Regulatory Considerations for Contribution of Effect of Drugs Used in Combination Regimens: Renal Cell Cancer Case Studies.

The development and review of combination drug regimens in oncology may present unique challenges to investigators and regulators. For regulatory approval of combination regimens, it is necessary to demonstrate the contribution of effect of each monotherapy to the overall combination. Alternative approaches to traditional designs may be needed to accelerate oncology drug development, for example, when combinations are substantially superior to available therapy, to reduce exposure to less effective therapies, and for drugs that are inactive as single agents and that in combination potentiate activity of another drug. These approaches include demonstration of activity in smaller randomized trials and/or monotherapy trials conducted in a similar disease setting. This article will discuss alternative approaches used in the development of approved drugs in combination, based on examples of recent approvals of combination regimens in renal cell carcinoma.

Comparative Risk of Anaphylactic Reactions Associated With Intravenous Iron Products.

IMPORTANCE: All intravenous (IV) iron products are associated with anaphylaxis, but the comparative safety of each product has not been well established. OBJECTIVE: To compare the risk of anaphylaxis among marketed IV iron products. DESIGN, SETTING, AND PARTICIPANTS: Retrospective new user cohort study of IV iron recipients (n = 688,183) enrolled in the US fee-for-service Medicare program from January 2003 to December 2013. Analyses involving ferumoxytol were limited to the period January 2010 to December 2013. EXPOSURES: Administrations of IV iron dextran, gluconate, sucrose, or ferumoxytol as reported in outpatient Medicare claims data. MAIN OUTCOMES AND MEASURES: Anaphylaxis was identified using a prespecified and validated algorithm defined with standard diagnosis and procedure codes and applied to both inpatient and outpatient Medicare claims. The absolute and relative risks of anaphylaxis were estimated, adjusting for imbalances among treatment groups. RESULTS: A total of 274 anaphylaxis cases were identified at first exposure, with an additional 170 incident anaphylaxis cases identified during subsequent IV iron administrations. The risk for anaphylaxis at first exposure was 68 per 100,000 persons for iron dextran (95% CI, 57.8-78.7 per 100,000) and 24 per 100,000 persons for all nondextran IV iron products combined (iron sucrose, gluconate, and ferumoxytol) (95% CI, 20.0-29.5 per 100,000) , with an adjusted odds ratio (OR) of 2.6 (95% CI, 2.0-3.3; P < .001). At first exposure, when compared with iron sucrose, the adjusted OR of anaphylaxis for iron dextran was 3.6 (95% CI, 2.4-5.4); for iron gluconate, 2.0 (95% CI 1.2, 3.5); and for ferumoxytol, 2.2 (95% CI, 1.1-4.3). The estimated cumulative anaphylaxis risk following total iron repletion of 1000 mg administered within a 12-week period was highest with iron dextran (82 per 100,000 persons, 95% CI, 70.5- 93.1) and lowest with iron sucrose (21 per 100,000 persons, 95% CI, 15.3- 26.4). CONCLUSIONS AND RELEVANCE: Among patients in the US Medicare nondialysis population with first exposure to IV iron, the risk of anaphylaxis was highest for iron dextran and lowest for iron sucrose.

Rate of weight gain and cardiometabolic abnormalities in children and adolescents.

OBJECTIVE: To investigate whether the rate of weight gain is associated with cardiometabolic risk, independent of weight measured concurrently. STUDY DESIGN: Healthy 7- to 17-year-old risperidone-treated patients (N = 105, 88% were boys) had blood pressure, anthropometry, and laboratory tests performed. Growth history was extracted from medical records. The rate of change in age- and sex-adjusted weight and body mass index (BMI) z score after the initiation of risperidone was individually modeled. Multivariable linear regression analyses explored the association of the rate of weight or BMI z score change with cardiometabolic outcomes, independent of last measured weight or BMI z score, respectively. RESULTS: Following a mean of 1.9 years (SD = 1.0) of risperidone treatment, the absolute increase in weight and BMI z scores was 0.61 (SD = 0.61) and 0.62 (SD = 0.73), respectively. After controlling for the final weight z score, the rate of change in weight z score was significantly associated with final glucose (P < .04), C-peptide (P < .004), the homeostasis model assessment insulin resistance index (P < .02), high-density lipoprotein (HDL) cholesterol (P < .0001), a metabolic syndrome score (P < .005), adiponectin (P < .04), and high-sensitivity C-reactive protein (P < .04). After controlling for the final BMI z score, the rate of change in BMI z score was associated with final HDL cholesterol (P < .04), leptin (P < .03), and adiponectin (P < .04), with a suggestion of an association with the final homeostasis model assessment insulin resistance index (P < .08). CONCLUSIONS: Compared with weight measured concurrently, the rate of weight gain in risperidone-treated children accounts for an equal or larger share of the variance in certain cardiometabolic outcomes (eg, HDL cholesterol [ΔR(2) = 8% vs ΔR(2) = 11%] and high-sensitivity C-reactive protein [ΔR(2) = 5% vs ΔR(2) = 9%]) and may serve as a treatment target.

Correlates of weight gain during long-term risperidone treatment in children and adolescents.

