Pharmacokinetics of oral zidovudine administered during labour: a preliminary study.

OBJECTIVES: The aim of this study was to determine whether oral zidovudine (ZDV) given during labour would provide a similar systemic exposure to the established intravenous regimen used to prevent mother-to-child transmission in HIV-infected pregnant women. METHODS: ZDV pharmacokinetic parameters following oral administration during labour were determined in 10 HIV-infected pregnant women in active labour. All subjects were converted to intravenous ZDV prior to delivery. RESULTS: In cohort 1 (n=6), subjects received 300 mg oral ZDV every 3 h for three doses. Oral therapy was well tolerated but plasma ZDV concentrations were substantially lower than previously reported with continuous intravenous therapy. Based on the pharmacokinetic results from cohort 1, women in cohort 2 (n=4) received an initial 600 mg dose followed by two 400 mg doses every 3 h. ZDV area under the curve and concentrations in cohort 2 increased approximately in proportion to the increase in dose but varied 6-7-fold. In both cohorts, ZDV pharmacokinetic parameters suggested erratic absorption. CONCLUSIONS: While ZDV exposure improved with the increased dosing regimen, our sample size was small and larger studies are needed to establish whether oral ZDV administration during labour can consistently provide equivalent exposure to intravenous administration.

Design of antiretroviral clinical trials for HIV-1 infected pregnant women and their newborn infants.

Antiretroviral therapy has been highly successful in reducing mother to child transmission of human immunodeficiency virus-1 infection in pregnant women. However, the treatment regimens are intensive, difficult to deliver in less developed countries, and there are limited pharmacology studies addressing critical questions regarding maternal safety and fetal risk. There are currently 3 pharmacologically diverse classes of antiretroviral agents with inadequate information available to define drug disposition necessary to determine appropriate dose regimens and limited data on long-term adverse events. This article summarizes representative clinical studies for selected antiretrovirals that provide a framework for continuing the necessary clinical research to extend successful outcomes in developed countries to human immunodeficiency virus-1 infected pregnant women and infants world-wide and minimize the risk of long-term adverse effects.

Effect of food and pharmacokinetic variability on didanosine systemic exposure in HIV-infected children. Pediatric AIDS Clinical Trials Group Protocol 144 Study Team.

The effect of food on didanosine bioavailability and interpatient pharmacokinetic variability was examined in children infected with human immunodeficiency virus type 1 (HIV-1). Didanosine pharmacokinetics were determined during fasting and fed conditions in HIV-infected children enrolled in the Pediatric AIDS Clinical Trials Group Protocol 144 randomized to receive didanosine at 50 mg/m2 or 150 mg/m2 orally every 12 hr. Pharmacokinetic parameters from patients in the low (n = 39) and high (n = 38) dosing groups were not significantly different, but intersubject variability was substantial. The fraction absorbed was higher while fasting than with food (0.27+/-0.13 versus 0.19+/-0.09, p < 0.0001); the zero order absorption rate was faster (0.48+/-0.31 versus 0.76+/-0.72 hr, p = 0.003); and the plasma half-life was shorter (0.93+/-0.43 versus 1.39+/-0.65 hr, p < 0.0001). The lower fraction absorbed with food was offset by the absorption rate becoming rate limiting for elimination, resulting in similar areas under the concentration-time curves (normalized to 100 mg/m2) when fasted (853.9+/-465.8 microg/liter-hr) versus fed (796.3+/-367.5 microg/liter x hr). Oral clearances during fasting (152.5+/-81.7 liters/hr/m2) and fed states (163.6+/-99.3 liters/hr/m2) were similar, but these values in children are substantially higher than previously reported for adults. The systemic exposure (i.e., AUC) of didanosine was highly variable in children but similar in the presence and absence of food. Administration of didanosine with food in children may be permissible if total systemic exposure rather than maximum plasma concentration is sufficient for antiretroviral activity. The higher oral clearance and substantial pharmacokinetic variability suggest the need to reexamine current didanosine dose recommendations for HIV-infected children.

Single-dose pharmacokinetics and safety of the oral antiviral compound adefovir dipivoxil in children infected with human immunodeficiency virus type 1. The Pediatrics AIDS Clinical Trials Group.

