Phase I trial, including pharmacokinetic and pharmacodynamic correlations, of combination paclitaxel and carboplatin in patients with metastatic non-small-cell lung cancer.

PURPOSE: To determine the maximum-tolerated dose of paclitaxel with carboplatin with and without filgrastim support in patients with metastatic non-small-cell lung cancer (NSCLC) and to investigate the pharmacokinetics of paclitaxel and carboplatin and correlate these with the pharmacodynamic effects. PATIENTS AND METHODS: Thirty-six chemotherapy-naive patients with metastatic NSCLC were entered into this phase I dose-escalation and pharmacokinetic study. Paclitaxel was initially administered as a 24-hour infusion at a fixed dose of 135 mg/m2, and the carboplatin dose was escalated in cohorts of three patients, using Calvert's formula [dose(mg) = area under the concentration time curve (glomerular filtration rate + 25)], to target areas under the concentration time curve (AUCs) of 5, 7, 9, and 11 mg/mL x minute. A measured 24-hour urinary creatinine clearance was substituted for the glomerular filtration rate. Once the maximum-tolerated AUC (MTAUC) of carboplatin was reached, the paclitaxel dose was escalated to 175, 200, and 225 mg/m2. When the paclitaxel dose escalation began, the AUC of carboplatin was reduced to one level below the MTAUC. RESULTS: Myelosuppression was the major dose-limiting toxicity. Thrombocytopenia was observed at a carboplatin AUC of 11 mg/mL x minute after course 2 and thereafter. End-of-infusion plasma paclitaxel concentrations and median duration of time above 0.05 microM were similar in course 1 versus course 2 at the 135 and 175 mg/m2 dose levels. The neutropenia experienced by patients was consistent with that observed in patients who had received paclitaxel alone. Measured carboplatin AUCs were approximately 12% (20% v 3% with course 1 v course 2, respectively) below the desired target, with a standard deviation of 34% at all dose levels. A sigmoid-maximum effect model describing the relationship between relative thrombocytopenia and measured free platinum exposure indicated that patients who received the combination of carboplatin with paclitaxel experienced less severe thrombocytopenia than would be expected from carboplatin alone. Of the 36 patients entered onto the study, one experienced a complete response and 17 had partial responses, for an overall response rate of 50%. The recommended doses of paclitaxel (24-hour infusion) and carboplatin for future phase II studies of this combination are (1) paclitaxel 135 mg/m2 with a carboplatin dose targeted to achieve an AUC of 7 mg/mL x minute without filgrastim support; (2) paclitaxel 135 mg/m2 with a carboplatin dose targeted to achieve an AUC of 9 mg/mL x minute with filgrastim support; and (3) paclitaxel 225 mg/m2 with a carboplatin dose targeted to achieve an AUC of 7 mg/mL x minute with filgrastim support. CONCLUSION: The regimen of paclitaxel and carboplatin is well-tolerated and has promising activity in the treatment of NSCLC. There is no pharmacokinetic interaction between paclitaxel and carboplatin, but there is a pharmacodynamic, platelet-sparing effect on this dose-limiting toxicity of carboplatin.

Evaluation of the linearity of docetaxel pharmacokinetics.

The taxanes, paclitaxel and docetaxel, have favorable response rates in patients with breast, gynecologic, and lung cancers and have demonstrated activity against a variety of malignancies. In human trials, paclitaxel pharmacokinetics are nonlinear and are best fit by a three-compartment model with nonlinear distribution into the second compartment as well as nonlinear elimination. This finding is important for patients receiving paclitaxel at high doses or as a short infusion, as it results in disproportionately high peak concentrations and delayed elimination. The presence of nonlinear processes in docetaxel pharmacokinetics has not previously been examined. Therefore, plasma concentration data obtained from 53 patients receiving docetaxel at 55-115 mg/m2 over 1-24 h as part of phase I studies were modeled using the nonlinear three-compartment model found most suitable for paclitaxel and the results were compared with those obtained using the linear version. Docetaxel disposition was best described by the three-compartment nonlinear model in 28 of 53 data sets (53%). However, the difference in curve fit observed between the two models was modest (did not improve Akaike criteria) and unlikely to be of relevance. This study suggests that nonlinear processes in docetaxel pharmacokinetics may exist, but, unlike the case of paclitaxel, they are not likely to have a significant impact at the dose and administration schedule used in routine clinical practice (60-100 mg/m2 given over 1 h by infusion). The presence of nonlinear docetaxel pharmacokinetics at doses above 115 mg/m2 will have to be determined in case of further dose escalation.

