Phase IIa study of dabigatran etexilate in children with venous thrombosis: pharmacokinetics, safety, and tolerability.

Essentials Dabigatran etexilate may provide a new treatment option for pediatric venous thromboembolism. Children aged 1 to < 12 years were given dabigatran etexilate in an open-label, single-arm study. The pharmacokinetic-pharmacodynamic relationship was similar to that seen in adult patients. There were no serious adverse events, bleeding events or recurrent venous thromboembolism. SUMMARY: Background The current standard-of-care treatments for pediatric venous thromboembolism (VTE) have limitations. Dabigatran etexilate (DE), a direct thrombin inhibitor, may offer an alternative therapeutic option. Objectives To assess the pharmacokinetics, pharmacodynamics, safety, and tolerability of a DE oral liquid formulation (OLF) in pediatric patients with VTE. Patients/Methods Patients who had completed planned treatment with low molecular weight heparin or oral anticoagulants for VTE were enrolled in two age groups (2 to < 12 years and 1 to < 2 years), and received a DE OLF based on an age-adjusted and weight-adjusted nomogram. Originally, patients were to receive a DE OLF twice daily for 3 days, but the protocol was amended to a single dose on day 1. The primary endpoints were pharmacokinetics/pharmacodynamics-related: plasma concentrations of DE and its metabolites; activated partial thromboplastin time (APTT), ecarin clotting time (ECT), and dilute thrombin time (dTT); and pharmacokinetic (PK)-pharmacodynamic (PD) correlation. Safety endpoints included incidence rates of bleeding events and all other adverse events (AEs). Results Eighteen patients entered the study and received the DE OLF (an exposure equivalent to a dose of 150 mg twice daily in adults). The projected steady-state dabigatran trough concentrations were largely comparable between pediatric patients and adults. The PK/PD relationship was linear for ECT and dTT, and non-linear for APTT. No serious or severe AEs, bleeding events, or recurrent VTEs were reported. Mild AEs were reported in three patients in the single-dose group (screening period) and in one patient in the multiple-dose group (on-treatment period). Conclusion The current study supports the further evaluation of DE OLFs in pediatric patients with VTE.

Pharmacokinetics and safety of famciclovir in children with herpes simplex or varicella-zoster virus infection.

Two multicenter, open-label, single-arm, two-phase studies evaluated single-dose pharmacokinetics and single- and multiple-dose safety of a pediatric oral famciclovir formulation (prodrug of penciclovir) in children aged 1 to 12 years with suspicion or evidence of herpes simplex virus (HSV) or varicella-zoster virus (VZV) infection. Pooled pharmacokinetic data were generated after single doses in 51 participants (approximately 12.5 mg/kg of body weight [BW] for children weighing < 40 kg and 500 mg for children weighing > or = 40 kg). The average systemic exposure to penciclovir was similar (6- to 12-year-olds) or slightly lower (1- to < 6-year-olds) than that in adults receiving a 500-mg dose of famciclovir (historical data). The apparent clearance of penciclovir increased with BW in a nonlinear manner, proportional to BW(0.696). An eight-step weight-based dosing regimen was developed to optimize exposure in smaller children and was used in the 7-day multiple-dose safety phases of both studies, which enrolled 100 patients with confirmed/suspected viral infections. Twenty-six of 47 (55.3%) HSV-infected patients who received famciclovir twice a day and 24 of 53 (45.3%) VZV-infected patients who received famciclovir three times a day experienced at least one adverse event. Most adverse events were gastrointestinal in nature. Exploratory analysis following 7-day famciclovir dosing regimen showed resolution of symptoms in most children with active HSV (19/21 [90.5%]) or VZV disease (49/53 [92.5%]). Famciclovir formulation (sprinkle capsules in OraSweet) was acceptable to participants/caregivers. In summary, we present a weight-adjusted dosing schedule for children that achieves systemic exposures similar to those for adults given the 500-mg dose.

Low prevalence and assay discordance of "aspirin resistance" in children.