The acyclic phosphonate analog adefovir is a potent inhibitor of retroviruses, including human immunodeficiency virus (HIV) type 1, and, unlike some antiviral nucleosides, does not require the initial phosphorylation step for its activity. Two oral dosages of the adefovir prodrug adefovir dipivoxil were evaluated in a phase I study with children with HIV infection. A total of 14 patients were stratified into age groups ranging from 6 months to 18 years of age. Eight patients received 1.5 mg of adefovir dipivoxil per kg of body weight, and six patients received 3.0 mg of adefovir dipivoxil per kg. Serum samples were obtained at intervals during the 8 h postdosing and were analyzed for adefovir concentrations. Patients were monitored for adverse effects. All samples collected resulted in quantifiable levels of adefovir (lower limit of quantitation, 25 ng/ml) from each patient. The areas under the concentration-versus-time curves (AUCs) were similar (P = 0.85) for the 1.5- and 3.0-mg/kg doses, while the apparent oral clearance (CL/F) was significantly higher (P = 0.05) for the 3-mg/kg dose. Pharmacokinetic parameters differed by patient age. In comparing those children older and younger than the median age of 5.1 years, AUC (P = 0.03), maximum concentration of drug in serum (P = 0.004), and the concentration at 8 h postdosing (P = 0.02) were significantly lower for the younger children. There were no significant differences for apparent volume of distribution and CL/F normalized to body surface area, but there was a suggestive difference in half-life (P = 0.07) among the subjects in the older and younger age groups. No significant adverse events were encountered. These data provide the basis for a multidose phase II study of adefovir dipivoxil in HIV-infected infants and children.

Systemic pharmacokinetics and cellular pharmacology of zidovudine in human immunodeficiency virus type 1-infected women and newborn infants.

Systemic and intracellular pharmacokinetics of zidovudine were determined for 28 human immunodeficiency virus type 1-infected pregnant women and their newborn infants. Plasma zidovudine and intracellular zidovudine monophosphate and triphosphate concentrations were determined in serial maternal samples and cord blood at delivery. Higher levels of cord blood zidovudine were associated with lower maternal zidovudine clearance and longer infusion times. Median levels of zidovudine monophosphate and triphosphate in maternal (1556 and 67 fmol/106 cells) and cord (1464 and 70 fmol/106 cells) blood were similar but highly variable. Intersubject pharmacokinetic variability for zidovudine is substantial, but intravenous therapy provides plasma concentrations and intracellular zidovudine triphosphate levels consistent with high antiviral activity. The substantial amount of intracellular zidovudine triphosphate in cord blood provides an explanation for the clinical success of zidovudine in reducing vertical transmission. Studies of simpler oral regimens of zidovudine can now be evaluated regarding the ability to achieve these pharmacologic end points associated with highly effective parenteral therapy.

Cyclophosphamide for the treatment of progressive low-grade astrocytoma: a Pediatric Oncology Group phase II Study.

PURPOSE: Results of a phase II trial of cyclophosphamide (CPM) for children with progressive low-grade astrocytoma are reported. PATIENTS AND METHODS: Fifteen patients with a median age of 39 months (range, 2 to 71) were included in this study. The tumors of 11 children were located in the optic pathway, hypothalamus, or thalamus. Four courses of intravenous CPM 1.2 g/m2 were administered every 3 weeks during the upfront window portion of this protocol. Subsequently, chemotherapy was to continue with CPM, vincristine, and carboplatin for 2 years. RESULTS: By study design, the first 14 patients were centrally reviewed after completion of the initial 4 CPM courses. Toxicity was primarily hematologic. One patients had a complete response, 8 had stable disease, and 5 had progressive disease (PD). The excessive number of children with PD prompted study closure. CONCLUSION: CPM as used in this protocol showed insufficient activity against astrocytoma to justify further patient accrual.

High dose chemotherapy with autologous peripheral blood progenitor cell transplantation in an anephric child with multiply recurrent Wilms tumor.

