Pharmacokinetics and pharmacogenomics of daunorubicin in children: a report from the Children’s Oncology Group

Purpose

We explored the impact of obesity, body composition, and genetic polymorphisms on the pharmacokinetics (PK) of daunorubicin in children with cancer.

Patients and methods

Patients ≤21 years receiving daunorubicin as an infusion of any duration <24 h for any type of cancer were eligible. Plasma drug concentrations were measured by high-performance liquid chromatography. Body composition was measured by dual-energy X-ray absorptiometry. Obesity was defined as a BMI >95 % for age or as body fat >30 %. NONMEM was used to perform PK model fitting. The Affymetrix DMET chip was used for genotyping. The impact of genetic polymorphisms was investigated using SNP/haplotype association analysis with estimated individual PK parameters.

Results

A total of 107 subjects were enrolled, 98 patients had PK sampling, and 50 patients underwent DNA analysis. Population estimates for daunorubicin clearance and volume of distribution were 116 L/m²/h ± 14 % and 68.1 L/m² ± 24 %, respectively. Apparent daunorubicinol clearance and volume of distribution were 26.8 L/m²/h ± 5.6 % and 232 L/m² ± 10 %, respectively. No effect of body composition or obesity was observed on PK. Forty-four genes with variant haplotypes were tested for association with PK. FMO3-H1/H3 genotype was associated with lower daunorubicin clearance than FMO3-H1/H1, p = 0.00829. GSTP1*B/*B genotype was also associated with lower daunorubicin clearance compared to GSTP1*A/*A, p = 0.0347. However, neither of these associations was significant after adjusting for multiple testing by either Bonferroni or false discovery rate correction.

Conclusions

We did not detect an effect of body composition or obesity on daunorubicin PK. We found suggestive associations between FMO3 and GSTP1 haplotypes with daunorubicin PK that could potentially affect efficacy and toxicity.     

Phase I trial and pharmacokinetic study of raltitrexed in children with recurrent or refractory leukemia: a pediatric oncology group study.

PURPOSE: To evaluate the toxicity, antileukemic activity, and pharmacology of raltitrexed administered weekly for 3 weeks to patients with refractory or recurrent leukemia. EXPERIMENTAL DESIGN: Raltitrexed was administered as a 15-minute infusion for 3 consecutive weeks every 5 weeks, at doses ranging from 1.3 to 2.8 mg/m(2). The first course was used to determine the dose-limiting toxicities and maximum tolerated dose. Correlative studies included an assessment of raltitrexed pharmacokinetics and measurement of plasma 2'-deoxyuridine concentrations, a surrogate measure of thymidylate synthase inhibition. RESULTS: Twenty-one children (18 evaluable) with refractory leukemia received 25 courses of raltitrexed. The dose-limiting toxicity was reversible elevation in liver transaminases at the 2.8-mg/m(2) dose level and the maximum tolerated dose was 2.1 mg/m(2) per dose. Pharmacokinetics were best characterized by a two-compartment model with a clearance of 139 mL/min/m(2) (8.3 L/h/m(2)), a 2.4-L volume of distribution, an initial half-life (t(1/2alpha)) of 6 minutes, and a terminal half-life (t(1/2beta)) of 45 minutes. There were three objective responses. CONCLUSIONS: Raltitrexed was well tolerated when administered as a single agent to children with recurrent or refractory leukemia. We observed preliminary evidence of antileukemia activity using this weekly dosing schedule and these observations support further evaluation of raltitrexed in this population.     

