Pharmacokinetics of cladribine (2-chlorodeoxyadenosine) in children with acute leukemia.

Cladribine is a synthetic purine nucleoside with demonstrated activity in hairy cell leukemia and acute myeloid leukemia. We have studied the pharmacokinetics of this drug in 25 pediatric patients with acute leukemia treated with cladribine as a single agent, 8.9 mg/m2/24 h, for 5 days by continuous i.v. infusion. Twelve patients were in relapse, and acute myeloid leukemia was newly diagnosed in 13 patients. Plasma, urine, and cerebrospinal fluid cladribine concentrations were determined by a radioimmunoassay with a limit of detection of 1 nM. An open two-compartment model was fit to the plasma concentration data. The mean (SD) clearance was 39.4 (12.4) liters/h/m2 and ranged from 14.4-55.4 liters/h/m2. When clearance was normalized to body weight (liters/h/kg) it was negatively correlated with age, with older patients having slower clearances per unit of body weight. However, when clearance was normalized to body surface area, no significant correlation with age was observed. The mean (SD) steady-state plasma concentration (predicted 120-h concentration) was 37.7 (17.3) nM and ranged from 23.2-84.5 nM. The terminal phase half-life in 22 patients ranged from 14.3-25.8 h, with a mean (SD) of 19.7 (3.4) h. The volume of distribution at steady state was highly variable, with a mean (SD) of 356.6 (225.2) liters/m2. None of these parameters was significantly different between patients in relapse and patients with newly diagnosed disease. Renal clearance was determined in 7 patients and ranged from 34.6-643.6 ml/min/m2, with a mean (SD) of 317.9 (208.7) ml/min/m2. Renal clearance as a percentage of total systemic clearance ranged from 11.0-85.1%, with a mean of 51.0%. In 11 patients, the mean (SD) cerebrospinal fluid concentration was 6.1 (3.97) nM, a mean of 18.2% of the steady-state plasma concentration. The CSF:plasma concentration ratio was significantly higher on day 5 (22.7% in 7 patients) than on day 4 (7.6% in 3 patients; P = 0.03). Additional studies are needed to further define the metabolic fate of cladribine. In this paper we provide the first comprehensive description of the pharmacokinetics of this drug in children and provide data which suggest that cladribine may be useful in the treatment of patients with meningeal leukemia or malignancies of the central nervous system.

Teniposide (VM26) disposition in children with leukemia.

The clinical pharmacokinetics of teniposide (VM-26, NSC 122819) has been studied in 21 children (median age, 4.7 years) with acute lymphocytic leukemia. Teniposide was administered at a dosage of 165 mg/sq m as a 30- to 60-min i.v. infusion. Patients were studied either on the first or second dosage of the drug. Plasma samples were assayed for teniposide and metabolites by high-performance liquid chromatography with electro-chemical detection. Both compartmental and noncompartmental pharmacokinetic analyses were performed. Systemic clearance and apparent volume of distribution of steady state averaged 13.82 +/- 6.0 ml/min/sq m (S.D.) and 7.9 +/- 4.0 liter/sq m, respectively. Univariate and multivariate stepwise regression analyses were used to construct mathematical models to describe the relationships between certain patient-specific demographic and laboratory values and the pharmacokinetic parameters, systemic clearance, elimination rate constant, and area under the concentration-time curve. A significant relationship between serum alkaline phosphatase and systemic clearance, elimination rate constant, and area under the concentration-time curve was found, suggesting that liver function influences the disposition of this anticancer drug in humans.

Clinical pharmacodynamics of continuous infusion topotecan in children: systemic exposure predicts hematologic toxicity.