PURPOSE: An autologous peripheral blood progenitor cell (APBPC) transplant in an anephric child with multiply recurrent Wilms tumor using a conditioning regimen of high dose chemotherapy in conjunction with hemodialysis (HD) and peritoneal dialysis is described. PATIENT AND METHODS: The child had a left nephrectomy at 9 months of age for a stage II Wilms tumor. At 6 years of age, she required a right nephrectomy because of progressive, recurrent disease unresponsive to treatment with doxorubicin, actinomycin, and vincristine. She was maintained on peritoneal dialysis. Salvage chemotherapy consisted of 5 cycles of carboplatin and cyclophosphamide after APBPCs were collected after granulocyte colony-stimulating factor mobilization. After a preparative regimen of carboplatin, cyclophosphamide, and etoposide with closely timed HD, peripheral blood progenitor cells were infused and peritoneal dialysis was resumed. RESULTS: No nonhematopoietic toxicity occurred. Pharmacokinetic studies demonstrated that HD effectively eliminated carboplatin and provided safe, effective plasma concentrations in this anephric patient. Trilineage engraftment occurred by day +10 and the child was discharged from the hospital on day +14. She had a local recurrence on day +194 and died of progressive disease on day +660. CONCLUSIONS: With dialysis support and dose modification, high-dose chemotherapy followed by APBPC transplantation can be successfully performed in the anephric child. Given the lack of organ toxicity in this patient, increased doses of the drugs used in this preparative regimen may be possible for anephric children.

Conventional compared with individualized chemotherapy for childhood acute lymphoblastic leukemia.

BACKGROUND: The rate of clearance of antileukemic agents differs by a factor of 3 to 10 among children with acute lymphoblastic leukemia. We hypothesized that the outcome of treatment would be improved if doses were individualized to prevent low systemic exposure to the drugs in patients with fast drug clearance. METHODS: We stratified and randomly assigned 182 children with newly diagnosed acute lymphoblastic leukemia to postremission regimens that included high-dose methotrexate and teniposide plus cytarabine. The doses of these drugs were based on body-surface area (in the conventional-therapy group) or the rates of clearance of the three medications in each patient (in the individualized-treatment group). In the individualized-treatment group, doses were increased in patients with rapid clearance and decreased in patients with very slow clearance. RESULTS: Patients who received individualized doses had significantly fewer courses of treatment with systemic exposures below the target range than did patients who received conventional doses (P<0.001 for each medication). Among the patients with B-lineage leukemia, those who received individualized therapy had a significantly better outcome than those given conventional therapy (P=0.02); the mean (+/-SE) rates of continuous complete remission at five years were 76+/-6 percent and 66+/-7 percent, respectively. There was no significant difference between treatments for patients with T-lineage leukemia (P=0.54). In a proportional-hazards model, the time-dependent systemic exposure to methotrexate, but not to teniposide or cytarabine, was significantly related to the risk of early relapse in children with B-lineage leukemia. CONCLUSIONS: Adjusting the dose of methotrexate to account for the patient's ability to clear the drug can improve the outcome in children with B-lineage acute lymphoblastic leukemia.

Clinical effects and pharmacokinetics of the fusion protein PIXY321 in children receiving myelosuppressive chemotherapy.

UNLABELLED: A hemopoietin with the ability to accelerate both platelet and granulocyte recovery after intensive chemotherapy would have great clinical utility. The recombinant fusion protein composed of human granulocyte-macrophage colony-stimulating factor and interleukin-3 (PIXY321), showed some promise in early adult trials. However, studies for pediatric patients are limited, and there are no systematic data on the pharmacokinetics of PIXY321 given over prolonged periods at current dosage levels. PURPOSE: To determine the safety, clinical effects and plasma concentrations of increasing doses of PIXY321 in children treated with myelosuppressive chemotherapy. METHODS: A total of 39 children with relapsed or high-risk solid tumors were enrolled in this phase I/II study. PIXY321 was administered once or twice daily by subcutaneous injection in total doses of 500 to 1000 microg/m2 per day for 14 days after each course of chemotherapy with ifosfamide, carboplatin, and etoposide (ICE). Pharmacokinetic studies were performed on day 1 of the first course in 33 patients and repeated on day 14 in 13 patients (once-daily schedule only). RESULTS: Although mild local skin reactions and fever were frequent, no dose-limiting toxicity was identified at the maximum dose studied (1000 microg/m2 per day). There were no statistically significant differences in chemotherapy-induced hematologic toxicity with increasing doses of PIXY321 or with twice-daily vs once-daily dosing. On day 1, the median PIXY321 clearance was 657 ml/min per m2 (range 77 1804 ml/min per m2) and the median half-life was 3.7 h (range 2.1-20.8 h). On day 14, clearance increased in all patients studied (median increase 63%), with a corresponding decrease in the median 12-h concentration (from 1.2 to 0.25 ng/ml). Maximum concentrations were < 1 ng/ml in 81% of patients, and only two patients had maximum plasma concentrations equivalent to those required for consistent activity in vitro. CONCLUSIONS: The recombinant fusion protein PIXY321 proved safe in children treated with myelosuppressive ICE chemotherapy but had no demonstrable clinical benefits. The pharmacokinetic studies suggest that the observed lack of hematologic benefit may be explained by low plasma concentrations resulting from increased clearance with prolonged administration. Moreover, the significant increase in PIXY321 systemic clearance in the absence of increased circulating myeloid cells suggests that the upregulation of either extravascular compartment hematopoietic progenitor cells or nonhematopoietic cells may play an important role in controlling circulating concentrations of this unique cytokine. These findings highlight the importance of a thorough assessment of the systemic disposition of cytokines when determining the dose and schedule necessary to achieve clinical activity in patients.

