Clinical Pharmacology of Cancer Chemotherapy in Children

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Clinical Pharmacology of Cancer Chemotherapy in Children William E. Evans, Pharm D, * William P. Petros, Pharm D, t Mary V. Relling, pharm D,:j: William R. Crom, Pharm D§ Timothy Madden, Pharm D, t John H. Rodman, Pharm D, ** and Marc Sunderland, Pharm Dt

Anticancer drugs are a sine qua non of curative therapy for many childhood cancers. However, the clinical pharmacology and activity of these drugs are usually not characterized in children until well after they have been investigated in adult patients. Moreover, FDA decisions about their approval for use in the United States are typically based on studies conducted in adults. One purpose of this review is to exemplify differences in the clinical pharmacology of some anticancer drugs when children are compared to adults. Such pharmacokinetic and pharmacodynamic differences hallmark the limitations of extrapolating adult data to children. These differences, coupled with the different spectrum of malignancies in children versus adults, provide compelling justification for independent studies of anticancer drugs in children and adults, instead of relying on adult studies to identify those new drugs which may be active in children with cancer.

ANTIMETABOLITES 6- Mercaptopurine

Children have received 6-mercaptopurine (6-MP) as a component of leukemia therapy for several years; however, only recently have many of From the Pharmaceutical Division, Phannacokinetics/Dynamics Section, St. Jude Children's Research Hospital and The Center for Pediatric Pharmacokinetios and Therapeutics, University of Tennessee, Memphis, Tennessee. *Professor of Clinical Pharmacy and Pediatrics; Chairman, Department of Clinical Pharmacy tPostdoctoral Researoh Fellow :j:Assistant Professor; Assistant Member §Associate Professor; Associate Member **Associate Professor, Associate Member and Vice-Chairman

Pediatric Clinics of North America-Vol. 36, No.5, October 1989

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its pharmacokinetic and pharamcodynamic properties been investigated in this population. Eighteen years ago Pinkel et al. demonstrated a relationship between prescribed dosage and efficacy of acute lymphocytic leukemia (ALL) maintenance therapy, with children given half-dosages of 6-MP, vincristine, cyclophosphamide, and methotrexate experiencing significantly worse clinical responses. 113 Because of that report, many factors have been investigated for their relation to the efficacy, toxicity, and pharmacology of 6-MP in leukemia. A common problem with any orally administered agent is patientparent noncompliance with prescribed dosage regimens. Antileukemia treatment with 6-MP is not an exception to this rule, 149 and recent literature has demonstrated physician noncompliance as another important factor in determination of delivered-dose intensity. lOB Wide variations in the bioavailability of oral 6-MP have been reported (5-37 per cent), thought attributable to first-pass metabolism by xanthine oxidase. 12, 189 As expected for a drug with flow-limited intrinsic clearance, xanthine oxidase inhibitors, such as allopurinol, have produced dramatic increases in the systemic exposure of 6-MP when the drugs were given concurrently by the oral route, but not when given intravenously.lOO, 191 Interestingly, allopurinol also can deplete intracellular phosphoribosylpyrophosphate (required for metabolic activation of 6_MP).189 The net effect on antileukemic activity is not totally clear, Strategies to saturate catabolic first pass metabolism by increasing the dose of oral 6-MP have recently been studied in pediatric patients with ALL. 8 As the dose was increased from 75-500 mg per m 2 (approximately sevenfold) the bioavailability only increased fourfold, Thus, saturation of enzyme activity does not seem to occur in this dosage range. Japanese researchers are utilizing intermittent (rather than continuous) 6-MP, in higher individual doses for pediatric ALL with promising efficacy and toxicity data. 89 In addition to variations in compliance and bioavailability between patients, daily administration time also has been investigated for its effects on the pharmacodynamics and pharamcokinetics of 6-MP. A retrospective study of 118 children found a fourfold higher risk of relapsing leukemia in patients ingesting 6-MP in the morning versus the evening. 128 Unfortunately, compliance was not documented. The pharmacokinetics of 6-MP were evaluated in a randomized, crossover study of six children with ALL receiving the drug either at bedtime or in the morning. 95 Evening administration produced significantly higher areas under the concentration versus time curve. It could not be determined, however, whether this effect was due to altered absorption or metabolism. The relation between 6-MP dose, pharmacokinetics of parent or active metabolite, and biologic effects has been evaluated in several studies. 72, 98, 109,157 Systemic pharmacokinetics and toxicity of 6-MP were evaluated in 20 children with ALL by Sulh et al. 157 Two subjects experienced severe myelotoxicity attributable to 6-MP and interestingly, these two also demonstrated the highest systemic exposures to parent drug. Evaluation of intracellular 6-MP disposition has been conducted typically in studies of red blood cells, with the assumption that they reflect

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what transpires in normal and malignant white cells. A study of ten patients with cancer found a good correlation between 6-MP plasma concentrations with the person's red blood cell concentration of parent drug. 94 Lennard et al. recently reported a study of the systemic pharmacokinetics and intracellular disposition of 6-MP and its active metabolites. 98 These 19 pediatric patients with ALL demonstrated wide interpatient variability in both parent and metabolite characteristics. A relationship between 6-MP induced neutropenia and parent drug pharmacokinetics could not be established; however, a significant correlation was demonstrated when active metabolite (6-thioguanine nucleotide) concentrations were evaluated in relation to neutropenia (Fig. 1). Subjects experiencing substantial neutropenia at lO to 19 days after drug administration had significantly higher active metabolite concentrations in red blood cells. Multiple enzymes are involved in the metabolism of 6-MP, including those responsible for activation (hypoxanthine phosphoribosyltransferase), transformation of active products (alkaline phosphatase; cytoplasmic 5nucleotidase; thiopurine methyltransferase), and shunting parent drug away from activation pathways (thiopurine methyltransferase; xanthine oxidase). Marked variability in enzyme activity may be demonstrated between patients. 99 • l(lO, 112, 192, 193 Molecular causes of resistance to 6-MP may include alterations in any of these enzyme systems, which may be acquired or controlled by a common genetic polymorphism in the case of thiopurine methyltransferase. 171 Many groups treating pediatric leukemia with 6-MP have dose reduction criteria if the white blood cell count declines to an unacceptable

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leveP09, ll\ however, considerable controversy exists regarding dose increases beyond the standard 75 mg per m 2 per day for patients not experiencing depressed leukocyte counts within a "targeted" range. Whether prospective dosage adjustments based solely on white blood count will contribute significantly to outcome remains to be proven. At least the latter approach will provide a means to assess one potential cause of relapse. Cytosine Arabinoside Widespread utilization of cytosine arabinoside (ara-C) in the therapy of pediatric malignancies, in particular acute leukemias, has provided the opportunity for numerous investigations of this agent's clinical pharmacology. Considered by most to be a prodrug, ara-C is converted intracellularly by deoxycytidine kinase to an active metabolite (ara-CTP); however, in the extracellular environment ara-C is metabolized extensively by cytidine deaminase to uracil arabinoside (ara-V). Metabolic conversion of ara-C to ara-V may proceed at a slower rate in pediatric patients compared to adults,9 although wide interpatient variability can be demonstrated in both populations. Nonlinear metabolism of ara-C has been suggested in some situations in which higher dosages (>10 gm per m 2 over 72 hours) are usedY Ara- V has been implicated in the causation of some nonhematologic adverse effects (e.g., neurotoxicity) of ara-C therapy. In an attempt to increase the therapeutic index of ara-C, Kreis et al. simultaneouslyadministered tetrahydrouridine (an inhibitor of cytidine deaminase).92 Patients demonstrated up to tenfold increases in the systemic exposure to ara-C, depending on the dose of ara-C administered. This intervention may reduce systemic exposure to the potentially toxic ara-V metabolite for a given exposure of ara-C. Further studies will need to evaluate how these effects correlate to efficacy or toxicity. Ara-C transport into leukocytes occurs primarily via facilitated diffusion at plasma concentrations attained with standard dose protocols. In contrast, high-dose regimens, producing much higher plasma concentrations, can produce nonfacilitated intracellular transport. 179 Thus, intracellular accumulation of ara-C by facilitated diffusion is the rate-limiting step in active metabolite formation with standard doses, but not with high dose regimens. 177 Leukocyte subtypes may differ in their capacity for facilitated transport of ara-C, with myeloblasts demonstrating better ara-C accumulation in comparison to lymphoblasts. 18o Intracellular metabolic activity in patients with AML has been shown to correlate with response to ara-C. Some patients experiencing a relapse in disease have demonstrated either very low kinase activity or very high deaminase activity.37 Intermittent infusions of ara-C (infused over 2 hours) can saturate ara-CTP accumulation at steady-state plasma concentrations of approximately 7 j.LM,116 a concentration significantly lower than that produced by most high-dose regimens. Some have suggested moving away from the commonly prescribed high-dose regimens to more of an intermediate dose, based on these data. 9, 49, 116 Ara-C is commonly administered via the subcutaneous route due to its