PURPOSE: Topotecan pharmacokinetics and pharmacodynamics were studied following a 72-hour continuous infusion in 20 children with cancer (median age, 8 years; range, 3.5 to 18). METHODS: Serial plasma and urine samples were collected during the infusion and for up to 6 hours following the end of infusion. Topotecan (lactone) and total (lactone plus hydroxy acid) concentrations were determined by a sensitive and specific high-performance liquid chromatography (HPLC) assay with fluorescence detection. Using maximum a posteriori-Bayesian modeling, lactone and total plasma concentrations were described separately by a two-compartment model. Hematologic toxicity was expressed as the percent decrease in absolute neutrophil count (ANC) and platelet count. The relation between systemic exposure (SE) and hematologic toxicity was modeled using a sigmoid maximum-effect model. RESULTS: Systemic clearance rates for lactone and total topotecan were (mean +/- SD) 18.5 +/- 7.0 and 6.5 +/- 2.4 L/h/m2, respectively. Urinary recovery of total topotecan was (mean +/- SD) 67.5% +/- 25.2% (n = 12 patients). SE (area under the concentration-time curve from zero to infinity [AUC] or steady-state plasma concentration [Cpss]) to either topotecan lactone or total topotecan was significantly correlated to hematologic toxicity (P < .05). Overall, patients with a higher SE to topotecan experienced greater hematologic toxicity. CONCLUSION: These data demonstrate a relation between systemic exposure to topotecan and clinical effect (myelosuppression). Moreover, these data provide the basis for development of individualized topotecan administration schedules.

Effect of hydration on methotrexate plasma concentrations in children with acute lymphocytic leukemia.

Hydration and urinary alkalinization are used with high-dose methotrexate (HDMTX) to minimize renal toxicity resulting from methotrexate (MTX) precipitation in the kidney tubules. The effect of two hydration and alkalinization schedules on MTX plasma concentrations were evaluated in 100 children with acute lymphocytic leukemia (ALL) following two courses of MTX, 2 g/m2. The mean 21- and 44-hour MTX plasma concentrations were significantly lower in the group receiving the greater hydration and alkalinization schedule: 0.79 (0.90 SD) v 1.39 (1.99 SD) mumol/L for 21-hour MTX plasma concentrations, P = .01; and 0.18 (0.38 SD) v 0.25 (0.50 SD) mumol/L for 44-hour MTX plasma concentrations, P = .01. Although the overall incidence of toxic events was similar in both groups, the incidence of severe toxicity was reduced in the group that received the greater hydration and alkalinization, 6% v 16%. This study demonstrated that the amount of hydration and alkalinization can affect MTX plasma concentrations. Optimizing the hydration and alkalinization schedule is important for minimizing the incidence of severe toxicity associated with HDMTX.

Urinary N-acetyl-beta-D-glucosaminidase and serum creatinine concentrations predict impaired excretion of methotrexate.

We determined the risk of impaired excretion of methotrexate (MTX) in children with osteosarcoma, who also were receiving cisplatin, by analyzing urinary markers of renal tubular damage, as well as serum creatinine measured before each dose of MTX. MTX clearance was impaired in seven of the ten patients studied after cisplatin therapy. Patients with a urinary N-acetyl-beta-D-glucosaminidase (NAG) concentration of greater than 1.5 U/mmol creatinine or a greater than 50% increase in serum creatinine relative to the pretherapy level were approximately 30 times more likely to have MTX half-lives greater than 3.5 hours than were patients with lower values for these markers; MTX clearance was always impaired if both markers were elevated. If neither urinary NAG nor serum creatinine concentrations increased, the risk of impaired MTX excretion was negligible. Our findings demonstrate that urinary NAG and serum creatinine levels, measured before MTX administration, can be used to identify patients who will have difficulty in clearing the drug.

The effect of prior cisplatin therapy on the pharmacokinetics of high-dose methotrexate.