Pharmacokinetics of azithromycin after single- and multiple-doses in children.

STUDY OBJECTIVE: To characterize the disposition and tolerance of azithromycin after single and multiple oral doses of 12 mg/kg in children with and without cancer. DESIGN: Open-label, nonrandomized pharmacokinetic study. SETTING: Two pediatric hospitals. PATIENTS: Twelve children with cancer admitted to the inpatient unit for empiric antibiotic treatment of febrile neutropenia, and 16 hospitalized patients receiving antibiotic therapy INTERVENTIONS: Patients received azithromycin suspension either as a single dose or daily dose every morning for 5 consecutive days. Serial blood samples were collected up to 120 hours after a single dose or during and after multiple doses to characterize the pharmacokinetic parameters estimated for a two-compartment absorption model. MEASUREMENTS AND MAIN RESULTS: All 28 patients were evaluable for safety. Azithromycin was well tolerated except in one patient with cancer who experienced abdominal cramps and withdrew from the study. Pharmacokinetic results were not determined in five patients because of insufficient concentration-time data. The mean +/- SD estimates of oral clearance, terminal half-life, maximum concentration in serum (Cmax), and time to achieve Cmax in the 23 evaluable patients were 4.83 +/- 3.59 L/hour/kg, 54.5 +/- 36.4 hours, 318.2 +/- 174.5 microg/L, and 2.4 +/- 1.1 hours, respectively. These estimates did not differ between single-dose (14 patients) and multiple-dose (9 patients) groups. Pharmacokinetic parameters were not different between the 11 children with cancer and the 12 without cancer. CONCLUSION: Azithromycin 12 mg/kg results in proportionately higher serum concentrations than previously published results for lower doses (5 mg/kg). Variability in concentration profiles among patients is substantial, and age or other yet unidentified clinical factors may explain some of the differences observed.

Fentanyl pharmacokinetics in patients undergoing renal transplantation.

STUDY OBJECTIVE: To describe the pharmacokinetics of fentanyl in patients undergoing renal transplantation. DESIGN: Prospective. SETTING: A large university teaching hospital. PATIENTS: Eight patients (mean +/- SD age 35.5 +/- 11.5 yrs, weight 73.4 +/- 24.8 kg) with end-stage renal failure receiving kidneys from a living relative; three patients were never dialyzed, three were receiving peritoneal dialysis, and two were receiving hemodialysis. INTERVENTIONS: Plasma was sampled before and at intervals up to 8 hours after intravenous injection of fentanyl 25 microg/kg before skin incision. MEASUREMENTS AND MAIN RESULTS: Mean +/- SD (range) preoperative values were blood urea nitrogen (BUN) 66 +/- 30 (35-111) mg/dl; albumin 3.6 +/- 0.7 (2.6-4.5) g/dl; and triglycerides 414 +/- 352 (156-1270) mg/dl. Elimination half-life was 382 +/- 205 minutes; volume of distribution for the central compartment 0.74 +/- 0.48 L/kg; volume of distribution at steady state (Vd(ss)) 3.1 +/- 2.0 L/kg; total body clearance 7.5 +/- 5.1 ml x kg(-1) x min(-1). A significant inverse relationship between degree of azotemia and fentanyl clearance was found. The two patients with the highest preoperative BUNs had the lowest multiple of clearance and Vd(ss), and were also the only ones to require postoperative mechanical ventilation. CONCLUSION: Although all patients received a kidney that functioned well after revascularization, the large intersubject variability in fentanyl kinetics may, in part, reflect their heterogeneity in dialysis status and renal failure-induced abnormalities. Marked decreases in fentanyl clearance do occur in these patients, appear to be related to very high BUN concentrations, and can lead to prolonged postoperative ventilatory depression.