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convenience and potential for producing prolonged plasma concentrations. Recent comparative studies have disputed this concept, demonstrating similar disposition after intermittent intravenous and subcutaneous injections, in contrast to continuous subcutaneous or intravenous infusions. 147, 172 Interest in continuous infusion regimens of ara-C has stemmed from knowledge of its systemic and intracellular pharmacokinetics. Increasing only the duration of infusion has been shown to significantly increase the cell's exposure to ara-CTP and cytotoxicity associated with the regimen. 96, 104. 1I8 Ross et al. demonstrated further support for this approach by conducting an in vitro study of leukemic cells exposed to ara-C for 22 hours. They demonstrated a direct relationship between exposure to ara-C (0.01-1 j.LM) and intracellular ara-CTP formation or incorporation of ara-C into DNA.135 Clinical evaluations of the ability of an individual patient's leukemic cells to produce and retain ara-CTP have been conducted in adults with AML. Preisler et al. evaluated 59 patients with AML who received intermittent or continuous infusions of ara-C in standard doses as a part of induction, consolidation, and maintenance therapy. A statistically significant relationship was found between leukemic cell ara-CTP concentrations and duration of remission. 122 This observation was less evident as the overall intensity of the treatment program (or a subset of the program, e.g., induction) increased in a subsequent protocol. 122 The pharmacokinetics of intracellular ara-CTP have also been evaluated during intermittent infusions of high dose ara-C in refractory acute leukemias. 48 With this dosage regimen a significant relationship was found between accumulation of ara-CTP and response rate. Patients with complete responses demonstrated higher accumulation and delayed disappearance of ara-CTP from their blast cells than did those without response to therapy. 48 Investigators have utilized the above results as rationale for prospectively adjusting either the dosage intervals or rate of constant infusion based on initially measured ara-CTP concentrations in individual patients. I!7 At first, these studies adjusted the dosing interval at the expense of total infusion duration. This strategy was successful in producing intracellular ara-CTP concentrations above the target value in approximately 73 per cent of courses. No significant benefit in response rate could be demonstrated from these data, possibly due to the change in duration of therapy. However, dosage adjustment in the constant infusion regimen more reliably produced ara-CTP levels above the targeted range in comparison to the dose adjusted by interval alteration. 117 Prospective dosage adjustment based on extracellular pharmacokinetics may still play an important role in therapy in which intermediate or standard doses are used, owing to the wide interpatient variability in disposition of ara-C. Methotrexate Pharmacokinetic monitoring of patients receiving high-doses of methotrexate with leucovorin rescue can substantially reduce morbidity and mortality associated with this agent. 51, 155 This is achieved by using methotrexate plasma concentrations to identifY patients who are at high risk of

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toxicity, then adjusting the standard rescue measures (hydration, alkalinization, and leucovorin) based on drug disposition. 1 This strategy for monitoring methotrexate serum concentrations and adjusting leucovorin rescue to reduce toxicity, has been described in detail. 51 • 155 Children, on an average, have higher rates of methotrexate systemic clearance when compared to adults with serum creatinine within the normal range for age. However, considerable variability in both populations does not enable prediction of methotrexate clearance from age and body surface area. Figure 2 depicts this relationship for 153 pediatric54 and 17 adult subjects,88 and primarily reflects diminishing renal function with increasing age. Multiple factors can result in altered disposition of methotrexate after infusion of high doses including: renal function, pleural effusion, ascites, and GI obstruction. 31. so. 52 Some of our recent investigations have evaluated the degree of alkalinization and hydration prescribed around high-dose methotrexate (HDMTX) infusions. We found higher plasma methotrexate concentrations and increased toxicity in pediatric patients with ALL treated with a less intensive alkalinization and hydration regimen compared to a more conventional hydration and alkalinization regimen. 34 Another inter-

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esting investigation has shown that patients with Down's syndrome sustain higher methotrexate plasma concentrations, related in part to altered clearance, and develop more severe toxicity than control patients. 61 Some early work on methotrexate pharmacodynamics was conducted by the Children's Cancer Study Group, which demonstrated the potential importance of CSF pharmacokinetics in the efficacy of intrathecal methotrexate. 20 Using methods developed by Bleyer, children with ALL were dosed with intrathecal (IT) methotrexate based on volume of cerebrospinal fluid (CSF) in relation to age, rather than body size. This method was utilized to provide more uniform concentrations of methotrexate within the CSF and resulted in lower incidence of CNS leukemia compared to historical controls. 20 Intrathecal, combined with systemic HDMTX, is currently being proposed as the sole entity for CNS prophylaxis in children with ALL iIi favorable risk groups, stressing the importance of uniform qosing strategies. 2 When methotrexate is used to treat CNS leukemia, concentrations achieved in the CSF can be quite variable despite administration via an Ommaya reservoir. 156 Strother et al. recently have suggested an individualized dosing strategy for maintaining CSF methotrexate levels in a potentially cytotoxic range for a specified time. 156 Plasma concentrations of methotrexate following oral administration can be quite variable and absorption incomplete. Craft et al. utilized this variability to segregate children receiving oral methotrexate for therapy of ALL into two groups depending on their absorption characteristics. 38 Children not achieving a selected plasma concentration (0.44 IJ.M) were more likely to experience a relapse in their disease. Based on these data, patient compliance to a prescribed on~l methotrexate regimen may be an important factor in outcome. Measurement of methotrexate in erythrocytes can directly reflect the amount of drug ingested weekly. Because accumulation and elimination of methotrexate in the erythrocyte occurs over many weeks, this test may provide a good assessment of long-term compliance. 138 However, methotrexate is considered an important aspect in maintenance therapy of ALL and its optimal utilization with the lowest interpatient variability may lead to more parenteral administration. 159 We have evaluated the disposition of methotrexate in 108 pediatric patients with standard risk, newly diagnosed ALL. 54 Patients received methotrexate in a dosage of 1 gm per m 2 infused over 24 hours for a total of 15 postinduction courses. Significant prognostic variables for hematologic relapse included leukemia cell DNA content, hemoglobin, and steady-state plasma concentrations of methotrexate. Fifty-nine patients with median methotrexate concentrations <16 IJ.M (higher clearance) had a significantly lower probability of remaining in remission than the 49 patients with concentrations >16 IJ.M (lower clearance).54 However, the clinical importance of these pharmacodynamic data may be influenced by the intensity of other components of ALL therapy, necessitating prospective clinical trials to establish the situations in which individualized dosages are warranted. Borsi et al. have reported higher methotrexate clearances in children with ALL who relapsed, compared to those in continuous complete remission. 23 Moreover, some patients who had recurrent ALL were treated with