The pharmacokinetics of high-dose methotrexate (MTX, 5-15 g/m2) were evaluated in 11 children and adolescents who had previously received two to eight doses of cisplatin (90 mg/m2) in the treatment of malignant solid tumors. The half-life for disappearance of MTX from serum during the first 24 hours after infusion was determined from serum samples obtained at the end of a six-hour infusion and six, 12, and 24 hours after infusion. These values were compared to a mean half-life of 2.83 (+/- 0.34) hours following 489 courses administered to 71 patients who had not received cisplatin. Stepwise multiple linear regression analysis of patient variables revealed cumulative cisplatin dosage and time from last cisplatin dose as the best predictors of MTX half-life (r2 = 65.4%, p less than 0.001). The best predictors of 24-hour serum concentration were cumulative cisplatin dosage and MTX dosage (r2 = 54.2%, p less than 0.001) in the multiple linear regression model. Patients with delayed MTX clearance received additional leucovorin and experienced no severe toxicity. Patients receiving up to 270 mg/m2 of cisplatin appear to have minimal increases in MTX half-life, while the likelihood of delayed clearance increases in patients who have received 360 mg/m2 or more of cisplatin. All patients who have previously received cisplatin should be treated cautiously with high-dose MTX and prospective pharmacokinetic monitoring should be routinely performed.

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.

Etoposide pharmacokinetics in patients with normal and abnormal organ function.

Precise guidelines for dose modification of etoposide in patients with hepatic dysfunction have not been determined. Etoposide pharmacokinetics were determined in 17 patients. Nine patients had bilirubin less than or equal to 1 mg/dL and eight had bilirubin ranging from 1.9 to 23 mg/dL. Twelve patients received etoposide 100 mg/m2 days 1, 3, and 5, in combination with cisplatin 70 mg/m2 or iproplatin 225 mg/m2 on day 1. Five patients received only one dose of etoposide. Etoposide was measured using a published high pressure liquid chromatography (HPLC) method which also quantitates picro etoposide and its hydroxy acid. Systemic clearance, Vdss and t1/2 beta averaged (+/- SD) 21.4 (+/- 7.4) mL/min/m2, 10.7 (+/- 4.1) L/m2, and 8.1 (+/- 2.8) hours in the nine patients with bilirubin less than or equal to 1 mg/dL, and 22.4 (+/- 9.6) mL/min/m2, 13.6 (+/- 11.3) L/m2, and 8.4 (+/- 3.9) hours in the eight patients with bilirubin 1.9 to 23.0 mg/dL. Stepwise multiple linear regression analysis of liver and renal function tests and other patient-specific variables identified creatinine clearance as the strongest predictor of etoposide systemic clearance (r2 = 40.8). Serum albumin was identified as the next strongest predictor, improving the r2 to 57.3%. Cumulative biliary excretion of unchanged etoposide and glucuronide or sulfate conjugates over 48 hours accounted for less than 3% of the dose in six patients studied. Toxicity occurred in patients with normal and abnormal bilirubin and was unrelated to etoposide clearance. Patients with total bilirubin 1.9 to 23 mg/dL, but creatinine clearance greater than 30 mL/min/m2 had etoposide clearance within the range for patients with normal liver function (16.8 to 35 mL/min/m2). Although these patients did not have reduced etoposide clearance, the major routes of etoposide non-renal elimination remain to be clearly defined. Additional patients should be evaluated to establish more precise guidelines for dosing etoposide in patients with abnormal liver function.

Raised plasma methotrexate concentrations following intrathecal administration in children with renal dysfunction.

Plasma methotrexate (MTX) concentrations were measured following intrathecal (IT) MTX treatment in four patients with acute lymphocytic leukemia and acute renal dysfunction. All four patients had raised serum MTX concentrations to potentially cytotoxic concentrations for a prolonged period of time, (96-120 h). In contrast, serum MTX concentrations after the same dosage of IT treatment ranged from undetectable to 0.11 microM by 15-24 h in seven control patients with normal renal function, and were undetectable by 48 h in all controls. The terminal MTX T1/2 was 19-44 h in the patients with renal dysfunction. Decreased renal clearance or a rapid efflux of MTX from cerebrospinal fluid, or both, could account for the high and sustained concentrations. Plasma MTX concentrations after IT treatment were normal in two patients treated after their renal function returned to normal. Patients with renal dysfunction should be carefully monitored for plasma MTX concentrations and may require leucovorin to prevent systemic side-effects after IT MTX treatment.