BACKGROUND: Most clinical trials of antipsychotics in children are brief, failing to address their long-term safety, particularly when taken concurrently with other psychotropics. This hypothesis-generating analysis evaluates potential correlates of weight gain in children receiving extended risperidone treatment. METHODS: Medically healthy 7-17 year-old patients treated with risperidone for six months or more were enrolled. Anthropometric measurements were conducted. Developmental and medication history was obtained from the medical record. Information related to birth weight, dietary intake, physical activity, and parental weight was collected. Mixed regression analyses explored the contribution of various demographic and clinical factors to age- and sex-adjusted weight and body mass index (BMI) z scores over the treatment period. RESULTS: The sample consisted of 110 patients (89% males) with a mean age of 11.8 years (sd = 2.9) upon enrollment. The majority had an externalizing disorder and received 0.03 mg/kg/day (sd = 0.02) of risperidone, for 2.5 years (sd = 1.7), to primarily target irritability and aggression (81%). Polypharmacy was common with 71% receiving psychostimulants, 50% selective serotonin reuptake inhibitors (SSRIs), and 32% α2-agonists. Weight and BMI z score were positively correlated with baseline weight at the start of risperidone, treatment duration, and the weight-adjusted dose of risperidone but inversely associated with the weight-adjusted dose of psychostimulants and the concurrent use of SSRIs and α2-agonists. The effect of risperidone dose appeared to attenuate as treatment extended while that of psychostimulants became more significant. The rate of change in weight (or BMI) z score prior to and within the first 12 weeks of risperidone treatment did not independently predict future changes neither did birth weight, postnatal growth, dietary intake, physical activity, or parental weight. CONCLUSIONS: This comprehensive analysis exploring correlates of long-term weight (or BMI) change in risperidone-treated youths revealed that pharmacotherapy exerts significant but complex effects. TRIAL REGISTRATION: Not applicable.

Iron status in toddlerhood predicts sensitivity to psychostimulants in children.

OBJECTIVE: Iron deficiency is associated with impaired dopaminergic signaling and externalizing behavior. The authors examine, whether iron stores in toddlerhood influence later response to psychostimulants. METHOD: Youth participating in a study monitoring the long-term safety of risperidone were included in this analysis if they had received psychostimulant monotherapy for at least 3 weeks and had a complete blood count obtained before psychostimulant treatment. Sensitivity to psychostimulants was defined based on the weight-adjusted dose during the 1st year of treatment. Regression analysis examined whether the hematological tests based on the characteristics of red blood cells were associated with sensitivity to psychostimulants. RESULTS: A total of 29 participants (93% men; 76% Whites), primarily with ADHD (93%), comprised the current sample. The hematological tests were obtained, on average, 3 years before the initiation of psychostimulants monotherapy that occurred at 5.8 years of age and continued for a median of 0.85 years, at an average daily dose of 0.98 mg/kg (SD = 0.38) in methylphenidate equivalent. Compared with those who were poorly sensitive to psychostimulants, after adjusting for age, mean corpuscular volume was significantly higher in the highly and moderately psychostimulants sensitive groups. CONCLUSIONS: If replicated, these findings suggest that more attention should be paid to optimizing body iron in early childhood.

A cross-sectional evaluation of the effect of risperidone and selective serotonin reuptake inhibitors on bone mineral density in boys.

OBJECTIVE: The aim of the present study was to investigate the effect of risperidone-induced hyperprolactinemia on trabecular bone mineral density (BMD) in children and adolescents. METHOD: Medically healthy 7- to 17-year-old males chronically treated, in a naturalistic setting, with risperidone were recruited for this cross-sectional study through child psychiatry outpatient clinics between November 2005 and June 2007. Anthropometric measurements and laboratory testing were conducted. The clinical diagnoses were based on chart review, and developmental and treatment history was obtained from the medical record. Volumetric BMD of the ultradistal radius was measured using peripheral quantitative computed tomography, and areal BMD of the lumbar spine was estimated using dual-energy x-ray absorptiometry. RESULTS: Hyperprolactinemia was present in 49% of 83 boys (n = 41) treated with risperidone for a mean of 2.9 years. Serum testosterone concentration increased with pubertal status but was not affected by hyperprolactinemia. As expected, bone mineral content and BMD increased with sexual maturity. After adjusting for the stage of sexual development and height and BMI z scores, serum prolactin was negatively associated with trabecular volumetric BMD at the ultradistal radius (P < .03). Controlling for relevant covariates, we also found treatment with selective serotonin reuptake inhibitors (SSRIs) to be associated with lower trabecular BMD at the radius (P = .03) and BMD z score at the lumbar spine (P < .05). These findings became more marked when the analysis was restricted to non-Hispanic white patients. Of 13 documented fractures, 3 occurred after risperidone and SSRIs were started, and none occurred in patients with hyperprolactinemia. CONCLUSIONS: This is the first study to link risperidone-induced hyperprolactinemia and SSRI treatment to lower BMD in children and adolescents. Future research should evaluate the longitudinal course of this adverse event to determine its temporal stability and whether a higher fracture rate ensues.