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doses of methotrexate that were much higher than the doses used in initial therapy, and fast methotrexate clearance remained a poor prognostic factor regardless of methotrexate dosage. Although this article does not discern if the relapsed patients had developed relative resistance to methotrexate secondary to prior exposure to significant amounts of methotrexate on their initial treatment regimen, the overall results corroborate our previous findings of a relation between high-dose methotrexate clearance53 or systemic exposure 54 and clinical response in children with ALL. Prospective methotrexate dosage adjustment has been performed with the aid of a small test dose,29 providing pharmacokinetic data that are then used to derive a dosage for constant infusion. However, Bayesian estimation with a smaller number of samples after the test dose has been suggested as a more logical approach in the clinical setting. 27 Overall, this methodology has limited application since a test dose must be given just prior to each HDMTX infusion, and it is easier to adjust the dosage of methotrexate or leucovorin based on serum concentrations measured with the therapeutic (versus test) dosage of HDMTX. After minimizing the variation in systemic exposure to high-dose methotrexate, another possible pharmacokinetic consideration focuses on reducing variation in leucovorin rescue. Pharmacodynamic studies have attempted to determine optimal rescue regimens for a prescribed dose and plasma concentration of methotrexate,137 but these may not be optimal without characterization of the pharmacokinetics of leucovorin. However, leucovorin is administered as a racemic mixture with only one isomer exhibiting biologic activity. Assay methods that can distinguish different leucovorin isomers have been developed,169 but such methods are not yet widely available for large clinical studies of leucovorin dispOSition and the development of more precise dosages for rescue following HDMTX.

ANTHRACYCLINES Daunorubicin and Doxorubicin The anthracycline antibiotics, daunorubicin and its 14-hydroxy derivative, doxorubicin, have been in general clinical use for about 20 years and are among the most active drugs used to treat pediatric malignancies. The exact mechanism of the cytotoxic action of these drugs is poorly understood. DNA has long been thought to be the primary target for the cytotoxic effects of the anthracyclines, because they bind to DNA by intercalation and drug fluorescence accumulates in the nuclei of treated cells. 21. 30 However, SOme studies 161 have shown that anthracyclines can be cytotoxic without entering cells and may produce lethal effects by interaction with cell membranes. Other work suggests that these drugs result in lethality through the formation of free radicals 103 that attack DNA and cell membranes. Thus, several mechanisms may be at work in producing the anticancer effects of the anthracyclines. Doxorubicin and daunorubicin have basically the same toxicity profile. The acute dose-limiting toxicity for these drugs is myelosuppression, 21 while

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the chronic dose-limiting toxicity is cardiomyopathy, which is cumulative and is manifested as congestive heart failure. 30 In pediatrics, daunorubicin is generally used as part of the standard treatment for acute leukemias. It may be a component of induction therapy for acute lymphocytic leukemia and is commonly used in combination with cytarabine to treat acute myelocytic leukemia. Doxorubicin is also active against pediatric leukemias and is widely used to treat most pediatric solid tumors, including neuroblastoma, Wilms' tumor, osteosarcoma, Ewing's sarcoma, rhabdomyosarcoma, hepatoblastoma, and germ cell tumors. The anthracyclines undergo extensive metabolism and subsequent biliary elimination.1O Reduction of the C-9 carbonyl by cytoplasmic aldoketoreductases yields the alcohol metabolites, doxorubicinol or daunorubicinol, which also possess cytotoxic properties. II The parent drugs and their alcohol metabolites undergo reduction by a microsomal reductive glycosidase to form deoxyaglycones, in a reaction mediated by NADPH cytochrome P450 reductase and involving the formation of highly reactive free radicals. II The deoxyaglycones and their conjugates have been detected in bile, urine, plasma, and tissues in humans. The pharmacokinetics of doxorubicin have been evaluated in a number of studies, 13, 14, 17,32,33,40,66, 107, 126, 131 and this area recently has been reviewed in detail by Speth et al. 152 Biphasic or triphasic disposition curves are reported in most studies. The initial (alpha) half-life is less than 15 minutes and the secondary (beta) half-life is 1 to 5 hours in most studies. The terminal phase (gamma) half-life is generally 15 to 30 hours. Studies have reported clearances ranging from 200 to 1200 ml per min per m 2. Recently, Rodvold et al. 134 have reported a significantly slower clearance, longer terminal half-life, and greater area under the curve (AUC) for obese patients, compared to patients with a normal weight for height. No difference in toxicity or efficacy of doxorubicin was seen between the two groups, however. Patients with compromised hepatic function are thought to be at greater risk for the acute toxicities of the anthracyclines, particularly myelosuppression. On the basis of clinical observation and pharmacokinetic studies, Benjamin et al. 15, 16 have suggested empiric guidelines for dosage reductions of the anthracyclines, based on serum bilirubin and liver transaminase concentrations. We have observed markedly reduced doxorubicin clearance (200-300 ml per min Per m 2) in two children with serum bilirubin concentrations of 1. 7 and 4.5 mg per dl. 42 Limited data are available on the effects of hepatic function on the pharmacokinetics of the anthracyclines, however. Numerous studies l36, 167, 166 have demonstrated that there is a relationship between cumulative dosage of doxorubicin and the risk of development of cardiotoxicity. In general, the risk of toxicity increases significantly when the cumulative lifetime dosage exceeds 550 mg per m 2 of doxorubicin and 650 mg per m 2 of daunorubicin. In addition, very young pediatric patients may be more sensitive to the cardiotoxic effects of the anthracyclines,120 and therefore lower limits (350-450 mg per m 2 of doxorubicin) may be observed in children. Although the upper limits specified above are often regarded as absolute maximums for the lifetime dosage of anthracyclines,