Phase I and pharmacokinetic trial of paclitaxel in patients with hepatic dysfunction: Cancer and Leukemia Group B 9264.

PURPOSE: To characterize the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetics of paclitaxel in patients with abnormal liver function. PATIENTS AND METHODS: Adults with tumors appropriate for paclitaxel therapy who had abnormal liver function tests were eligible. Patients were assigned to one of three treatment cohorts: I, AST level twofold normal and bilirubin level less than 1.5 mg/dL; II, bilirubin level 1.6 to 3.0 mg/dL; and III, bilirubin level greater than 3.0 mg/dL. Doses were explored in at least three patients within each cohort. Although designed to assess a 24-hour infusion schedule, the trial was extended to also assess a 3-hour regimen. Pharmacokinetics were to be studied in all patients. RESULTS: Eighty-one patients were assessable for toxicity. Patients with bilirubin levels greater than 1.5 mg/dL had substantial toxicity at all doses explored, whereas the toxicity for patients with elevated AST levels occurred at doses that ranged from 50 to 175 mg/m2 administered over 24 hours. In most patients, the DLT was myelosuppression. The pharmacokinetic data were insufficient to adequately evaluate the relationship between pharmacokinetics and toxicity in patients who received 24-hour infusions but provided evidence of a longer exposure to paclitaxel than anticipated for the doses used in this study in the 3-hour infusion group. CONCLUSION: If paclitaxel is used for patients with elevated levels of AST or bilirubin, dose reductions are necessary, and an increase in toxicity can be anticipated. The increased myelosuppression observed is at least partially because of altered paclitaxel pharmacokinetics in such patients.

Pharmacokinetics of the taxanes.

The pharmacokinetics of the taxanes paclitaxel and docetaxel have been studied extensively in humans. Paclitaxel has distinctly nonlinear pharmacokinetics, with saturable distribution and elimination features. Docetaxel pharmacokinetics are well described by linear processes, although some investigators detected subtle nonlinear characteristics. Clinically, nonlinear pharmacokinetics produce a disproportional relationship between dose and drug exposure. This affects dose adjustments and calculation and use of dose intensity to compare chemotherapy regimens. Although the underlying mechanism of nonlinearity in paclitaxel disposition is not well understood, both metabolic and distributive processes may be involved.

GDNF protection against 6-OHDA: time dependence and requirement for protein synthesis.

Glial cell line-derived neurotrophic factor (GDNF) injected intranigrally protects midbrain dopamine neurons against 6-hydroxydopamine (6-OHDA) toxicity. The timing between GDNF administration and exposure to 6-OHDA is critical in achieving optimal protection. When injected 6 hr before an intranigral injection of 6-OHDA, GDNF provides complete protection as measured by the number of surviving neurons in the substantia nigra of adult rats. The surviving neuronal population decreases by approximately 50% with 12 and 24 hr separating GDNF and 6-OHDA administrations. In controls with 6-OHDA lesions, there is <10% survival of nigral dopamine neurons. No significant increase in survival is seen with either concurrent injections of GDNF and 6-OHDA or 1 hr GDNF pretreatment. Based on HPLC measurements, striatal and midbrain dopamine levels are at least twofold higher on the lesioned side in animals receiving GDNF 6 hr before a 6-OHDA lesion compared with vehicle recipients. Protein synthesis is necessary for GDNF-induced neuroprotective effects because cycloheximide pretreatment that inhibits protein synthesis also blocks neuroprotection.

Considerations regarding the less-than-expected thrombocytopenia encountered with combination paclitaxel/carboplatin chemotherapy.

Whenever drugs are given in combination for the treatment of a disease, the potential for synergistic, additive, or antagonistic effects exists. Evaluation of the effects of drugs in combination requires that the effect of each drug as a single agent be well described. Recently, combination chemotherapy with carboplatin and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has met with much clinical interest. Toxicity expectations of the combination were based on the established pharmacokinetic/pharmacodynamic relationships of each drug as a single agent. In several independent studies, investigators have noted that carboplatin-associated thrombocytopenia was less than expected in patients treated with combination carboplatin/paclitaxel. Although the mechanism underlying this observation has not been identified, carboplatin underdosing, variation in analytic or computational techniques, and pharmacokinetic interactions can be ruled out as contributing factors.