Unmyelinated nerve fiber degeneration in chronic inflammatory demyelinating polyneuropathy

To determine whether unmyelinated nerve fibers escape degeneration as one might expect in an immune response exclusively directed at myelin, we performed a morphometric examination of unmyelinated axons and myelinated nerve fibers in sural nerve biopsy specimens of 14 patients with a chronic inflammatory demyelinating polyneuropathy (CIDP) and of 12 age-matched normal controls. The numbers of unmyelinated axons, myelinated nerve fibers, denervated Schwann cell units and collagen pockets were quantified and related to the clinical and electrophysiological data of the patients with CIDP. In 4 patients with a rapid onset of the neuropathy and a highly elevated CSF protein, the numbers of both unmyelinated axons and myelinated nerve fibers were decreased equally. In 8 patients we found that the unmyelinated axons were relatively spared compared with the loss of myelinated nerve fibers. In these patients, however, the presence of denervated Schwann cell units and of collagen pockets was increased. We conclude that unmyelinated nerve fibers are affected in patients with CIDP.     

Do apples need an Elmo sticker? Children’s classification of unprocessed edibles

Healthy eating campaigns that promote unprocessed foods to children using character licensing and fun appeals hope to offset the aggressive marketing of highly processed, unhealthy foods to children. Such campaigns are equally premised on the assumption that fruits, vegetables, and other whole foods are not desirable enough in the current food environment and must be marketed as child friendly to be appealing. This paper examines how children in Canada classify foods and whether they think of whole, unprocessed foods as ‘for them.’ Children aged 7–12 (n = 183) completed a survey asking them to classify various foods (fruit, vegetables, milk, eggs, beef, whole grains) as for ‘kids’, ‘adults’ or ‘both’. Most children classified these foods as for both adults and kids, suggesting that promotional initiatives to convince children that whole foods are uniquely children’s fare may not be necessary. Given the questionable efficacy of marketing whole foods as fun and ‘for kids,’ alongside the ethical stakes of commercializing childhood, we recommend that public health initiatives reject attempts to market whole foods as kids’ foods. Instead a key opportunity exists to emphasize the message that good food is for everyone – which is the most conducive to a building a healthy food environment and positive food habits across a lifetime.     

A SERCA2 pump with an increased Ca2+ affinity can lead to severe cardiac hypertrophy, stress intolerance and reduced life span

Abnormal Ca(2+) cycling in the failing heart might be corrected by enhancing the activity of the cardiac Ca(2+) pump, the sarco(endo)plasmic reticulum Ca(2+)-ATPase 2a (SERCA2a) isoform. This can be obtained by increasing the pump's affinity for Ca(2+) by suppressing phospholamban (PLB) activity, the in vivo inhibitor of SERCA2a. In SKO mice, gene-targeted replacement of SERCA2a by SERCA2b, a pump with a higher Ca(2+) affinity, results in cardiac hypertrophy and dysfunction. The stronger PLB inhibition on cardiac morphology and performance observed in SKO was investigated here in DKO mice, which were obtained by crossing SKO with PLB(-/-) mice. The affinity for Ca(2+) of SERCA2 was found to be further increased in these DKO mice. Relative to wild-type and SKO mice, DKO mice were much less spontaneously active and showed a reduced life span. The DKO mice also displayed a severe cardiac phenotype characterized by a more pronounced concentric hypertrophy, diastolic dysfunction and increased ventricular stiffness. Strikingly, beta-adrenergic or forced exercise stress induced acute heart failure and death in DKO mice. Therefore, the increased PLB inhibition represents a compensation for the imposed high Ca(2+)-affinity of SERCA2b in the SKO heart. Limiting SERCA2's affinity for Ca(2+) is physiologically important for normal cardiac function. An improved Ca(2+) transport in the sarcoplasmic reticulum may correct Ca(2+) mishandling in heart failure, but a SERCA pump with a much higher Ca(2+) affinity may be detrimental.     

The Prodromal Questionnaire: a case for IRT‐based adaptive testing of psychotic experiences?