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it is important to recognize that the risk of cardiotoxicity increases continuously across the dosage range. In the large study by von Hoff et al. 167 for children up to 14 years of age, the risk of cardiotoxicity was about 1.5 per cent at a dosage of 350 mg per m 2, 2.6 per cent at 450 mg per m 2, and 6 per cent at 550 mg per m 2, increasing to about 50 per cent at a dosage of 950 mg per m 2 • Because of the wide spectrum of activity of these drugs, and their use in pediatric diseases in which there is a high likelihood of cure, an emphasis in current research protocols has been to reduce the incidence and severity of their chronic cardiotoxicity, and permit the use of higher cumulative lifetime dosages. Chief among these approaches is the use of low weekly dosages or continuous infusions, in place of the more traditional higher dosages administered every 3 weeks. Several studies have reported a lower incidence of heart failure when doxorubicin is administered on a weekly intravenous schedule l73, 174 or by continuous intravenous infusion. 60, 97. 150, 151 These studies suggest that higher cumulative lifetime dosages of these drugs may be administered without increasing the likelihood of developing congestive heart failure, which may result in the increased efficacy of these compounds. Cumulative dosages of up to 1100 mg per m 2 of doxorubicin have been delivered without evidence of cardiac toxicity in 48- to 96-hour infusions. lSI Studies performed to date have not demonstrated a decrease in the clinical efficacy of doxorubicin administered in lower weekly doses, or by continuous infusion,102 Continuous infusion anthracycline administration avoids high peak plasma concentrations, which may be associated with the development of cardiotoxicity, while maintaining equivalent areas under the concentration-time curve (AUC). Similarly lower weekly dosages of anthracyclines yield lower peak plasma concentrations relative to high dosages given every 3 weeks, Although these results appear promising in early adult studies, prospective, randomized, controlled clinical trials are needed to prove that continuous infusion therapy results in reduced toxicity and equivalent therapeutic efficacy. In addition, all studies reported to date have been performed in adults, and no pediatric studies have been performed to demonstrate similar improvement in the therapeutic index of anthracyclines given in this fashion. Complexes of doxorubicin with liposomes, DNA, starch and albumin microspheres, and iron have been developed in attempts to reduce cardiotoxicity.127 In general, these complexes reduce the peak doxorubicin concentrations and function as slow-release dosage forms. Animal studies l65 have demonstrated reduced cardiotoxicity with doxorubicin in liposomes, without loss of efficacy, and human phase I studies have been initiated. Complexes of DNA and doxorubicin have been evaluated in clinical studies,13, 67, 93 as have microspheres for the local delivery of doxorubicin. lIO, 178 A slow release form of doxorubicin ([2"-Rl-4'-0-tetrahydropyranyldoxorubicin [THP-doxorubicin]) has been investigated in clinical studies, 59 and has antitumor activity similar to that of doxorubicin. 158 All of these approaches remain investigational and no substantial advantage for these methods have yet been conclusively demonstrated. The safety and efficacy of these approaches have not been evaluated in pediatric patients at this time. Although some pharmacodynamic relationship between high anthra-

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cycline concentrations and the likelihood of developing cardiotoxicity is suggested by the above data, it has been more difficult to establish a correlation between pharmacokinetic parameters and the efficacy of the anthracyclines. Kokenberg et a1. 90, 91 have studied daunorubicin pharmacokinetics in 37 adult patients with acute nonlymphocytic leukemia during induction therapy. These investigators measured daunorubicin concentrations in plasma, white blood cells, and bone marrow nucleated cells but found no correlation between any pharmacokinetic parameter and the response to therapy, defined as a complete remission, partial response, or resistant disease. This may be due to the biologic heterogeneity of acute nonlymphocytic leukemia, and the variability in the inherent sensitivity of tumor cells to daunorubicin. In general, the chronobiology of anticancer drug therapy has not been extensively studied. Hrushesky74, 75 has studied the effect of circadian rhythm on the toxicity and efficacy of anticancer therapy, to determine the optimal time of day to administer anticancer drugs. These studies suggest that this may be an important factor for doxorubicin in some drug-sensitive malignancies, but further studies are needed to corroborate these early results and to determine the importance of chronobiology in pediatric malignancies. Research efforts to improve the clinical use of the anthracyclines have focused on reducing the cardiotoxicity of these important agents. Although a number of approaches has shown promise in adult studies, none has been evaluated in pediatric patients, and all remain under investigation. Conclusive evidence that one or more of these approaches will permit the use of greater cumulative dosages of the anthracyclines in patients with sensitive malignancies will be an important development in anticancer drug therapy.

OXAZAPHOSPHORINES Ifosfamide

Ifosfamide is a structural isomer of cyclophosphamide, which is gaining increasing use in pediatrics, primarily because of its clinical activity against soft tissue sarcomas, osteosarcoma, Ewing's sarcoma, Wilms' tumor, and neuroblastoma. 188 Although this agent was developed many years ago, until recently its use was severely limited by its dose-limiting toxicity: hemorrhagic cystitis. The introduction in the early 1980s of a specific antidote for the uroepithelial toxicity, mesna (sodium 2-mercaptoethane-sulphonate), has allowed for use of effective doses of ifosfamide without the complication of hemorrhagic cystitis.142 The same metabolite, acrolein, appears to cause both cyclophosphamide- and ifosfamide-induced hemorrhagic cystitis. 142 The metabolic scheme for the two agents (Fig. 3) is qualitatively similar,58 although there are important quantitative differences. A larger percentage of ifosfamide is eliminated as both unchanged parent drug and as the dechloroethylated metabolite. 24, 188 This may partially explain why larger doses of ifosfamide, compared to cyclophosphamide, are required for anticancer effect. Dechlo-

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roethylation results in formation of chloroacetaldehyde, which probably contributes to neurotoxicity62 and has been suggested as a contributor to bladder toxicity. The 4-hydroxyoxazaphosphorine breaks down to release phosphoramide mustard and acrolein. In addition to its presence in the bladder, acrolein may be released throughout the body; however, there is a relative lack of sulfhydryl-containing compounds in the bladder and therefore there is little or no detoxifying mechanism for acrolein present in the urine. 142 Mesna has pharmacokinetic properties that make it well suited to use as a uroprotective. 142 , 188 It may be given orally or intravenously; within minutes it is oxidized to an inactive form (dimesna) and stays largely in the extracellular intravascular compartment prior to its glomerular filtration into the urine. In adults, it has a rapid half-life of 1.5 hours. Filtered dimesna is readily reduced to the thiol mesna by renal tubular cells; this is then free to bind to acrolein and thus prevent urotoxicity. Dimesna has few systemic effects, although it can cause gastrointestinal toxicity (nausea, vomiting, cramps, and diarrhea) at higher doses. It does not interfere with anticancer effects or with non urinary toxicities of ifosfamide. There are currently no published pharmacokinetic data for ifosfamide in children; studies are ongoing. In adults, about 55 per cent of ifosfamide is recovered in urine as unchanged drug. 5 The importance of renal elimination for ifosfamide is supported by evidence that prior therapy with greater than three courses of the nephrotoxic drug cisplatin was associated with a lower WBC nadir, more severe neurotoxicity, and more nephrotoxicity.64 In adults, plasma concentration data best fit a two-compartment model with a 16-hour terminal half-life after single doses of 3. 8 to 5 gm per m 2, and a one-compartment model with a 6.9-hour half-life after divided daily doses of 1.6 to 2.5 gm per m 2. The schedule and dosing of ifosfamide in children is still under investigation. At our institution, mesna is administered at 25 per cent of the ifosfamide dose immediately following ifosfamide and then 3 and 6 hours later, with good success at prevention of cystitis or gross hematuria (1 case of hematuria out of over 200 courses), with occasional episodes of vomiting and diarrhea. When compared to cyclophosphamide in a group of adults with soft tissue sarcomas treated in a phase II study, there was a higher response rate in the group receiving ifosfamide with less leukopenia, although nausea and vomiting were more common with ifosfamide. 25 Ifosfamide has been shown to have antitumor activity even in patients who had been previously treated with cyclophosphamide, so there is not total cross-resistance between the two drugs. 121 Ifosfamide causes more nephro- and neurotoxicity than does cyclophosphamide. The biochemical basis for its nephrotoxic effects is not understood; chloroacetaldehyde has been postulated to be causative for neurotoxicity because it is structurally similar to metabolites of ethanol and chloral hydrate, and chloroacetaldehyde plasma concentrations were higher in ifosfamide-treated patients with neurotoxicity than those without. 62 Although it has largely been studied in patients who have failed standard regimens, it appears that ifosfamide will find a niche in pediatric oncology distinct from that of cyclophosphamide.