Effect of acute phase response on phenytoin metabolism in neurotrauma patients.

The purpose of this prospective study was to correlate measures of the acute phase response, associated therapeutic interventions, and other clinical variables with the process of altered drug metabolism previously observed in patients with severe neurotrauma. Nine patients with severe head injury (Glasgow Coma Scale < or = 8) requiring intravenous phenytoin were included in the study. A loading dose of phenytoin was followed by daily maintenance doses. Serial blood samples were taken after the loading dose and every even-numbered study day for 10 to 14 days for measurement of total and unbound concentrations of phenytoin, interleukin-1 beta, interleukin-6 (IL-6), tumor necrosis factor alpha, alpha 1-acid-glycoprotein, C-reactive protein, and albumin. Time-invariant and time-variant Michaelis-Menten models were fit to the phenytoin concentration-time data. Protein intake was closely monitored. The mean (+/- SEM) unbound fraction of phenytoin increased from 0.17 +/- 0.02 on day 1 to 0.24 +/- 0.04 on day 10 (P < 0.05). The time-variant model was superior in describing the concentration-time data of unbound phenytoin in eight of nine patients. Mean (+/- SEM) pharmacokinetic parameter estimates for unbound phenytoin were: Vmax delta = 605 +/- 92 mg/day, VmaxB = 149 +/- 26.3 mg/day, K(ind) = 0.013 +/- 0.004 hr-1. Interleukin-6 was the only cytokine with significant concentration changes over time; it was inversely correlated with Vmax,t. Peak concentrations of interleukin-6 also proved to be inversely correlated with VmaxB. The daily amount of protein administered was significantly correlated with Vmax,t. Significant alterations in the metabolism of phenytoin occur after severe neurotrauma. The etiology of these changes is probably multifaceted. These results suggest that low initial phenytoin Vmax may be explained by the presence of interleukin-6. An increase in oxidative metabolism that correlated with nutritional protein administration was observed later in these patients.

A systemic and cellular model for zidovudine plasma concentrations and intracellular phosphorylation in patients.

In a pharmacokinetic model for the systemic and cellular disposition of zidovudine in patients, serial measurements of plasma zidovudine and intracellular metabolites were used to simultaneously characterize systemic pharmacokinetics and intracellular phosphorylation in 6 human immunodeficiency virus-infected patients. First-order processes are sufficient to describe zidovudine monophosphate kinetics in peripheral blood mononuclear cells (PBMC), and the pharmacokinetic model provided reliable parameter estimates for each subject. The amount of zidovudine monophosphate in PBMC was inversely correlated with plasma zidovudine concentrations, and patients with higher systemic clearance had less intracellular zidovudine monophosphate. Zidovudine triphosphate values were measurable but not different at each time point. Lower lymphocyte counts were associated with higher intracellular zidovudine monophosphate but lower zidovudine triphosphate. The pharmacokinetic model proposed provides a quantitative link between systemic zidovudine concentrations and zidovudine monophosphate in PBMC from patients that will be useful in evaluating alternative therapeutic strategies.

Formation of platinum-DNA adducts in pediatric patients receiving carboplatin.

STUDY OBJECTIVE: To determine the extent of platinum-DNA (Pt-DNA) adduct formation in peripheral white blood cells of children with cancer. DESIGN: Prospective study. SETTING: Pediatric research hospital. PATIENTS: Twenty-seven children receiving carboplatin as part of therapy as defined by clinical research protocols. INTERVENTIONS: Patients received various dosages of carboplatin over 1, 3, or 24 hours as a primary component of combination chemotherapy for pediatric solid tumors, brain tumors, or large cell lymphoma. MEASUREMENTS AND MAIN RESULTS: The Pt-DNA adducts were detectable in 10 (37%) of 27 patients. The median value was 3.4 fmol Pt/micrograms DNA (range 1.7-31.2 fmol) in patients with measurable values. CONCLUSION: The Pt-DNA adducts were detected less frequently in pediatric patients than reported in adults. Variables that influenced their detection were higher carboplatin dosages or systemic exposure and short (1-3 hrs) versus prolonged (24 hrs) infusions.

Carboplatin pharmacokinetics in young children with brain tumors.