Treatment of childhood acute myelogenous leukemia with an intensive regimen (AML-87) that individualizes etoposide and cytarabine dosages: short- and long-term effects.

The purpose of this study was to assess the feasibility and efficacy of a treatment regimen for pediatric acute myelogenous leukemia (AML) that uses four rotating drug pairs and adjusts dosages of etoposide and cytarabine to target specific plasma concentrations. Thirty-one girls and 27 boys (median age, 9.7 years) with de novo AML were treated on the protocol. Six cycles of chemotherapy were planned. Cycles 1 to 4 comprised the drug combinations cytarabine plus etoposide, cytarabine plus daunomycin, etoposide plus amsacrine, and etoposide plus azacitidine, respectively. For cycles 5 and 6, the first two combinations were repeated. Dosages were adjusted to achieve plasma concentrations of 1.0 microM +/- 0.1 microM cytarabine and 30 microM +/- 0.3 microM etoposide. Forty-four patients (76%) entered complete remission. Of those, 24 have had relapses; 23 remain alive in first or subsequent remission. The 5-year event-free survival (EFS) estimate was 31.0% +/- 5.9%; the 5-year survival estimate was 41.4% +/- 6.3%. Six patients (10%) died of the toxic effects of therapy. Severe neutropenia occurred in all cycles. Long-term complications of therapy included hepatitis C, cardiac insufficiency, and hearing loss. Adjustment of cytarabine and etoposide dosage was feasible for achieving targeted plasma drug concentrations; however, the potential clinical efficacy of this approach was offset by substantial acute and long-term toxicity.

Use of the automatic interaction detector method to identify patient characteristics related to methotrexate clearance.

Systemic methotrexate (MTX) clearance was determined in 108 children who received 15 courses of MTX, 1000 mg/m2 iv over 24 hours, as a component of therapy for acute lymphocytic leukemia. The median MTX clearance was used as the representative value for each patient, and these values ranged from 44.7 to 132.1 ml/min/m2 (X = 78.4 ml/min/m2). The automatic interaction detector approach was used to determine the patient characteristics that correlated with MTX clearance. Characteristics examined were sex, age, estimated creatinine clearance, SGPT, and body surface area. The initial splits were based on creatinine clearance, and mean MTX clearances in three subgroups (50 to 100, 100 to 150, and greater than 150 ml/min/m2) were 73.1, 78.3, and 90.5 ml/min/m2, respectively. For patients with the slowest creatinine clearance, abnormal SGPT concentrations (greater than 35 IU/L) were associated with slower MTX clearance (77.6 vs. 67.8 ml/min/m2). In the latter subgroup, boys had faster clearance than girls (77.4 vs. 60.9 ml/min/m2). These results demonstrate that for children with normal serum creatinine concentrations, interpatient variability in MTX clearance can partly be explained by measures of renal and hepatic function, which indicates that the observed variability in MTX clearance is not totally random.

Age-related differences in hepatic drug clearance in children: studies with lorazepam and antipyrine.