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Cyclophosphamide Cyclophosphamide has been used for many years in the treatment of pediatric malignancies, including Hodgkin's and non-Hodgkin's lymphomas, acute lymphocytic leukemia (ALL), rhabdomyosarcoma, and Ewing's sarcoma. Cyclophosphamide also is frequently used as part of preparative regimens for bone marrow transplantations. Its purpose is both to cause immunosuppression (to decrease the risk of graft versus host disease) and to kill any remaining malignant cells. Because it can be given in higher doses than are possible without marrow rescue, cyclophosphamide activity is seen even against tumors that are normally resistant (e.g., acute myelogenous leukemia [AMLJ). It is used with both allogeneic marrow transplants, for various leukemias and aplastic anemia, and for autologous transplants, thereby permitting high-dose chemotherapy for several cyclophosphamideresponsive pediatric solid tumors as well as hematologic malignancies. There are a number of pharmacokinetic, scheduling, and toxicity considerations for cyclophosphamide used in this fashion. It has been suggested that there is a significant intrapatient decrease in cyclophosphamide half-life after repeated doses, attributed to autoinduction of cytochrome P450 drug metabolizing enzymes for cyclophosphamide. 139 This is relevant to its use pretransplantation because cyclophosphamide is often given in two to four daily doses of 40 to 60 mg per kg per day. Schuler et al. studied cyclophosphamide plasma pharmacokinetics and active metabolites (by assay of acrolein) in plasma. 139 Eleven subjects received cyclophosphamide 50 mg per kg per day for 4 days prior to allogeneic transplant. There were significant decreases in cyclophosphamide half-life from day 1 to day 2 and from day 1 to day 4 (mean 7.1, 5.5, and 4.3 hours, respectively). The plasma AVC values for the active metabolites increased from day 1 to day 2 and from day 1 to day 4, although the urinary excretion of cyclophosphamide as a percentage of administered dose did not change over the 4-day period. Whether there was an inductive effect on the dechloroethylation of cyclophosphamide was not addressed. In addition, the half-life of cyclophosphamide is lower in children (1-6.5 hours) than that reported in adults (4-lO hours).43 When considered along with evidence that therapeutic efficacy for cyclophosphamide may be enhanced with low-level persistent 4-hydroxycyclophosphamide plasma concentrations as opposed to high peak levels,l66 these data indicate that scheduling and dosing of multiple doses of cyclophosphamide may be important considerations for its use pretransplantation. Cyclophosphamide frequently is given along with total body irradiation (TBI) prior to transplantation for hematologic malignancies because of its additional immunosuppressive as well as cytotoxic effects. Therefore, it is sometimes difficult to differentiate the toxicities associated with TBl. 187 TBI is associated with fever, nausea, vomiting, diarrhea, interstitial pneumonitis, and venocclusive disease. The combination of cyclophosphamide and TBI is associated with severe oral mucositis that may last for 2 to 4 weeks. Specific toxicities of cyclophosphamide include alopecia, hemorrhagic cystitis (about 25 per cent of patients without concurrent mesna), inappropriate antidiuretic hormone secretion, and cardiotoxicity. The maximal dose of cyclophosphamide for transplantation is 200 mg per kg, with the nonhe-

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matologic dose-limiting toxicity being cardiac. 6. 160 Long-term, cyclophosphamide and TBI result in sterility in most postpubertal patients and delayed or hampered secondary sex characteristics in prepubertal patients. 187 Sterility caused by cyclophosphamide alone is reversible in some patients. One potentially important consideration is the order in which cyclophosphamide and TBI are given. Traditionally, preparative chemotherapy has preceded TBI. Recently, however, that order has been reversed, 26. 125 based on studies in mice demonstrating that fewer residual leukemic cells survived when Tin was followed by cyclophosphamide. In a study of allogeneic bone marrow transplant in children with leukemia,26 the results were 5-year disease-free survival estimates of 64, 42, and 23 per cent for ALL in second, third, and fourth remission, and 66, 75, and 33 per cent for AML in first, second, and third remission or relapse, respectively, which compare favorably with previous studies. As preparative regimens for bone marrow transplantation become more complex (e. g., addition of cytarabine, carmustine, and thioguanine), clinicians must be cognizant of the potential for drug interactions, leading to the development of unexpected toxicity.6 More complete pharmacokinetic and pharmacodynamic characterization of cyclophosphamide and its metabolites may prove useful tools in predicting and avoiding these interactions. It has been suggested that a phenotypic deficiency of aldehyde dehydrogenase could lead to low formation of an inactive metabolite, carboxyphosphamide, and in turn an increase in the formation of phosphoramide mustard. 68 In a study of 14 cancer patients given cyclophosphamide, five were characterized as "low carboxylators" and nine as "high carboxylators," based on per cent recovery as carboxyphosphamide in the urine. Although the clinical relevance Or genetic basis of these findings is not known, this study suggests that interindividual differences in oxazaphosphorine metabolizing enzymes may account for large differences in exposure to active metabolites.

EPIPODOPHYLLOTOXINS Teniposide and Etoposide Etoposide (VP 16) and teniposide (VM 26) are semisynthetic derivatives of podophyllotoxin, developed because of the unacceptable toxicity associated with the natural parent product. 86 They are phase-specific cytotoxic drugs which induce a pre mitotic block in the cell cycle possibly by stabilizing the DNA-topoisomerase II complex such that the strand rejoining activity of the enzyme is impaired. 35 They differ by a substitution on the carbohydrate moiety and are qualitatively similar when tested in vitro for cytotoxicity.79 However, clinical evaluation and the pharmacokinetic studies of the two agents have identified some potentially important differences. Etoposide is probably one of the most active single agents in the treatment of small cell lung cancer (SCLC), refractory testicular cancer, lymphomas, Kaposi's sarcoma, and acute nonlymphocytic leukemia. Teni-

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po side is extensively used in pediatric oncology, especially for acute lymphocytic leukemia, neuroblastoma, and brain tumor.35 The epipodophyllotoxin derivatives have been used successfully in combination with other anticancer drugs, most notably teniposide with cytosine arabinoside in acute lymphoblastic leukemia l29. 130 or with cisplatin for neurobiastoma70 and etoposide with cyclophosphamide or with cisplatin for lung cancer. 143 Myelosuppression, mainly leukopenia, is the primary dose-limiting toxicity when etoposide or teniposide are given in conventional doses without marrow support. lOS It usually occurs between day 7 and day 10 after the administration and resolves by day 20 to 24.43 Other less severe toxicities include moderate nausea, vomiting, diarrhea, and stomatitis. Hypersensitivity reactions have been reported in up to 45 per cent of patients treated with epipodophyllotoxins and consist of urticaria, flushing, and bronchospasm. 87. 176 These reactions usually resolve with interruption of the infusion and can be treated or often prevented by antihistamines and steroids. !O5 The higher incidence of hypersensitivity reactions with teniposide suggests that the vehicle rather than the drug itself may be responsible. The surfactant in teniposide, cremaphor (a compound known to cause histamine release in dogs and not used in the etoposide formulation), has been implicated in hypersensitivity reactions of other investigational agents. 106 Teniposide was initially administered as a 50- to 200-mg per m2 dose infused over 1 to 2 hours and repeated every 1 to 2 weeks. 43 Today, teniposide is commonly used at higher doses as part of remission induction and maintenance therapy for newly diagnosed or relapsed acute lymphocytic leukemia patients. Doses up to 600 mg per m2 given in divided doses over 3 to 5 days and repeated every 6 to 8 weeks, are now commonly administered in combination with cytosine arabinoside (900 mg per m2 per course). Prolonged teniposide continuous infusions have been investigated in an effort to increase the total dose administered, improve the therapeutic response by maintaining the exposure of cancer cells to cytotoxic concentrations of epipodophyllotoxins throughout DNA synthesis and reduce the risk of adverse effects associated with higher concentrations. 132. 140 Doses of etoposide range between 300 and 600 mg per m 2 divided over 3 to 5 days and repeated every 3 to 4 weeks. 43. 60 Weekly or twice weekly etoposide is believed to be less effective than the same total dosage given over 3 to 5 days.35 Moreover, Slevin demonstrated that patients receiving five consecutive daily doses of etoposide had a much better response rate compared with a 24 hour continuous infusion (78 versus 10 per cent). 148 Etoposide doses above the maximal tolerated dose (MTD) defined during phase I studies (300-600 mg per m2 over 3 to 5 days) have been administered to solid tumor patients. As discussed by Frei, the doseresponse curve for most chemotherapeutic agents is steep and is related to the sensitivity of a tumor to the drug. 57 However, hematologic toxicity usually limits the escalation of dose intensity to the maximally effective level. Autologuous bone marrow transplant following intensive treatment with an epipodophyllotoxin may allow one to go beyond dose-limiting hematologic toxicity by ensuring bone marrow recovery. Etoposide has

