Activity and safety of brigatinib in ALK-rearranged non-small-cell lung cancer and other malignancies: a single-arm, open-label, phase 1/2 trial.

BACKGROUND: Anaplastic lymphoma kinase (ALK) gene rearrangements are oncogenic drivers of non-small-cell lung cancer (NSCLC). Brigatinib (AP26113) is an investigational ALK inhibitor with potent preclinical activity against ALK mutants resistant to crizotinib and other ALK inhibitors. We aimed to assess brigatinib in patients with advanced malignancies, particularly ALK-rearranged NSCLC. METHODS: In this ongoing, single-arm, open-label, phase 1/2 trial, we recruited patients from nine academic hospitals or cancer centres in the USA and Spain. Eligible patients were at least 18 years of age and had advanced malignancies, including ALK-rearranged NSCLC, and disease that was refractory to available therapies or for which no curative treatments existed. In the initial dose-escalation phase 1 stage of the trial, patients received oral brigatinib at total daily doses of 30-300 mg (according to a standard 3 + 3 design). The phase 1 primary endpoint was establishment of the recommended phase 2 dose. In the phase 2 expansion stage, we assessed three oral once-daily regimens: 90 mg, 180 mg, and 180 mg with a 7 day lead-in at 90 mg; one patient received 90 mg twice daily. We enrolled patients in phase 2 into five cohorts: ALK inhibitor-naive ALK-rearranged NSCLC (cohort 1), crizotinib-treated ALK-rearranged NSCLC (cohort 2), EGFRT790M-positive NSCLC and resistance to one previous EGFR tyrosine kinase inhibitor (cohort 3), other cancers with abnormalities in brigatinib targets (cohort 4), and crizotinib-naive or crizotinib-treated ALK-rearranged NSCLC with active, measurable, intracranial CNS metastases (cohort 5). The phase 2 primary endpoint was the proportion of patients with an objective response. Safety and activity of brigatinib were analysed in all patients in both phases of the trial who had received at least one dose of treatment. This trial is registered with ClinicalTrials.gov, number NCT01449461. FINDINGS: Between Sept 20, 2011, and July 8, 2014, we enrolled 137 patients (79 [58%] with ALK-rearranged NSCLC), all of whom were treated. Dose-limiting toxicities observed during dose escalation included grade 3 increased alanine aminotransferase (240 mg daily) and grade 4 dyspnoea (300 mg daily). We initially chose a dose of 180 mg once daily as the recommended phase 2 dose; however, we also assessed two additional regimens (90 mg once daily and 180 mg once daily with a 7 day lead-in at 90 mg) in the phase 2 stage. four (100% [95% CI 40-100]) of four patients in cohort 1 had an objective response, 31 (74% [58-86]) of 42 did in cohort 2, none (of one) did in cohort 3, three (17% [4-41]) of 18 did in cohort 4, and five (83% [36-100]) of six did in cohort 5. 51 (72% [60-82]) of 71 patients with ALK-rearranged NSCLC with previous crizotinib treatment had an objective response (44 [62% (50-73)] had a confirmed objective response). All eight crizotinib-naive patients with ALK-rearranged NSCLC had a confirmed objective response (100% [63-100]). Three (50% [95% CI 12-88]) of six patients in cohort 5 had an intracranial response. The most common grade 3-4 treatment-emergent adverse events across all doses were increased lipase concentration (12 [9%] of 137), dyspnoea (eight [6%]), and hypertension (seven [5%]). Serious treatment-emergent adverse events (excluding neoplasm progression) reported in at least 5% of all patients were dyspnoea (ten [7%]), pneumonia (nine [7%]), and hypoxia (seven [5%]). 16 (12%) patients died during treatment or within 31 days of the last dose of brigatinib, including eight patients who died from neoplasm progression. INTERPRETATION: Brigatinib shows promising clinical activity and has an acceptable safety profile in patients with crizotinib-treated and crizotinib-naive ALK-rearranged NSCLC. These results support its further development as a potential new treatment option for patients with advanced ALK-rearranged NSCLC. A randomised phase 2 trial in patients with crizotinib-resistant ALK-rearranged NSCLC is prospectively assessing the safety and efficacy of two regimens assessed in the phase 2 portion of this trial (90 mg once daily and 180 mg once daily with a 7 day lead-in at 90 mg). FUNDING: ARIAD Pharmaceuticals.

Relationship between force and size in human single muscle fibres.

When the contractile properties of single muscle fibres are studied, force is typically normalized by fibre cross-sectional area and expressed as specific force. We studied a set of 2725 chemically skinned human single muscle fibres from 119 healthy adults to determine whether specific force is the optimal way to express the relationship between single-fibre force and size. A linear mixed effects model was used to estimate the slope and slope variability among individuals of log-log plots of force and diameter. For type I fibres, the slope estimate was 0.99 (95% confidence interval 0.36-1.62), and for type IIa fibres it was 0.94 (95% confidence interval 0.77-1.11), indicating that force is proportional to fibre diameter, rather than to cross-sectional area. If force were proportional to cross-sectional area, the slope estimate would be 2.0. In future studies using the chemically skinned single fibre preparation, force may be normalized to fibre diameter rather than cross-sectional area. We propose that a new term, 'normalized force', be used for this variable, with units of newtons per metre. We demonstrate using our data set that when populations of single fibres are compared with one another, the determination of whether the size and force relationship is the same or different is dependent upon the method used to account for fibre size (i.e. specific force versus 'normalized force').