BACKGROUND: Although "aspirin resistance" (AR-inadequate platelet inhibition as suggested by in vitro testing of aspirin-treated patients) has been widely studied in adults and linked to increased risk of adverse outcomes, its prevalence and clinical significance are largely unknown in children. PROCEDURE: To determine AR prevalence in children and its relationship to assay methodology, we undertook a cross-sectional study of 44 children (1-17 years, 24 male) on aspirin for various indications and considered three published definitions of AR in adults: platelet aggregation >/=70% to 10 microM adenosine diphosphate and >/=20% to 0.5 mg/ml arachidonic acid (AA), normal PFA-100(R) closure time and elevated urinary 11-dehydro thromboxane B(2) (11dhTxB(2)) concentration. RESULTS: Six subjects exhibited AR according to at least one of the criteria (5 by PFA-100(R), 1 by aggregometry and 11dhTxB(2) criteria); nearly all subjects had low levels of 11dhTxB(2) compared with controls. Subjects studied prior to therapy showed pronounced changes in AR parameters after aspirin dosing (e.g., mean aggregation to AA decreased from 82% to 6%, P < 0.001), confirming an aspirin effect. Subjects with AR did not differ from aspirin responsive subjects in terms of age, race, platelet count, or aspirin dose, indication or therapy duration. There was minimal correlation between assays. CONCLUSIONS: In this initial prevalence study of a clinically diverse group of pediatric patients, frequencies of AR were assay-dependent; however, the prevalence of true AR is likely low in children (2.3%; 95% CI 0.1-10.7%), in agreement with adult studies. To better define the clinical relevance of AR in children, multicenter, prospective cohort studies are imperative.

Ontogeny of dextromethorphan O- and N-demethylation in the first year of life.

The exponential increase in the number of drugs used to treat infant and childhood illnesses necessitates an understanding of the ontogeny of drug biotransformation for the development of safe and effective therapies. Healthy infants received an oral dose (0.3 mg/kg) of dextromethorphan (DM) at 0.5, 1, 2, 4, 6, and 12 months of age. DM and its major metabolites were measured in urine. CYP2D6 genotype was determined by polymerase chain reaction-restriction fragment length polymorphism. Genotyping data indicated a strong correlation between CYP2D6 genotype and DM O-demethylation (beta=-0.638; 95% CI: -0.745, -0.532; P<0.001). CYP2D6 activity was detectable and concordant with genotype by 2 weeks of age, showed no relationship with gestational age, and did not change with post natal age up to 1 year. In contrast, DM N-demethylation developed significantly more slowly over the first year of life. Genotype and the temporal acquisition of drug biotransformation are critical determinants of a drug response in infants.

A phase I study of irinotecan administered on a weekly schedule in pediatric patients.

BACKGROUND: The objectives of this study were to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics, and anti-tumor effect of irinotecan in pediatric patients with recurrent or refractory malignancies. PROCEDURE: Twenty-three patients between 1 and 21 years of age, with a solid tumor refractory to standard therapy or for which there was no standard therapy were enrolled. Irinotecan was administered over 90 min weekly 4x, every 6 weeks. The initial dose level was 125 mg/m(2)/day, with subsequent escalations to 160 and 200 mg/m(2)/day. A MTD was defined in heavily-pretreated and less-heavily-pretreated (< or =2 prior chemotherapy regimens, no prior bone marrow transplantation, and no central axis radiation) patients. Pharmacokinetic studies were also performed. RESULTS: Neutropenia and diarrhea were the DLTs in heavily pretreated patients; the MTD was 125 mg/m(2)/day. Neutropenia was the DLT in less-heavily pretreated; the MTD was 160 mg/m(2)/day. Five patients had stable disease for two to four cycles including one patient each with rhabdomyosarcoma, Ewing sarcoma, neuroblastoma, and two patients with ependymoma. Irinotecan clearance was greater that that previously reported for children receiving high dose irinotecan. CONCLUSIONS: The recommended phase II dose of irinotecan administered weekly 4x, every 6 weeks in children with solid tumors is 125 mg/m(2)/dose for heavily pretreated patients and 160 mg/m(2)/dose for less heavily pretreated patients.

Phase I trial of intrathecal liposomal cytarabine in children with neoplastic meningitis.

PURPOSE: We performed a phase I trial of intrathecal (IT) liposomal cytarabine (DepoCyt; Enzon Pharmaceuticals, Piscataway, NJ and SkyePharma Inc, San Diego, CA) to determine the maximum-tolerated dose, the dose-limiting toxicities, and the plasma and CSF pharmacokinetics of IT lipsomal cytarabine in children >/= 3 years of age with advanced meningeal malignancies. PATIENTS AND METHODS: Eighteen assessable patients received IT liposomal cytarabine through either an indwelling ventricular access device or via lumbar puncture. Liposomal cytarabine was given once every 2 weeks during induction, once every 4 weeks during consolidation, and once every 8 weeks during the maintenance phase of treatment. The initial dose was 25 mg, with subsequent escalations to 35 and 50 mg. CSF pharmacokinetic samples were obtained in a subset of patients. RESULTS: Arachnoiditis, characterized by fever, headache, nausea, vomiting, and back pain was noted in the first two patients at the 25 mg dose level. Therefore, subsequent patients were treated with dexamethasone, beginning the day of liposomal cytarabine administration and continuing for 5 days. Headache (grade 3) was dose limiting in two of eight patients enrolled at the 50 mg dose level. Eight of the 14 patients assessable for response demonstrated evidence of benefit manifest as prolonged disease stabilization or response. CONCLUSION: The maximum-tolerated dose and recommended phase II dose of liposomal cytarabine in patients between the ages of 3 and 21 years is 35 mg, administered with dexamethasone (0.15 mg/kg/dose, twice a day for 5 days). A phase II trial of IT liposomal cytarabine in children with CNS leukemia in second or higher relapse is in development.