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been escalated up to 2.4 gm per m2 with bone marrow support,I83, 184 and some investigators have administered even higher doses (3.5 gm per m2) without transplantation. 119 High-dose etoposide also has been combined with other drugs, for example, cisplatin65 or cyclophosphamide3 or irradiation 22 plus bone marrow support. The time required between the marrow ablative therapy and the bone marrow transplantation still needs to be defined, since etoposide or its active metabolites may be present at low but cytotoxic levels and therefore affect marrow regeneration. 73. 101 A minimum of 48 to 72 hours after the last dose of etoposide is now the general practice for marrow transplants. The epipodophyllotoxin derivatives have appreciable differences in their respective pharmacokinetics. Etoposide has a shorter-half-life and is excreted to a greater extent unchanged in the urine. The mean half-life has been reported to range from 4 to 8 hours for etoposide and 6 to 12 hours for teniposide. Recovery of unmetabolized etoposide in the urine ranges from 30 to 50 per cent of the total dose. For teniposide, only 5 to 20 per cent of the administered dose is accounted for as unchanged drug in urine. Hepatic metabolism and biliary excretion of the two drugs is not well understood. 35 Plasma protein binding of teniposide is about 99 per cent compared to about 94 per cent for etoposide. The higher protein binding and the lower renal clearance of teniposide could explain its slower elimination. 4 Etoposide has been administered orally. Bioavailability from the investigational solution and hydrophilic capsule is about 50 per cent. 41 However, there is considerable intra- and interpatient variability in bioavailability, so that consistent absorption cannot be assured. 35 Information on the dose adjustment of epipodophyllotoxins in patients with renal or hepatic dysfunction is limited. A significant correlation between etoposide AVC and plasma creatinine (r = 0.5, p < 0.001) was described by Clark. 36 Based on a significant correlation between creatinine clearance and etoposide clearance, D'Incalci suggested that etoposide dose should be reduced in patients with renal dysfunction, although no guidelines were provided. 44 Arbuck and coworkers demonstrated that creatinine clearance was a predictor of etoposide systemic clearance (r = 0.41). Albumin was the next strongest predictor, improving the r to 0.79. 7 Renal dysfunction, due to prior cisplatin, also has been associated with a significant decrease in etoposide renal and systemic clearance. III Etoposide systemic clearance is not reduced in patients with abnormal bilirubin, 7, 44, 69 although an association between etoposide systemic clearance and other clinical indicators such as AST and alkaline phosphatase has been described. lll, 145 Recent work has revealed that cancer patients with abnormal liver function tests (low albumin and increased total bilirubin) are more likely to have an increased etoposide free fraction. Low albumin concentrations have also been associated with higher systemic clearance. 7, 145 Therefore, it is- plausible that the expected decrease in systemic clearance in patients with abnormal liver function (i.e., increased bilirubin) is not observed because they usually have decreased protein binding owing to lower serum albumin. These offsetting changes in metabolism and protein binding could yield little or no change in systemic clearance of total drug,

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although clearance of free (active) etoposide may be diminished in these patients. 153 For teniposide, a significant decrease in systemic clearance has been associated with increased alkaline phosphatase and GGT. 28. 144 There has been no single investigation of the pharmacokinetics of etoposide or teniposide in both children and adults using the same methodology. Comparative evaluations of reports on the pharmacokinetics of epipodophyllotoxins in children or adults have failed to show any difference in the systemic clearance of etoposide or teniposide. 43 However, the systemic clearance of teniposide in children is age related, with younger children having a more rapid clearance than older children, as depicted in Figure 4.56 Pfluger reported a longer elimination half-life in elderly patients, although the association of aging with other indicators (renal or hepatic function) cannot be excluded. III Teniposide clearance in children and adults is lower than etoposide and may be related to higher protein binding of teniposide compared with etoposide (99 per cent versus 94 per cent),4. 43 and attributable to differences in their metabolism. Relationship between the pharmacokinetics of the epipodophyllotoxins and their clinical effects have been explored by several investigators. Although some could not demonstrate any correlation between marrow toxicity and pharmacokinetic parameters of etoposide, Bennett et al. described a relationship between the steady state concentration during a continuous infusion and bone marrow toxicity. 18 In a small pediatric study, Sinkule found a correlation between etoposide elimination rate constant and thrombocytopenia. 145 Granulocyte count nadirs were found to be generally lower in patients with larger area under the concentration-time curve (AVe) and lower clearance, although these relationships were weak. 154 Oncolytic response to teniposide therapy, measured as the decrease in circulating leukemic blasts has been correlated with teniposide area under the curve l44 and concentrations at steady state. 132 In the latter study, gastrointestinal toxicity (mucositis) was also related to the concentration during the continuous infusion (Fig. 5). As reviewed by Frei, dose is a critical factor for many anticancer drugs when administered to patients with drug-sensitive tumors. 57 An increased proportion of patients responding to epipodophyllotoxin therapy has been demonstrated with higher dose levels. 184 Hryniuk proposed a dose-intensity concept that takes into account not only the total dose but also the amount of time over which the dose is administered. In his analysis, it was demonstrated that etoposide at a dose of 500 mg per m 2 per week had a 65 per cent probability to induce a complete or partial remission in non-small cell lung cancer, compared with a 20 per cent response rate when the dose intensity was 250 mg per m 2 per week. 76 A further step in refining the dosage of epipodophyllotoxins may be to standardize therapeutic intensity by individualizing doses to achieve a target systemic exposure. Systemic exposure can be defined by pharmacokinetic parameters such as clearance or area under the plasma concentration curve (AV e). Because pharmacokinetic parameters (e. g., clearance) of most anticancer drugs vary between patients by a factor of 2 to 10, a similar variation in the systemic exposure occurs when standardized dosages are administered. For anticancer drugs with steep dose-response curves and

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highly variable pharmacokinetics (i.e., most anticancer drugs), systemic exposure may be a more informative index of treatment than dose intensity. Our laboratory recently reported the result of a phase I and II study of continuous infusion teniposide pharmacokinetics, toxicity, and clinical response in children with leukemia and solid tumors.132 A tenfold variation in teniposide clearance yielded substantial overlap of steady-state serum concentrations between various dose levels. An important finding of this study was the significant relation between systemic exposure and oncolytic response as depicted in Figure 5. Moreover, there was a poor relation between dose and response. In a subsequent study, we demonstrated the feasibility of adjusting teniposide doses to a target steady-state concentration (10 /-Lg per ml) as a strategy to adjust therapy for the wide interpatient pharmacokinetic variability. Blood samples were obtained at 1 and 6 hours from the start of the infusion and dose adjustments were made by hour 12. The 36-hour concentration Oust before the end of the infusion) was used to assess the precision of the dose adjustment. A mean end of infusion concentration of 12.4 /-Lg per ml (CV: 36 per cent) was attained, demonstrating the feasibility of minimizing interpatient variability in systemic exposure.1 33 Given the variation in systemic exposure associated with standardized dosages, its relation with clinical outcome, and the feasibility of individualizing drug therapy, it is our opinion that dose escalation in phase I studies should not be the endpoint; rather maximal tolerated systemic exposure