The disposition of intravenous antipyrine and lorazepam, administered as model substrates for hepatic oxidative metabolism and conjugation, was evaluated in 50 children (mean age, 7.8 years; range, 2.3 to 17.8 years) with acute lymphocytic leukemia in complete remission and compared with a group of ten healthy adults. Antipyrine clearance normalized to body weight was significantly greater in children than in adults (0.91 versus 0.59 ml/min/kg; p = 0.012), but was not different when normalized to body surface area. In contrast, lorazepam total clearance (CL) and unbound clearance (CLu) normalized to body weight were not significantly different between children and adults but were smaller in children when normalized to body surface area (CL = 31.9 versus 40.6 ml/min/m2, p = 0.036; CLu = 352 versus 485 ml/min/m2, p = 0.010). The mean lorazepam fraction unbound in children was 0.087, which was not different from adult volunteers (0.084). This study has identified significant differences between children and adults in the disposition of these two compounds, with higher milliliter per minute per kilogram clearance for antipyrine but not lorazepam.

Hepatic drug clearance in patients with mild cystic fibrosis.

The plasma disposition of three model substrates (lorazepam, indocyanine green, and antipyrine) and the formation clearance of antipyrine metabolites (3-hydroxymethylantipyrine, norantipyrine, and 4-hydroxyantipyrine) were evaluated in 15 subjects with mild cystic fibrosis and in 15 healthy control subjects. Plasma clearance was significantly greater in patients with cystic fibrosis for both lorazepam (1.7 +/- 0.4 versus 1.2 +/- 0.5 ml/min/kg) and indocyanine green (14.2 +/- 6.1 versus 9.1 +/- 3.0 ml/min/kg). In contrast, the clearance of antipyrine was not significantly different (1.0 +/- 0.7 versus 0.8 +/- 0.3 ml/min/kg), but the formation clearance for 3-hydroxymethylantipyrine was significantly greater in patients with cystic fibrosis. Lorazepam and antipyrine apparent steady-state volume of distribution were not different between groups. These results suggest that clearance of drugs that undergo conjugation (e.g., lorazepam) or biliary excretion (e.g., indocyanine green) is increased in patients with mild cystic fibrosis. In contrast, the increased formation clearance of only one antipyrine metabolite suggests that alterations in clearance of drugs metabolized by cytochrome P450 enzymes are substrate specific and isoform specific in patients with cystic fibrosis.

Bleomycin disposition in children with cancer.

Bleomycin kinetics were determined in 14 children after intravenous bolus and prolonged infusion doses. Plasma and urine bleomycin concentrations were determined by radioimmunoassay. After intravenous bolus, bleomycin concentrations were adequately described by a two-compartment open model with a mean t1/2 alpha and t1/2 beta of 0.3 +/- 0.1 and 3.2 +/- 0.7 hr (mean +/- SEM). Volume of the central compartment and volume of distribution at steady-state (Vss) were 4.3 +/- 0.5 and 9.9 +/- 1.1 l/m2. Total plasma (CLT) and renal (CLR) clearance were 51.8 +/- 6.1 and 33.5 +/- 2.4 ml/min/m2. Three intravenous bolus courses were given to two patients who received more than four courses of cisplatin (greater than 300 mg/m2); CLT and CLR for these courses were 18.0 +/- 3.3 and 8.2 ml/min/m2. Conversely, children under 3 yr old eliminated bleomycin more rapidly than older children. Decline in bleomycin concentrations after seven 24- or 48-hr intravenous infusions was described by a one-compartment model. Mean values for plasma t1/2, Vss, CLT, and CLR were 2.1 +/- 0.1 hr, 11.0 +/- 2.6 l/m2, 57.1 +/- 13.5 ml/min/m2, and 33.2 +/- 6.4 ml/min/m2. One patient received his bleomycin infusion when ureteral obstruction was present; CLT and CLR for this course were 4.8 and 4.1 ml/min/m2. These data indicate that young children eliminate bleomycin more rapidly than older children and that children with impaired renal function may have prolonged elevations in plasma concentration due to reduced bleomycin clearance. Bleomycin disposition in older children is as in adults.

Simultaneous administration of multiple model substrates to assess hepatic drug clearance.