PURPOSE: The pharmacokinetic parameters and maximal tolerated systemic exposure were determined for carboplatin in young children given in combination with cyclophosphamide and etoposide. PATIENTS AND METHODS: Carboplatin was administered as part of a multiagent chemotherapy regimen to 21 pediatric patients less than 5 years of age with newly diagnosed, malignant central nervous system tumors. Patients, received cyclophosphamide, 1.2 g/m2, on day 1 and carboplatin on day 2 followed by etoposide, 100 mg/m2, each day. Carboplatin doses were calculated to achieve a targeted area under the serum concentration versus time curve (TAUC) of 5, 6.5 or 8 mg/ml.min based on each patient's measured glomerular filtration rate (GFR). Carboplatin pharmacokinetic parameters were determined after course 1 and then after every third course of therapy. RESULTS: The median carboplatin clearance and GFR after course 1 were 118 and 98 ml/min per m2, respectively. Targeted doses based on measured GFR reliably achieved the TAUC for carboplatin. The median (range) carboplatin clearance for four children less than 1 year of age was 76 (66-84) ml/min per m2, significantly lower (P = 0.05) than the value of 131 (80-158) ml/min per m2 for children from 1 to 4 years of age. The mean carboplatin clearance declined by 23% in 12 patients studied from course 1 to course 4 of therapy. The decrease was greater than 20% (range 20-53%) in 7 of the 12 patients studied. CONCLUSION: Carboplatin clearance for children aged between 1 and 4 years at diagnosis is approximately 45% higher than previously reported for pediatric patients, but declines after four courses of therapy. For children less than 1 year of age, carboplatin clearance per square meter is approximately 40% lower than patients 1 to 4 years of age. There are corresponding differences in GFR that provide a plausible explanation for the age and therapy-related changes in carboplatin clearance. Toxicity was acceptable for patients treated at a TAUC of 6.5 mg/ml.min for carboplatin given with etoposide and cyclophosphamide. The average carboplatin dose required for this AUC was 767 mg/m2.

Renal function and methotrexate clearance in children with newly diagnosed leukemia.

STUDY OBJECTIVES: To determine whether glomerular filtration rate (GFR) changes during induction chemotherapy in children with leukemia, and to examine GFR as a determinant of pharmacokinetic variability of methotrexate clearance. DESIGN: Prospective, unblinded observational study in consecutive patients. SETTING: A research hospital. PATIENTS: Thirty-eight children newly diagnosed with acute lymphoblastic leukemia. INTERVENTIONS: The patients received either high-dose methotrexate 1 g/m2 intravenously over 24 hours or low-dose methotrexate 30 mg/m2 orally every 6 hours for six doses; both regimens were followed by an intensive six-drug chemotherapy regimen given over 6 weeks. Glomerular filtration rate was determined in each subject before and at the conclusion of induction therapy. MEASUREMENTS AND MAIN RESULTS: The GFR was determined from 99mTc-DTPA serum clearance in all patients, and methotrexate clearance was estimated from serial serum concentrations in 18 of these children who received high-dose methotrexate. Median values for GFR at diagnosis (131 ml/min/1.73 m2) and after induction therapy (120 ml/min/1.73 m2) were not significantly different (p = 0.26) but were highly variable (range 49-274 ml/min/1.73 m2). Body size, age, and serum creatinine were correlated significantly with GFR at diagnosis. Amphotericin B therapy (6 patients) significantly decreased GFR (p = 0.046) without a corresponding increase in serum creatinine. Methotrexate clearance (58-155 ml/min/m2) was significantly (p = 0.007) correlated with GFR, but GFR accounted for only 37% of the variability of methotrexate clearance. CONCLUSIONS: The GFR was normal but highly variable in these children with leukemia and was significantly altered by amphotericin. Our results explain little of the intersubject variability in methotrexate clearance.

Pharmacokinetic variability in the adolescent: implications of body size and organ function for dosage regimen design.

Although there are convincing clinical studies demonstrating important pharmacokinetic differences between the adult and pediatric patient, guidelines for adjusting the dosages of specific drugs are often based on empirical and limited data. Adult doses often provide the reference point for therapy in children with adjustment for body size. Both body weight and body surface area (BSA) are commonly used to adjust adult doses for pediatric patients but yield substantially different absolute doses. For the child age five years, the BSA-based dose will be more than 50 percent greater than the dose adjusted for body weight. The choice of weight or BSA is often arbitrary and may be an important confounding variable when evaluating drugs over wide ranges of age in pediatric patients or comparing two drugs for which doses are not adjusted in a similar manner. For example, comparative trials for HIV-infected pediatric patients are evaluating zidovudine dosed by BSA with zalcitabine dosed by body weight. Organ function changes with age in pediatric patients yet little information is available on the effects of maturation on hepatic or renal function and the consequences for drug disposition. The use of model substrates for organ function offers potential for elucidating organ function relative to maturation and, in particular, to those functional capacities associated with the onset of puberty and gender differentiation.