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(MTSE) should be defined. Consequently, our group has undertaken a phase I and II study to determine the MTSE of teniposide in leukemic children with bone marrow relapse. Our rationale is based on the assumption that the proportion of patients responding to therapy increases with systemic exposure, a hypothesis consistent with previous in vitro studies by Wolff.185 We postulate that the use of individualized dosages to achieve the MTSE in each patient should be more likely to produce oncolytic responses in future phase II clinical trials with epipodophyllotoxins and other anticancer agents. 55

VINCA ALKALOIDS Vincristine and Vinblastine Vincristine and vinblastine are alkaloids derived from the periwinkle plant, Vinca rosea Linn. Both agents have been in clinical use for over 25 years, and are important therapeutic agents in the treatment of several childhood malignancies. Vinca alkaloids exert their cytotoxic effects by binding to tubulin, which is required for a number of cellular functions including mitosis. Vinca binding leads to dissolution of the mitotic spindle structure, 182 which results in halted mitosis or cell death. Although vincristine and vinblastine are structurally similar, their activities and toxicity are quite different. Vincristine is active against leukemia, lymphoma, sarcoma, and neuroblastoma. Vinblastine is useful in the treatment oflymphoma, testicular cancer, breast cancer, and other solid tumors. Neuropathy is the dose-limiting toxicity of vincristine,175 whereas the dose-limiting toxicity of vinblastine is myelosuppression. The importance of these agents is underscored by their inclusion as first-line therapy in several malignancies that can be cured by chemotherapy, including acute lymphocytic leukemia, Hodgkin's disease, and various lymphomas. Investigations of the pharmacokinetic properties of the vinca alkaloids have been performed primarily in adult populations. The only pharmacokinetic study of these agents in children reported parameters similar to those previously found in adult studies. Limitations of these studies include small patient populations and the lack of a specific assay. To date, most studies assessing the pharmacokinetics of vinca alkaloids have used radioimmunoassay (RIA) techniques. As typically used, RIA techniques are of limited value because they cannot differentiate between parent compound and metabolites. Sensitive and specific high-performance liquid chromatographic techniques recently have been developed, and should lead to better understanding of the pharmacokinetics of these drugs. 46 The pharmacokinetic information obtained from clinical studies has led to investigations of alternative dosing regimens. Standard utilization of vincas has been by weekly intravenous bolus. 84 Reasons for exploring other dosing regimens include observations with in vitro models that demonstrate the superiority of daily dosing compared to single bolus doses 39 and the discovery that optimal cytostatic effects of vinca alkaloids depend not only on drug

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concentration, but also on length of exposure as well. 163 Additionally it has been shown that vinca alkaloids given as infusions are active in advanced refractory human cancer. 124, 170 Although these regimens are usually well tolerated, prolonged vincristine infusions have yet to demonstrate Significant increases in activity. Toxicity caused by continuous infusion vincristine was assessed in nine pediatric patients treated with high-dose chemotherapy and radiation for consolidation of remission in neuroblastoma or sarcoma. Patients received vincristine (1.5 mg per m 2 ) as a bolus followed by a 5-day continuous infusion of vincristine (0.5 mg per m 2 per day). The most notable toxicity was deep muscle pain occurring at the end of infusion. Peripheral neuropathy was not a problem. 115 Although continuous infusion vincristine appears safe, and results in protracted vincristine serum concentrations, increased effectiveness must be demonstrated in comparative trials before this approach can be recommended. The development of tumor resistance to vinca alkaloids has been demonstrated in vitro. 146, 181 Currently, the only clinical approach to bypassing drug resistance is combination therapy using drugs with alternative mechanisms of action. In experimental models, vinca resistance has been linked to enhanced drug effiux. In vitro studies suggest that reducing drug effiux or enhancing drug influx may enhance vinca activity in resistant cells. 162 Agents that alter transmembrane calcium transport (calcium channel blockers, calmodulin inhibitors, cepharathine, and quinacrine) have been shown in vitro to inhibit vincristine effiux in resistant tumor cells. 19. 78, 85 Bessho investigated the clinical application of diltiazem (a calcium channel blocker) to overcome vincristine resistance in children with refractory acute lymphocytic leukemia. Five children received diltiazem (orally) in combination with vincristine 1.5 mg per m 2 as an intravenous bolus. In four of five children a cytolytic effect was observed. One patient experienced tumor lysis syndrome, and required hemodialysis. Reversible conduction defects were seen in two children (second degree AV block with bradycardia). No increase in neurotoxicity was reported. Further study is required to determine the clinical usefulness and added toxicity of these agents. In addition to attempting to enhance cytotoxicity of vinca alkaloids in target cells, attempts have been made to reduce their acute and chronic toxicities. Trials of folinic acid, glutamic acid, and thiamine in conjunction with vinca alkaloids have been performed with little success. 81 - 83 The neuroprotective effects of Cronassial, a mixture of purified bovine brain gangliosides, has recently been examined. 71 Although Cronassial did not interfere with antitumor activity, it conferred minimal protection against chronic neurologic toxicities of vincristine. In a retrospective review of pediatric patients receiving induction therapy for acute lymphocytic leukemia, Woods reported a high incidence of neurotoxicity in infants smaller than 0.5 m 2 . All doses had been calculated utilizing body surface area (BSA). When recalculated using body weight, infants received 0.07 to 0.09 mg per kg of vincristine, compared with 0.03 mg per kg for adults. 186 It was recommended that children with a BSA of less than 1 square meter should receive doses based on body weight; however the clinical usefulness and pharmacokinetic basis of this dosing strategy remain to be completely defined. Alternatively, our center doses

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vincristine on the basis of body weight for all children less than one year of age. Vincristine and vinblastine are eliminated primarily via hepatic metabolism and biliary excretion. Hepatic insufficiency may impair elimination and thereby increase toxicity. Two published reports demonstrated increased toxicity in patients with elevated alkaline phosphatase (ALP).45. 164 Elevated ALP resulted in a prolonged elimination half-life and an increased AUe. The severity of neurotoxicity was directly related to the Aue and not to total cumulative dose (Fig. 6). This suggests that vincristine neurotoxicity may be related to reduced clearance (resulting in greater systemic exposure) and not to cumulative effects alone. These data suggest that a dose reduction in patients with elevated ALP may reduce toxicity. However, we feel these provocative findings must be corroborated in a prospective clinical trial using a specific vincristine assay, before they can be recommended for routine clinical dosing of vincristine. SUMMARY

The pharmacokinetics of most anticancer drugs are highly variable in children, and are commonly different when children are compared to

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adults. Several recent studies have demonstrated that variability in systemic exposure due to interpatient pharmacokinetic variability, may be related to the probability of oncolytic effects or toxicity for some anticancer drugs. This review has exemplified differences in the clinical pharmacology of several anticancer drugs, when children are compareq to adults. Such agerelated differences in the pharmacokinetics and pharmacodynamics of these drugs, together with biologic differences between pediatric and adult cancers, provide the rationale for systematically conducting pediatric phase I through IV studies of anticancer drugs and denote the risks of relying on adult trials to identify new therapeutic strategies for childhood cancers. ACKNOWLEDGMENTS The authors wish to thank Ms. Maureen Tice for her excellent secretarial support in preparing this manuscript, including a heroic effort in organizing the references. Supported in part by: NIH MERIT award R37 CA36401, Leukemia Program Project CA20180, Solid Tumor Program Project CA23066, Cancer Center CORE grant CA21765, by a Center of Excellence grant from the State of Tennessee, and by ALSAC.