We have evaluated a method to simultaneously assess three major processes involved in hepatic drug clearance using three model substrates administered simultaneously as a 5-minute intravenous injection. Lorazepam, indocyanine green, and antipyrine are used to assess conjugation, liver blood flow, and microsomal oxidative metabolism, respectively. These substrates were administered individually and as a mixture to 10 healthy adult male volunteers to determine if clearances of any of the compounds were affected by simultaneous administration. Mean clearances of the substrates were not different when administered alone (9.97, 0.78, and 0.53 ml/min/kg) vs. together (11.5, 0.89, and 0.52 ml/min/kg), using a paired t test. Since we were using this method to assess hepatic drug clearance in children with leukemia, the effect of short-term allopurinol was assessed. The three model substrates were administered to the volunteers after 0, 1, 8, and 22 days of treatment with allopurinol, 200 mg t.i.d. There was no change in mean clearance of any of the three compounds at any point during allopurinol treatment (repeated-measures ANOVA). We conclude that this technique is a simple and valid method to simultaneously assess three major processes involved in hepatic drug clearance and is not affected by up to 22 days of oral allopurinol treatment. This simple technique, requiring a single set of blood samples, has potential applications in the assessment of developmental changes in hepatic drug clearance, as well as the effects of environmental, therapeutic, and pathophysiologic factors on three major processes involved in hepatic drug clearance.

Dextromethorphan and caffeine as probes for simultaneous determination of debrisoquin-oxidation and N-acetylation phenotypes in children.

The feasibility and reliability of simultaneously determining debrisoquin oxidation and N-acetylation phenotypes was assessed in children with use of two innocuous substrate probes given by mouth, 30 mg dextromethorphan (Pertussin ES) and 25 to 46 mg caffeine (Coca-Cola beverage). Twenty-six children and adolescents (aged 3 to 21 years) were studied three times, once with each substrate given alone and once with the two substrates given together. Urine was collected for 4 hours, and the molar urinary metabolic ratios for dextromethorphan:dextrorphan and for two caffeine metabolites (AFMU:1X) were determined by HPLC ultraviolet assays. The urinary metabolic ratios for both substrates were not significantly different when the substrates were given alone compared with when they were given together. There also was no difference in either the oxidation or acetylation phenotype assignments when the two substrates were given alone and when they were given together. No adverse effects were observed. We conclude that dextromethorphan and caffeine can be given together to simultaneously determine oxidation and acetylation phenotypes and can thereby provide an innocuous, noninvasive method for the assessment of polymorphic drug metabolism in various pediatric populations.

Methotrexate cerebrospinal fluid and serum concentrations after intermediate-dose methotrexate infusion.

Twenty-nine children with acute lymphocytic leukemia were given 24-hr infusions of intermediate-dose methotrexate (MTX, 1000 mg/m2) with and without intrathecal (IT) MTX (12 mg/m2), followed by leucovorin rescue. There was substantial interpatient variability in MTX systemic clearance (98.3 +/- 51 ml/min/m2), inducing total steady-state serum MTX concentrations ranging from 5.4 to 33.7 microM. The cerebrospinal fluid (CSF) concentration at the end of the infusion was 0.27 (+/- 0.1) microM when no IT-MTX was given and correlated with total steady-state (24-hr) serum concentration of MTX. By stepwise regression, the CSF MTX concentration correlated better with the nonprotein bound (free) steady-state serum MTX concentration (r = 0.66, P less than 0.01) than with total steady-state serum MTX concentration. Mean CSF: serum MTX concentration ratio was 0.023 (+/- 0.04) when no IT MTX was given. When an IT MTX dose (12 mg/m2) was given at the start of the MTX infusion, the steady-state CSF MTX concentration was 1.1 (+/- 0.4) microM, leading to a mean CSF: serum ratio of 0.073 (+/- 0.05). Despite 7-hydroxy-MTX serum concentrations exceeding MTX concentrations immediately after infusion, 7-hydroxy-MTX was not detectable in CSF of most patients (21 of 29), and was less than 50% of the concurrent MTX concentration when detectable. These data establish the substantial interpatient variability in CSF distribution of MTX after intermediate-dose MTX infusions and establish a significant correlation between steady-state free concentration of MTX in serum and CSF MTX concentration.