Weekly paclitaxel with and without concurrent radiation therapy: toxicity, pharmacokinetics, and response.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has shown in vitro and clinical activity against non-small cell lung cancer and astrocytic brain tumors, tumors traditionally thought of as relatively resistant to chemotherapy and radiotherapy. Because of its ability to block dividing cells in the G2/M portion of the cell cycle (the most radiosensitive phase of the cell cycle), paclitaxel is also a potentially potent radiosensitizer. To exploit these and other properties of paclitaxel, we explored a weekly, outpatient administration schedule, with and without concurrent radiation therapy, in patients with non-small cell lung cancer and astrocytic brain tumors. Our experience has shown that weekly outpatient administration is feasible, that remarkably high dose intensities can be achieved with acceptable toxicity, and that the specific dose-limiting toxicity appears to depend on administration schedule, type of concurrent radiotherapy, and certain patient characteristics. Preliminary response data are very encouraging. At the same time, pharmacokinetic studies have suggested possible reasons for our ability to use such exorbitant dose intensities safely, and also have shown that sustained plasma paclitaxel levels above the putative radiosensitizing threshold can be achieved continuously during a 6-week course of radiotherapy. Specific results, dosing recommendations, and plans for future studies are discussed.

Phase I study of weekly outpatient paclitaxel and concurrent cranial irradiation in adults with astrocytomas.

PURPOSE: Astrocytomas are extremely resistant to currently available treatments. Cranial irradiation is a mainstay of frontline therapy, but tumor recurrence is nearly universal. Paclitaxel has shown antitumor efficacy against astrocytoma cell lines, and is a potent radiosensitizer. For these reasons, we conducted a phase I study of weekly paclitaxel and concurrent cranial irradiation in patients with newly diagnosed astrocytomas. PATIENTS AND METHODS: Patients with astrocytomas were eligible for this study following initial surgery if they had a Karnofsky performance score (KPS) > or = 60%; normal hematologic, liver, and renal function; and could give informed consent. Beginning on day 1 of treatment, patients received paclitaxel by 3-hour infusion once weekly for 6 weeks, concurrent with standard cranial irradiation. Pharmacokinetic studies were performed on 10 patients. RESULTS: Sixty patients were enrolled; 56 were fully assessable. Forty-eight had glioblastomas (GBMs), 10 anaplastic astrocytomas (AAs), and two astrocytomas. Age ranged from 21 to 81 years (median, 55); KPS ranged from 60 to 100 (median, 70). The paclitaxel dose was escalated from 20 mg/m2 to 275 mg/m2. No clinically significant anemia or thrombocytopenia occurred. Only one patient (175 mg/m2) became neutropenic. Sensory neuropathy was dose-limiting. The maximum tolerated dose (MTD) was 250 mg/m2. Paclitaxel pharmacokinetic profiles in study patients were identical to those of previously reported patients with other solid tumors. CONCLUSION: The MTD of paclitaxel administered weekly for 6 weeks by 3-hour infusion is 250 mg/m2. Since patients with brain tumors often have preexisting neurologic deficits, we suggest 225 mg/m2 as the optimum dose for phase II trials in this group of patients.

Plasma pharmacokinetics, bioavailability, and tissue distribution in CD2F1 mice of halomon, an antitumor halogenated monoterpene isolated from the red algae Portieria hornemannii.

The purpose of the present study was to define the plasma pharmacokinetics, bioavailability, and tissue distribution in mice of halomon, a halogenated monoterpene from Portieria hornemanii that is active in vitro against brain-, renal-, and colon-cancer cell lines. Halomon formulated in cremophor:ethanol:0.154 M NaCl (1:1:6, by vol.) was injected i.v. at 20, 60, 90, or 135 mg/kg into female CD2F1 mice. Doses of 135 mg/kg were also given i.p., s.c., and by enteral gavage to female CD2F1 mice and i.v. to male CD2F1 mice. Plasma halomon concentrations were measured with a gas-chromatography system using electron-capture detection. Halomon concentrations were also determined in the brains, hearts, lungs, livers, kidneys, spleens, skeletal muscles, fat, red blood cells, and, if present, testes of mice given 135 mg/kg i.v. Halomon plasma pharmacokinetics were well fit by a two-compartment, open linear model and were linear between 20 and 135 mg/kg. Population estimates of parameters describing halomon plasma pharmacokinetics in female CD2F1 mice were developed with a standard two-stage technique and also by simultaneous modeling of data from 20-, 60-, 90-, and 135-mg/kg i.v. studies in female mice. Halomon bioavailability was 45%, 47%, and 4% after i.p., s.c., and enteral dosing, respectively. Urinary excretion of the parent compound was minimal. Halomon was distributed widely to all tissues studied but was concentrated and persisted in fat. Halomon concentrations measured in the brain were comparable with concomitant concentrations detected in plasma and most other tissues. These data and models are helpful in the simulation and evaluation of conditions produced by preclinical screening and toxicology studies.