REFERENCES 1. Abelson HT, Fosburg MT, Beardsley GP, et al: Methotrexate-induced renal impairment: clinical studies and rescue from systemic toxicity with high-dose leucovorin and thymidine. J Clin Oncol 1:208-216, 1983 2. Abromowitch M, Ochs J, Pui CH, et al: Efficacy of high-dose methotrexate in childhood acute lymphocytic leukemia: Analysis by contemporary risk classifications. Blood 71:866--869, 1988 3. Ahmed T, Gingrich SA, Ciavarella D, et al: Myeloablative chemotherapy followed by autologous bone marrow transplant (ABMT) for patients with refractory Hodgkin's dise;lse. Proc Am Soc Clin Oncol 6:A589, 1987 4. Allen LM, Creaven PJ: Comparison of the human pharmacokinetics of VM-26 and VP16, two antineoplastic epipodophyllotoxin glucopyranoside derivatives. Eur J Cancer 11:697-707, 1975 5. Allen LM, Creaven pJ, Nelson RL: Studies on the human pharmacokinetics of isophosphamide. Cancer Treat Rep 60:451, 1976 6. Appelbaum FR, Buckner CD: Overview of the clinical relevance of autologous bone marrow transplantation. Clin HaematoI15:1-17, 1986 7. Arbuck SG, Douglass HO, Crom WR, et al: Etoposide pharmacokinetics in patients with normal and abnormal organ function. J Clin Onc 4:1690-1695, 1986 8. Arndt CA, Balis FM, McCully CL, et al: Bioavailability of low-dose vs high-dose 6mercaptopurine. Clin Pharmacol Ther 43:588-591, 1988 9. Avramis VI, Bjener R, Krailo M, et al: Biochemical pharmacology of high dose 1-betaD-arabinofuranosylcytosine in childhood acute leukemia. Cancer Res 47:6786--6792, 1987 10. Bachur NR: Adriamycin (NSC-123127) pharmacology. Cancer Chemother Rep (Part 3) 6:153-158, 1975 11. Bachur NR: Anthracycline antibiotic pharmacology and metabolism. Cancer Treat Rep 63:817-8~0, 1979 12. Balis FM, Holcenberg JS, Zimm S, et al: The effect of methotrexate on the bioavailability of oral 6-mercaptopurine. Clin Pharmacol Ther 41:384-387, 1987 13. Baurain R, Deprez-De Campeneere D, Zenebergh A, et al: Plasma levels of doxorubicin after IV bolus injection and infusion of the doxorubicin-DNA complex in rabbits and man: Comparison with free doxorubicin. Cancer Chemother Pharmacol 9:93-96, 1982

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14. Benjamin RS, Riggs CE, Bachur NR: Pharmacokinetics and metabolism of Adriamycin in man. Clin Pharmacol Ther 14:592-600, 1973 15. Benjamin RS, Wiernik PH, Bachur NR: Adriamycin chemotherapy-efficacy, safety, and pharmacologic basis of an intermittent single high-dosage schedule. Cancer 33:19-27, 1974 16. Benjamin RS: A practical approach to Adriamycin (NSC-123127) toxicology. Cancer Chemother Rep Part 3 6:191-194, 1975 17. Benjamin RS, Riggs CE, Bachur NR: Plasma pharmacokinetics of Adriamycin and its metabolites in humans with normal hepatic and renal function. Cancer Res 37:15161520, 1977 18. Bennett CL, Sinkule JA, Schilsky RL, et al: Phase I clinical and pharmacological study of 72-hour continuous infusion of etoposide in patients with advanced cancer. Cancer Res 47:1952-1956 19. Bessho F, Kinumaki H, Kobayashi M, et al: Treatment of children with refractory acute lymphocytic leukemia with vincristine and diltiazem. Med Ped Oncology 13:199, 1985 20. Bleyer A, Coccia PF, Sather HN, et al: Reduction in central nervous system leukemia with a pharmacokinetically derived intrathecal methotrexate dosage regimen. J Clin Oncoll:317-323, 1983 21. Blum RH, Carter SK: Adriamycin: a new anticancer drug with significant clinical activity. Ann Intern Med 80:249-259, 1974 22. Blume KG, Forman SJ, O'Donnell MR, et al: Total body irradiation and high-dose etoposide: a new preparatory regimen for bone marrow transplantation in patients with advanced hematologic malignancies. Blood 69:1015-1020, 1987 23. Borsi JD, Moe PJ: Systemic clearance of methotrexate in the prognosis of acute lymphoblastic leukemia in children. Cancer 60:3020-3024, 1987 24. Brade WP, Herdrich K, Varini M: Ifosfamide-pharmacology, safety and therapeutic potential. Cancer Treat Rev 12:1-47, 1985 25. Bramwell VHC, Mouridsen. HT, Santoro A, et al: Cyclophosphamide versus ifosfamide: final report of a randomized phase II trial in adult soft tissue sarcomas. Eur J Cancer Clin Oncol 23:311-321, 1987 26. Brochstein JA, Kernan NA, Groshen S, et al: Allogeneic bone marrow transplantation after hyperfractionated total-body irradiation and cyclophosphamide in children with acute leukemia. N Engl J Med 317:1618-1624, 1987 27. Bruno R, Iliadis A, Favre R, et al: Dosage predictions in high-dose methotrexate infusions. Part 2. Bayesian estimation of methotrexate clearance. Cancer Drug Deliv 2:277-282, 1985 28. Canal P, Bugat R, Roche MH, et al: Pharmacokinetics of teniposide (VM 26) after IV administration in serum and malignant ascites of patients with ovarian carcinoma. Cancer Chemother Pharmacol 15:149-152, 1985 29. Cano JP, Bruno R, Lena N, et al: Dosage predictions in high-dose methotrexate infusions. Part 1. Evaluation of the classic test-dose protocol. Can Drug Deliv 2:271-275, 1985 30. Carter SK: Adriamycin-a review. JNCI 55:1265-1274, 1975 31. Chan H, Evans WE, Pratt CB: Recovery from toxicity associated with high-dose methotrexate: Prognostic factors. Cancer Treat Rep 61:797-804, 1977 32. Chan KK, Cohen JL, Gross JF, et al: Prediction of Adriamycin disposition in cancer patients using a physiologic, pharmacokinetic model. Cancer Treat Rep 62:1161-1171, 1978 33. Chan KK, Chlebowski RT, Tong M, et al: Clinical pharmacokinetics of Adriamycin in hepatoma patients with cirrhosis. Cancer Res 40:1263-1268, 1980 34. Christensen ML, Rivera GK, Crom WR, et al: Effect of hydration on methotrexate plasma concentrations in children with acute lymphocytic leukemia. J Clin Oncol 6:797-801, 1988 35. Clark PI, Slevin ML: The clinical pharmacology of etoposide and teniposide. Clin Pharmacokinet 12:223-252, 1987 36. Clark PI, Joel SP, Houston S: Predictors of etoposide pharmacokinetics in man. Proc Am Assoc Cancer Res 29:A764, 1988 37. Colly LP, Peters WG, Richel D, et al: Deoxycytidine kinase and deoxycitidine deaminase values correspond closely to clinical response to cytosine arabinoside remission induction therapy in patients with acute myelogenous leukemia. Semin Oncol14(Suppl 1):257-261, 1987

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