Computerized adaptive tests (CATs) for positive and negative psychotic experiences were developed and tested in N = 5705 help‐seeking, non‐psychotic young individuals. Instead of presenting all items, CATs choose a varying number of different items during test administration depending on respondents' previous answers, reducing the average number of items while still obtaining accurate person estimates. We assessed the appropriateness of two‐parameter logistic models to positive and negative symptoms of the Prodromal Questionnaire (PQ), computed measurement precision of all items and resulting adaptive tests along psychotic dimensions by Real Data Simulations (RDS), and computed indices for criterion and predictive validities of the CATs. For all items, mean absolute differences between observed and expected response probabilities were smaller than 0.02. CAT‐POS predicted transition to psychosis and duration of hospitalization in individuals at‐risk for psychosis, and CAT‐NEG was suggestively related to later functioning. Regarding psychosis risk classifications of help‐seeking individuals, CAT‐POS performed less than the PQ‐16. Adaptive testing based on self‐reported positive and negative symptoms in individuals at‐risk for psychosis is a feasible method to select patients for further risk classification. These promising findings need to be replicated prospectively in a non‐selective sample that also includes non‐at‐risk individuals. Copyright © 2016 John Wiley & Sons, Ltd.     

Inhibition of translocation of viable Escherichia coli from the gastrointestinal tract of mice by bacterial antagonism.

The incidence of translocation of viable Escherichia coli C25 from the gastrointestinal tract to the mesenteric lymph nodes was compared in gnotobiotic mice colonized with only E. coli C25 and in gnotobiotic mice colonized with E. coli C25 plus the whole cecal flora from specific pathogen-free mice. The population levels of E. coli C25 in the ilea and ceca of these mice also were compared. E. coli C25 maintained high population levels in the gastrointestinal tracts of the monoassociated gnotobiotes, and the incidence of translocation to the mesenteric lymph nodes was 100%. The gastrointestinal population levels of E. coli C25 were reduced drastically in the gnotobiotes associated with both E. coli C25 and a cecal flora with concomitant reduction in the incidence of translocation of E. coli C25 from 100 to 0%. A decrease in the numbers of viable E. coli C25 per mesenteric lymph node also accompanied the decrease in C. coli C25 population levels in the gastrointestinal tracts of these mice. Thus, high population levels of E. coli C25 in the gastrointestinal tracts of monoassociated gnotobiotic mice appear to promote translocation of viable E. coli C25 to the mesenteric lymph nodes. Bacterial antagonism of E. coli population levels in conventional mice, therefore, could be one mechanism whereby viable E. coli are confined to the gastrointestinal tract.     

The evaluation of cardiac biometry in major cardiac defects detected in early pregnancy

The objective was to evaluate early cardiac biometry in fetuses with structural cardiac defects between 10 and 17 weeks of gestation using our normative data about fetal heart biometry. A retrospective case series, patients were selected from all cases with congenital heart disease diagnosed between 10 and 17 weeks of gestation in our prenatal unit between 1999 and 2000. A schematic sonographic examination, including nuchal translucency (NT) thickness measurements, was performed and was followed by fetal Doppler echocardiography. The transversal heart diameter, both ventricular dimensions, heart area, heart circumference, thoracic diameter, thoracic circumference, thoracic area, pulmonary trunk diameter and aortic diameter were measured and the cardiothoracic ratios were calculated. Doppler evaluation of the umbilical arteries, ductus venosus and umbilical vein was performed. Fetal karyotyping was obtained by amniocentesis or chorionic villous sampling. During the study period, 31 cases of congenital heart disease between 10 and 17 weeks of gestation were diagnosed. Of these, two fetuses presented with ectopia cordis and six with insufficient cardiac biometric measurements. In the remaining 23 fetuses, different complex abnormalities with a high rate of chromosomal abnormalities (91%) were present. Fetal heart biometry was normal in 22% and abnormal in 78%. NT thickness measurements were performed before 14 weeks of gestation and ten of 12 fetuses (83%) presented with an increased NT. Both fetuses with normal NT showed an abnormal fetal heart biometry. Venous Doppler evaluation was performed in 22 cases and 12 fetuses (55%) demonstrated an abnormal venous Doppler. There were ten fetuses (45%) with normal venous Doppler; in seven of these cases, fetal heart biometry was partly abnormal. This study shows the feasibility of first and early second trimesters' fetal echocardiography and the applicability of cardiac biometry in these instances. In this context, early fetal heart biometry and NT thickness measurements may be complementary methods for the prenatal diagnosis of some major congenital heart defects. In early pregnancy, some cardiac defects like tricuspid valve dysplasia, coarctation of the aorta, aortic stenosis, tetralogy of Fallot or pulmonary stenosis may already show similar changes in the relation of the diameters of the fetal heart and great arteries, as seen in the second trimester. Therefore, evaluating the different cardiac ratios may have a high diagnostic value in early pregnancy.     