Pharmacokinetics of paclitaxel and carboplatin in combination.

We studied the pharmacokinetics of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and carboplatin administered in combination to 21 patients with advanced non-small cell lung cancer. Paclitaxel was administered as a 24-hour intravenous infusion at doses of 135 to 200 mg/m2. Carboplatin, dosed to a target area under the concentration-time curve of 5, 7, 9, or 11 mg/mL.min, was administered as a 20-minute infusion immediately following paclitaxel. Neither the paclitaxel concentrations at the end of the infusion nor the terminal elimination of paclitaxel, as assessed by the duration of time that plasma paclitaxel concentrations were 0.05 mumol/L or greater, were different compared with historical data of paclitaxel as a single agent. Thus, we concluded that carboplatin had no perceived effect on the pharmacokinetics of paclitaxel in this schedule. The observed areas under the concentration-time curves for carboplatin were consistently 10% to 15% less than the target values. Although this may indicate a possible interaction between paclitaxel and carboplatin, it also may have been a result of inadequate assessment of glomerular filtration rate, which was used to determine the carboplatin dose.

Weekly, outpatient paclitaxel and concurrent cranial irradiation in adults with brain tumors: preliminary results and promising directions.

In a phase I study, paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) was given weekly by 3-hour infusion for 6 weeks concurrent with daily cranial irradiation as initial treatment for patients with newly diagnosed astrocytic brain tumors. The primary goal of the study was to establish the maximum tolerated dose of paclitaxel when administered by this schedule. Sixty patients were entered into the study and received at least one course of therapy. Fifty-six patients completed treatment. The treatment regimen was well tolerated, with minimal hematologic toxicity. Peripheral neuropathy was dose-limiting. Median survival was 9.2 months for patients with glioblastoma multiforme and has not been reached for patients with anaplastic astrocytoma or astrocytoma. The maximum tolerated dose of paclitaxel in this study was 250 mg/m2 administered weekly. However, because five of six patients receiving this dose of paclitaxel developed peripheral neuropathy, and because patients with brain tumors may adapt to a superimposed neuropathy less well than patients without pre-existing nervous system dysfunction, we propose 225 mg/m2 as the recommended dose for subsequent phase II trials.

Paclitaxel disposition in plasma and central nervous systems of humans and rats with brain tumors.

BACKGROUND: Paclitaxel (Taxol) has been shown to sensitize some malignant cells to the effects of radiation. A number of clinical protocols, combining paclitaxel with radiation therapy, have been designed to exploit this phenomenon. The radiation-potentiating effect of paclitaxel is likely dependent on the ability of the drug to penetrate the tissue being radiated. Paclitaxel is known to have limited access to the central nervous system (CNS) of rats and mice, but its ability to penetrate malignant tissue in the CNS is inadequately documented. PURPOSE: Our purpose was to examine the concentrations of paclitaxel in the cerebrospinal fluid (CSF) of patients with CNS malignancies and in normal and malignant tissues from the brains of Fischer rats bearing the C6 rat glioma and then to compare those paclitaxel concentrations with concomitant paclitaxel concentrations in the plasma of those same patients and animals. METHODS: Four patients were treated with 3-hour infusions of paclitaxel at doses between 90 and 200 mg/m2. Plasma and CSF were sampled at 0.33, 1.5, 3.25, 5, 6, and 24 hours after initiation of the paclitaxel infusion. Four Fischer rats had 20,000 C6 glioma cells stereotactically implanted into their right frontal lobes; 28 days later, they were given 3-hour infusions of paclitaxel at 10 mg/kg. Plasma was sampled during the paclitaxel infusion. At the completion of the infusion, rats were killed, and portions of their normal and malignant CNS tissues were removed for histologic assessment. Concentrations of paclitaxel in plasma, CSF, and brain tissue were determined with high-pressure liquid chromatography. RESULTS: Plasma pharmacokinetics of paclitaxel in patients with brain tumors were comparable to those previously described in patients with other malignancies. Paclitaxel could be measured in CSF of all patients, but concentrations were very low. Peak paclitaxel concentrations in CSF ranged between 5 and 83 nM and occurred between 3.25 and 5 hours after initiation of the paclitaxel infusion. Peak paclitaxel concentrations in CSF were between 0.12% and 8.3% of those present in concomitant plasma samples. Paclitaxel was not detectable in the normal or malignant CNS tissue of any rat, despite the fact that plasma concentrations of paclitaxel at the time of tissue acquisition ranged from 0.62 to 153 microM. CONCLUSIONS: Paclitaxel has only limited access to the CSF of patients with CNS malignancies and to normal and malignant CNS tissues of rats bearing brain tumors. IMPLICATIONS: The utility of combining paclitaxel with radiation therapy to treat CNS malignancies should be considered in light of the documented limited access of paclitaxel to the CNS.