Altered etoposide pharmacokinetics and time to engraftment in pediatric patients undergoing autologous bone marrow transplantation.

PURPOSE: To determine the pharmacokinetics and clinical response of high-dose etoposide in combination with carboplatin for pediatric cancer patients undergoing autologous bone marrow transplant. PATIENTS AND METHODS: Pharmacokinetic parameters for etoposide were determined at doses of 960, 1,200, and 1,500 mg/m2 when given with high-dose carboplatin and followed by autologous marrow rescue. Twenty-nine patients (age 1.6 to 23 years) with refractory or relapsed solid tumors were studied. Etoposide was administered in three divided doses as a 6-hour infusion on alternate days with carboplatin. Etoposide concentrations (n = 14) were determined during and following each of three doses. Patient characteristics, drug dose, and pharmacokinetic parameters were examined as predictors of marrow engraftment as reflected by recovery of granulocytes and platelets. RESULTS: The median values for clearance (Cl) and terminal half-life (T1/2 beta) of etoposide were 14.3 mL/min/m2 (range, 6.8 to 29.6) and 5.9 hours (range, 3.7 to 39). After adjustment for body size, Cl and volume of distribution did not correlate with any laboratory parameter or patient characteristic. However, seven patients who received concomitant anticonvulsant therapy had significantly higher (P < .01) average etoposide Cl values (23.7 mL/min/m2) than 22 patients who did not receive drugs known to alter hepatic metabolism (13.4 mL/min/m2). The median etoposide Cl value in patients who received concurrent carboplatin but no anticonvulsant agents is substantially lower than values previously reported in either children or adults. Higher etoposide concentrations were significantly associated with longer times to recovery of granulocyte and platelet counts. CONCLUSION: Etoposide Cl is significantly higher in patients who receive concomitant anticonvulsant therapy, which is consistent with clinically important hepatic enzyme induction. The lower etoposide Cl associated with high-dose carboplatin suggests that carboplatin may impair etoposide metabolism. Furthermore, high etoposide concentrations appeared to prolong time to recovery of hematopoietic function.

Patient characteristics associated with high-risk methotrexate concentrations and toxicity.

PURPOSE: Following high-dose methotrexate (HD-MTX) treatment, delayed MTX elimination is an important problem because it necessitates increased leucovorin rescue and additional hospitalization for hydration and urinary alkalinization. Our purpose was to identify factors associated with high-risk MTX plasma concentrations (defined by plasma concentration > or = 1.0 mumol/L at 42 hours from the start of MTX) and with toxicity. PATIENTS AND METHODS: Variables associated with MTX concentrations and toxicity were assessed in 134 children treated with one to five courses of HD-MTX (900 to 3,700 mg/m2 intravenously [i.v.] over 24 hours for a total of 481 courses) for acute lymphoblastic leukemia (ALL). RESULTS: High-risk MTX concentrations, toxicity (usually mild mucositis), and delay in resuming continuation chemotherapy occurred in 106 (22%), 123 (26%), and 66 (14%) of 481 courses, respectively. Using a mixed effects model for repeated measures, high-risk MTX concentrations were significantly associated with a higher MTX area-under-the-concentration-time curve (AUC), low urine pH, emesis, low MTX clearance, low urine output relative to intake, use of antiemetics during the MTX infusion, and concurrent intrathecal therapy (all p values < .01). Clinical toxicities and delay in resumption of continuation chemotherapy due to myelosuppression were more common in those with high 42-hour MTX concentrations, despite increased leucovorin rescue for all patients with high-risk MTX concentrations. However, with individualized rescue, no patient developed life-threatening toxicity. A more aggressive hydration and alkalinization regimen for subsequent courses reduced the frequency of high-risk MTX concentrations to 7% of courses (13 of 183) (P = .0001), and the frequency of toxicity decreased to 11% of courses (P = .0074). CONCLUSION: This study identified several clinical variables that influence MTX disposition that, when modified, can reduce the frequency of high-risk MTX concentrations and toxicity.