplatin. Clin Pharmacol Ther 56:503–511, 1994[Medline] 40. Relling MV, Nemec J, Schuetz EG, et al: O-demethylation of epipodophyllotoxins is catalyzed by human cytochrome P450 3A4. Mol Pharmacol 45:352–358, 1994[Abstract]
41. Gentile DM, Tomlinson ES, Maggs JL, et al: Dexamethasone metabolism by human liver in vitro: Metabolite identification and inhibition of 6-hydroxylation. J Pharmacol Exp Ther 277:105–112, 1996 42. Relling MV, Crom WR, Pieper JA, et al: Hepatic drug clearance in children with leukemia: Changes in clearance of model substrates during remission-induction therapy. Clin Pharmacol Ther 41:651–660, 1987[Medline] Submitted June 13, 2002; accepted December 15, 2002.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
8 hours daily, were unable to receive all 22 days of etoposide because of toxicity. There was no difference in the AUC at day 1 or day 8 with once- versus twice-daily doses (P = .55 and P = .86, respectively). 