Paclitaxel pharmacokinetics and pharmacodynamics.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) displays nonlinear pharmacokinetics in humans. Both peak plasma paclitaxel concentrations and areas under the curve (AUCs) of the concentration versus time profiles will change disproportionately to changes in dose. Models that accurately describe the plasma paclitaxel profile contain two separate saturable processes, both described by Michaelis-Menten kinetics. Pharmacokinetic models using only linear components ultimately fail to describe adequately the disposition of paclitaxel in the body. The major toxicity of paclitaxel, neutropenia, appears to be related to the duration of time that plasma paclitaxel concentrations are at or above a threshold value. This relationship is well described by a sigmoid-Emax (maximum effect) model. Neutropenia is not directly related to either peak paclitaxel plasma concentration or to paclitaxel areas under the curve. A relationship between therapeutic efficacy and paclitaxel disposition is, as yet, undefined.

GDNF protects nigral dopamine neurons against 6-hydroxydopamine in vivo.

Glial cell line-derived neurotrophic factor (GDNF), a novel member of the TGF-beta superfamily, has been shown to promote the survival and morphological differentiation of fetal dopamine neurons in culture and increase dopamine levels and metabolism in adult rats. Since several other trophic factors are able to rescue specific populations of mature CNS neurons following injury, the present study was designed to investigate a possible neuroprotective role by GDNF for midbrain dopamine neurons in rats exposed to the neurotoxin 6-hydroxydopamine (6-OHDA). Prior to surgery, young adult male Fisher 344 rats were divided into the following groups (n = 7-8/group): (1) intranigral saline + intranigral 6-OHDA; (2) intranigral GDNF + intranigral 6-OHDA; (3) intranigral saline + intrastriatal 6-OHDA; and (4) intranigral GDNF + intrastriatal 6-OHDA. The saline treated groups received a single 2 microliters intranigral injection of phosphate buffered saline (PBS) while the GDNF treated rats received 10 micrograms/2 microliters GDNF in PBS. Twenty-four hours later, the animals received a unilateral 4 micrograms/microliters 6-OHDA infusion either into the substantia nigra or striatum. The rats were sacrificed two weeks postsurgery and the brains processed for tyrosine hydroxylase (TH) immunocytochemistry. Representative TH immunoreactive (TH-IR) sections were also counterstained with hematoxylin and eosin to determine the total number of neurons remaining in the substantia nigra pars compacta and ventral tegmental area. In the nigral lesion groups, there was significantly less loss of TH-IR neurons in the substantia nigra pars compacta of GDNF (47% survival) vs. PBS (9% survival) treated animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/pharmacodynamic relationships in humans.