Serum levels of vitamin D metabolites and breast cancer risk in the prostate, lung, colorectal, and ovarian cancer screening trial.

Experimental and epidemiologic studies suggest that vitamin D metabolites (1,25-dihydroxyvitamin D [1,25(OH)(2)D] and its precursor 25-hydroxyvitamin D [25(OH)D]) may reduce breast cancer risk. We examined subsequent breast cancer risk related to serum levels of these metabolites. In a cohort of women ages 55 to 74 years, who donated blood at baseline (1993-2001) in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, we identified 1,005 incident breast cancer cases during follow-up through 2005 (mean time between blood draw and diagnosis, 3.9 years). Noncases (n = 1,005) were frequency matched to the cases based on age and year of entry. Sample weights that accounted for unequal probabilities of selecting cases and noncases were applied to make inferences that reflected the entire Prostate, Lung, Colorectal, and Ovarian cohort. Using Cox proportional hazards modeling, we computed breast cancer relative risks (RR) and 95% confidence intervals (95% CI) by quintile for each metabolite. The RR of breast cancer for the highest quintile of 25(OH)D concentration versus the lowest was 1.04 (95% CI, 0.75-1.45; P(trend) = 0.81). Similarly, the breast cancer RR for the highest quintile of 1,25(OH)(2)D compared with the lowest was 1.23 (95% CI, 0.91-1.68; P(trend) = 0.14). Excluding the first 2 years of follow-up did not materially alter these estimates. There was also no evidence of inverse risk in older women (> or =60 years) versus younger women (<60 years). In this prospective study of postmenopausal women, we did not observe an inverse association between circulating 25(OH)D or 1,25(OH)(2)D and breast cancer risk, although we cannot exclude an association in younger women or with long-term or earlier exposure.     

Acid-inhibitory effects of omeprazole and lansoprazole in Helicobacter pylori-negative healthy subjects

Background:

Omeprazole 20 mg once daily (o.d.) and lansoprazole 30 mg o.d. have similar acid-inhibitory effects in healthy Helicobacter pylori-positive subjects. However, little is known about the acid-inhibitory effects of the o.d. and twice daily (b.d.) doses in H. pylori-negative subjects.

Aim:

To compare the decrease in gastric acidity of omeprazole 20 mg (o.d. and b.d.) with lansoprazole 30 mg (o.d. and b.d.) in healthy H. pylori-negative subjects on day 6–7 of dosing.

Methods:

A randomized, investigator-blind, crossover study design was used. Intragastric pH was measured continuously with glass electrodes positioned in the gastric corpus. Sixteen H. pylori-negative subjects, whose intragastric acidity fell below pH 4 for 70% of a 24-h baseline period, were entered in the study.

Results:

Both dosing regimens of omeprazole and lansoprazole significantly increased median gastric pH and percentages of time above pH 4 during the entire 24-h period, night- and daytime, compared to baseline. There were no significant differences in median gastric pH values or time above pH thresholds 3, 4 and 5 between the o.d. dosing regimens. During the night the percentage of time spent above pH 3 and 4 was significantly higher with omeprazole 20 mg b.d. than with lansoprazole 30 mg b.d.

Conclusions:

This comparative study demonstrates that daily doses of omeprazole 20 mg and lansoprazole 30 mg are equally effective in raising intragastric pH in H. pylori-negative subjects on day 6 of dosing. During the night, omeprazole 20 mg b.d. provides superior gastric acid suppression compared to lansoprazole 30 mg b.d.