Hepatic drug clearance in children with leukemia: changes in clearance of model substrates during remission-induction therapy.

We administered a "cocktail" of three model substrates for hepatic processes: antipyrine for oxidation, lorazepam for glucuronidation, and indocyanine green for hepatic blood flow, to children with acute lymphocytic leukemia (ALL). The plasma clearance of these substrates was determined before and after remission-induction therapy in 14 children with ALL. We found an improvement in clearance of antipyrine (0.65 to 0.95 ml/min/kg; P less than 0.01) and lorazepam (0.93 to 1.20 ml/min/kg; P less than 0.05) in 12 of 14 patients, with a mean increase of 67% and 52%, respectively, from before to after remission. There was no significant difference in mean indocyanine green clearance from before to after induction (14.8 vs. 14.4 ml/min/kg). There were no significant differences in liver function test results (SGOT, prothrombin time, or serum bilirubin) from before to after induction. Plasma concentrations of albumin, alpha 1-acid glycoprotein, and apolipoprotein A changed by a mean of +11.1%, -38.2%, and +68.6%, respectively, from before to after remission. However, these changes did not account for the changes in total plasma clearance of lorazepam, because lorazepam free fraction did not change and lorazepam free clearance increased by a mean of 83%. Our hypothesis is that eradication of hepatic leukemic infiltration by ALL remission therapy resulted in an improvement in microsomal metabolism of antipyrine and lorazepam.

Clinical pharmacokinetics and pharmacodynamics of anticancer drugs in children.

Pharmacokinetic variability in children with cancer is substantial and confounds drawing conclusions regarding optimal therapy based only on dose-response relationships. Careful pharmacokinetic studies performed during drug development in conjunction with an assessment of patient characteristics, such as age, renal and hepatic function, and concomitant therapy, is essential for defining those factors that may alter drug disposition. By integrating pharmacokinetic studies with measures of efficacy and toxicity, a pharmacodynamic framework can be established for guiding therapy to minimize differences in systemic exposure among subpopulations of patients (eg, impaired renal function and neonates). In selected instances when pharmacokinetic variability cannot be predicted by patient covariates, the potential for individualizing dosages based on patient-specific pharmacokinetic parameters is now a clinically feasible option. The need for and benefits of incorporating such strategies into routine therapy represents an exciting area for further clinical research.

A model for dosing gentamicin in children and adolescents that adjusts for tissue accumulation with continuous dosing.

The pharmacokinetics of gentamicin were evaluated in 50 children and adolescents during a multiple dose course of therapy. Parameters of a 2-compartment pharmacokinetic model were derived from serial serum concentrations and urinary excretion rates measured for up to 11 days following the last dose of gentamicin administered to 10 of these patients. These parameters were used to simulate changes in serum concentrations and half-lives that would occur during a standard 6-hour dosing interval with continuous dosing. The data indicated that the half-life for decline in serum concentrations after the first dose was 76 +/- 8% of the half-life at steady-state, and that the half-life after the fourth dose exceeded 90% of the steady-state half-life. These underestimations of the steady-state serum half-life were incorporated into a 1-compartment model to simulate steady-state peak and nadir serum concentrations by using pharmacokinetic parameters measured after the first dose of gentamicin administered to 40 patients. Steady-state serum concentrations predicted by the true 1-compartment model and by the adjusted model were compared with concentrations measured at steady-state. The concentrations predicted by the former model were significantly different from and consistently less than measured concentrations. Concentrations predicted by the adjusted model were not significantly different from concentrations measured at steady-state. These data indicate that the new model offers a simple and more accurate method of simulating steady-state concentrations from pharmacokinetil for individualising therapy.