Pharmacokinetic interactions of cyclosporine with etoposide and mitoxantrone in children with acute myeloid leukemia.

The purpose of this study was to assess the effect of the multidrug resistance modulator cyclosporine (CsA) on the pharmacokinetics of etoposide and mitoxantrone in children with de novo acute myeloid leukemia (AML). Serial blood samples for pharmacokinetic studies were obtained in 38 children over a 24-h period following cytotoxin treatment with or without CsA on days 1 and 4. Drug concentrations were quantitated using validated HPLC methods, and pharmacokinetic parameters were determined using compartmental modeling with an iterative two-stage approach, implemented on ADAPT II software. Etoposide displayed a greater degree of interindividual variability in clearance and systemic exposure than mitoxantrone. With CsA treatment, etoposide and mitoxantrone mean clearance declined by 71% and 42%, respectively. These effects on clearance, in combination with the empiric 40% dose reduction for either cytotoxin, resulted in a 47% and 12% increases in the mean AUC for etoposide and mitoxantrone, respectively. There were no differences in the rates of stomatitis or infection between the two groups. CsA treatment resulted in an increased incidence of hyperbilrubinemia, which rapidly reversed upon conclusion of drug therapy. The variability observed in clearance, combined with the empiric 40% dose reduction of the cytotoxins, resulted in statistically similar systemic exposure and similar toxicity.

The development of camptothecin analogs in childhood cancers.

Camptothecin analogs, agents that target the intranuclear enzyme topoisomerase I, represent a promising new class of anticancer drugs for the treatment of childhood cancer. In preclinical studies, camptothecins, such as topotecan and irinotecan, are highly active against a variety of pediatric malignancies including neuroblastomas, rhabdomyosarcomas, gliomas, and medulloblastomas. In this paper, we review the status of completed and ongoing clinical trials and pharmacokinetic studies of camptothecin analogs in children. These and future planned studies of this novel class of cytotoxic agents are critical to defining the ultimate role of topoisomerase I poisons in the treatment of childhood cancer.

Pharmacokinetics and cerebrospinal fluid penetration of phenylacetate and phenylbutyrate in the nonhuman primate.

INTRODUCTION: Phenylbutyrate (PB) and its metabolite phenylacetate (PA) demonstrate anticancer activity in vitro through promotion of cell differentiation, induction of apoptosis through the p21 pathway, inhibition of histone deacetylase, and in the case of PB, direct cytotoxicity. We studied the pharmacokinetics, metabolism, and cerebrospinal fluid (CSF) penetration of PA and PB after intravenous (i.v.) administration in the nonhuman primate. METHODS: Three animals received 85 mg/kg PA and 130 mg/kg PB as a 30-min infusion. Blood and CSF samples were obtained at 15, 30, 35, 45, 60 or 75 min, and at 1.5, 2.5, 3.5, 5.5, 6.5, 8.5, 10.5 and 24.5 h after the start of the infusion. Plasma was separated immediately, and plasma and CSF were frozen until HPLC analysis was performed. RESULTS: After i.v. PA administration, the plasma area under the concentration-time curve (AUC) of PA (median +/- SD) was 82 +/- 16 mg/ml.min, the CSF AUC was 24 +/- 7 mg/ml.min, clearance (Cl) was 1 +/- 0.3 ml/min per kg, and the AUCCSF:AUCplasma ratio was 28 +/- 19%. After i.v. PB administration, the plasma PB AUC was 19 +/- 3 mg/ml.min, the CSF PB AUC was 8 +/- 11 mg/ml.min, the PB Cl was 7 +/- 1 ml/min per kg, and the AUCCSF:AUCplasma ratio was 41 +/- 47%. The PA plasma AUC after i.v. PB administration was 50 +/- 9 mg/ml.min, the CSF AUC was 31 +/- 24 mg/ml.min, and the AUCCSF:AUCplasma ratio was 53 +/- 46%. CONCLUSIONS: These data indicate that PA and PB penetrate well into the CSF after i.v. administration. There may be an advantage to administration of PB over PA, since the administration of PB results in significant exposure to both active compounds. Clinical trials to evaluate the activity of PA and PB in pediatric central nervous system tumors are in progress.

Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine.

PURPOSE: To assess thiopurine S-methyltransferase (TPMT) phenotype and genotype in patients who were intolerant to treatment with mercaptopurine (MP) or azathioprine (AZA), and to evaluate their clinical management. PATIENTS AND METHODS: TPMT phenotype and thiopurine metabolism were assessed in all patients referred between 1994 and 1999 for evaluation of excessive toxicity while receiving MP or AZA. TPMT activity was measured by radiochemical analysis, TPMT genotype was determined by mutation-specific polymerase chain reaction restriction fragment length polymorphism analyses for the TPMT*2, *3A, *3B, and *3C alleles, and thiopurine metabolites were measured by high-performance liquid chromatography. RESULTS: Of 23 patients evaluated, six had TPMT deficiency (activity < 5 U/mL of packed RBCs [pRBCs]; homozygous mutant), nine had intermediate TPMT activity (5 to 13 U/mL of pRBCs; heterozygotes), and eight had high TPMT activity (> 13.5 U/mL of pRBCs; homozygous wildtype). The 65.2% frequency of TPMT-deficient and heterozygous individuals among these toxic patients is significantly greater than the expected 10% frequency in the general population (P <.001, chi(2)). TPMT phenotype and genotype were concordant in all TPMT-deficient and all homozygous-wildtype patients, whereas five patients with heterozygous phenotypes did not have a TPMT mutation detected. Before thiopurine dosage adjustments, TPMT-deficient patients experienced more frequent hospitalization, more platelet transfusions, and more missed doses of chemotherapy. Hematologic toxicity occurred in more than 90% of patients, whereas hepatotoxicity occurred in six patients (26%). Both patients who presented with only hepatic toxicity had a homozygous-wildtype TPMT phenotype. After adjustment of thiopurine dosages, the TPMT-deficient and heterozygous patients tolerated therapy without acute toxicity. CONCLUSION: There is a significant (> six-fold) overrepresentation of TPMT deficiency or heterozygosity among patients developing dose-limiting hematopoietic toxicity from therapy containing thiopurines. However, with appropriate dosage adjustments, TPMT-deficient and heterozygous patients can be treated with thiopurines, without acute dose-limiting toxicity.

The inactivation of doxorubicin by long ultraviolet light.

PURPOSE: Irradiation of doxorubicin (DOX) dissolved in RPMI medium 1640 by long ultraviolet (UVA) light results in a rapid decline in the cytotoxic activity of the drug. The present study was designed to sort out which component(s) of this medium are associated with the UVA inactivation of DOX. METHODS: The effects of UVA irradiation of DOX in solutions of various compositions were evaluated by measuring the changes in the drug growth inhibitory activity in P388 cells and in the DOX absorbance spectrum. RESULTS: Riboflavin seemed to be the major photosensitizing component in the medium and the effect was enhanced by the presence of histidine, methionine, tryptophan and tyrosine but not by other amino acids. The changes in DOX resulting from UVA irradiation in the presence of riboflavin, were not blocked by 1,4-diazabicyclo [2.2.2]octane (5 mM), superoxide dismutase (300 units/ml), catalase (150 units/ml) or sodium benzoate (50 mM). The effects of UVA light on doxorubicin could be prevented by excess ascorbic acid. CONCLUSIONS: The effects of UVA on DOX are mediated by riboflavin. The photoexcited riboflavin apparently interacts directly with DOX rather than by first forming reactive oxygen species. The results suggest that the photoinactivation of DOX may involve an oxidation step. The mechanism by which certain amino acids facilitate the photoinactivation of DOX is not known. It is suggested that patient intake of riboflavin and exposure to the sun and fluorescent light could affect the outcome of anthracycline treatment.

Lymphoid malignancies following Kawasaki disease.

Kawasaki disease is a childhood multisystem vasculitic syndrome of unknown etiology. Associated immunological dysregulation is consistently observed and may be pathogenic in the known cardiac and noncardiac complications of the disease. Despite the well-known association between acquired immunodeficiency states and neoplasia, there are no reports of cancer accompanying or following the onset of this disease. We report here two children who were diagnosed with lymphoid malignancies shortly following the diagnosis of Kawasaki disease, suggesting an association between the two entities.