PURPOSE: To characterize and model the disposition of paclitaxel in humans and define a pharmacodynamic relationships between paclitaxel disposition and its toxicity and efficacy. PATIENTS AND METHODS: Paclitaxel pharmacokinetics were studied in 55 courses of therapy in 30 patients. Paclitaxel was administered at 135 mg/m2 or 175 mg/m2 by either a 3- or a 24-hour infusion schedule to patients with advanced ovarian cancer (n = 15), or at 225 mg/m2 by 3-hour infusion to patients with advanced breast cancer (n = 15). Paclitaxel and 6 alpha-hydroxylpaclitaxel were quantified by high-performance liquid chromatography (HPLC). Pharmacokinetics were assessed by noncompartmental and model-dependent methods. Pharmacodynamic correlations were evaluated statistically and by regression models. RESULTS: Paclitaxel disposition is nonlinear in humans and, on the 3-hour schedule, 6 alpha-hydroxylpaclitaxel was identified in the plasma of all patients treated. The plasma disposition of paclitaxel and 6 alpha-hydroxylpaclitaxel was well described by a model that featured multiple nonlinear processes. Neutropenia was not related to the areas under the curves (AUCs) of paclitaxel or 6 alpha-hydroxylpaclitaxel, or to palitaxel peak concentrations (Cmax). Neutropenia was related to the duration that plasma concentrations were > or = 0.05 mumol/L, a relationship that is well described by a sigmoid maximum response (Emax) model. CONCLUSION: The disposition of paclitaxel in humans is nonlinear. Paclitaxel metabolism to 6 alpha-hydroxylpaclitaxel is likely an important detoxification pathway. Myelosuppression is related to the duration that plasma paclitaxel concentrations are > or = 0.05 mumol/L. Trials of new doses and schedules of paclitaxel should take into account its nonlinear disposition to rule out adverse clinical consequences, especially if the drug is administered by short infusion. Our pharmacokinetic model should prove to be a powerful tool in predicting paclitaxel disposition, regardless of dose and schedule, and should facilitate further pharmacodynamic investigations.

The Interaction of Photoperiod and Temperature in Diapause Timing: A Copepod Example.

In many organisms, photoperiod and temperature are thought to be the most significant token cues for seasonally timed life history events, including diapause in arthropods. A common pattern in many species of terrestrial insects and several copepod species is the existence of a critical daylength on one side of which the animals do not enter diapause and on the other side of which they do. Temperature plays a secondary role as modifier of the critical daylength. In some species, however, including the freshwater copepod Diaptomus sanguineus, the fraction of females making subitaneous eggs (eggs that hatch immediately) undergoes a very gradual transition as daylength changes over the natural range of photoperiods experienced in nature. Here we show that temperature is as important as photoperiod in cuing diapause timing in a population of D. sanguineus living in Bullhead Pond, Rhode Island. When ecologically relevant photoperiod and temperature cues are provided in the laboratory, the copepods rapidly switch from producing subitaneous eggs to producing diapausing eggs in a way that is typical of the seasonal switch seen in the pond. We provide a graphical model that illustrates how copepod sensitivities to photoperiod and temperature interact to produce an abrupt transition, and we discuss how natural selection should act on D. sanguineus diapause response to produce the variation in diapause timing seen within and between natural populations.

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.

Splenosis presenting as a left renal mass: a report of two cases.

The development of splenosis is a recognized consequence of splenic trauma. We present 2 cases of splenosis that were initially diagnosed as left renal cell carcinomas. The diagnosis of splenosis was made by technetium sulfur colloid scans. The clinical presentation and diagnosis of these 2 cases of splenosis masquerading as renal cell carcinoma are reviewed.

Disposition of recombinant human granulocyte colony-stimulating factor in children with severe chronic neutropenia.

The disposition of recombinant human granulocyte colony-stimulating factor (G-CSF) was studied in 11 children with severe chronic neutropenia given 6 to 48 micrograms G-CSF per kilogram subcutaneously. Serum concentrations of G-CSF were measured by bioassay. Peak serum G-CSF concentrations were proportional to dosage and occurred 2 to 8 hours after subcutaneous administration. Nine of the eleven children had a significant increase in absolute neutrophil count (ANC). The median ANC in responding patients was 6.7 x 10(9)/L on day 14 versus 0.17 x 10(9)/L on day 1 of therapy (p < 0.01). The G-CSF clearance increased as ANC increased, and the relationship was well described by a sigmoid model. Maximal clearance approached 2 ml/min per kilogram at ANCs > 17.0 x 10(9)/L; minimal clearance was 0.29 ml/min per kilogram at ANCs of 0. The half-life of G-CSF was inversely related to ANC; mean half-life was 4.7 hours at ANCs of 0 but < 2 hours at ANCs greater than 17.0 x 10(9)/L. The two patients who failed to achieve a clinical response had no change in G-CSF clearance or half-life, nor did they have an increase in ANC when G-CSF dosages were escalated to 18 or 48 micrograms/kg twice a day. These results indicate that G-CSF pharmacokinetics are directly influenced by ANC; higher serum concentrations, slower clearances, and longer half-lives are associated with low ANCs.