Effects of Strong CYP2C8 or CYP3A Inhibition and CYP3A Induction on the Pharmacokinetics of Brigatinib, an Oral Anaplastic Lymphoma Kinase Inhibitor, in Healthy Volunteers.

In vitro data support involvement of cytochrome P450 (CYP)2C8 and CYP3A4 in the metabolism of the anaplastic lymphoma kinase inhibitor brigatinib. A 3-arm, open-label, randomized, single-dose, fixed-sequence crossover study was conducted to characterize the effects of the strong inhibitors gemfibrozil (of CYP2C8) and itraconazole (of CYP3A) and the strong inducer rifampin (of CYP3A) on the single-dose pharmacokinetics of brigatinib. Healthy subjects (n = 20 per arm) were administered a single dose of brigatinib (90 mg, arms 1 and 2; 180 mg, arm 3) alone in treatment period 1 and coadministered with multiple doses of gemfibrozil 600 mg twice daily (BID; arm 1), itraconazole 200 mg BID (arm 2), or rifampin 600 mg daily (QD; arm 3) in period 2. Compared with brigatinib alone, coadministration of gemfibrozil with brigatinib did not meaningfully affect brigatinib area under the plasma concentration-time curve (AUC0-inf ; geometric least-squares mean [LSM] ratio [90%CI], 0.88 [0.83-0.94]). Coadministration of itraconazole with brigatinib increased AUC0-inf (geometric LSM ratio [90%CI], 2.01 [1.84-2.20]). Coadministration of rifampin with brigatinib substantially reduced AUC0-inf (geometric LSM ratio [90%CI], 0.20 [0.18-0.21]) compared with brigatinib alone. The treatments were generally tolerated. Based on these results, strong CYP3A inhibitors and inducers should be avoided during brigatinib treatment. If concomitant use of a strong CYP3A inhibitor is unavoidable, the results of this study support a dose reduction of brigatinib by approximately 50%. Furthermore, CYP2C8 is not a meaningful determinant of brigatinib clearance, and no dose modifications are needed during coadministration of brigatinib with CYP2C8 inhibitors.

The Effect of a High-Fat Meal on the Pharmacokinetics of Brigatinib, an Oral Anaplastic Lymphoma Kinase Inhibitor, in Healthy Volunteers.

Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, received accelerated approval in the United States for the treatment of patients with metastatic ALK+ non-small-cell lung cancer who have progressed on or are intolerant to crizotinib. A clinical study was conducted to assess the effect of food on brigatinib pharmacokinetics (PK). Healthy subjects received a single oral dose of brigatinib 180 mg (2 × 90-mg tablets) after a 10-hour fast or after a high-fat meal in a 2-period, 2-sequence crossover study. Plasma samples for PK characterization were collected over 168 hours postdose. Twenty-four subjects were enrolled (mean age 44 years; 58% male), with 21 included in the PK-evaluable population. Brigatinib peak concentration was reduced by 13% under fed (high-fat meal) versus fasted conditions, with no effect on area under the concentration-time curve. The median time to peak concentration of brigatinib was longer under fed conditions (5 hours) than in fasted conditions (2 hours). Treatment-emergent adverse events were similar under fasted (48%) and fed (46%) conditions and were of mild intensity. Consumption of a high-fat meal decreased the rate of brigatinib oral absorption but had no impact on the extent of absorption, thereby supporting brigatinib administration without regard to meals. These recommendations are reflected in the US prescribing information for brigatinib.

Diagnostic crossover in anorexia nervosa and bulimia nervosa: implications for DSM-V.

OBJECTIVE: The Diagnostic and Statistical Manual of Mental Disorders (DSM) is designed primarily as a clinical tool. Yet high rates of diagnostic "crossover" among the anorexia nervosa subtypes and bulimia nervosa may reflect problems with the validity of the current diagnostic schema, thereby limiting its clinical utility. This study was designed to examine diagnostic crossover longitudinally in anorexia nervosa and bulimia nervosa to inform the validity of the DSM-IV-TR eating disorders classification system. METHOD: A total of 216 women with a diagnosis of anorexia nervosa or bulimia nervosa were followed for 7 years; weekly eating disorder symptom data collected using the Eating Disorder Longitudinal Interval Follow-Up Examination allowed for diagnoses to be made throughout the follow-up period. RESULTS: Over 7 years, the majority of women with anorexia nervosa experienced diagnostic crossover: more than half crossed between the restricting and binge eating/purging anorexia nervosa subtypes over time; one-third crossed over to bulimia nervosa but were likely to relapse into anorexia nervosa. Women with bulimia nervosa were unlikely to cross over to anorexia nervosa. CONCLUSIONS: These findings support the longitudinal distinction of anorexia nervosa and bulimia nervosa but do not support the anorexia nervosa subtyping schema.

A personality classification system for eating disorders: a longitudinal study.

BACKGROUND: Studies of eating disorders (EDs) suggest that empirically derived personality subtypes may explain heterogeneity in ED samples that is not captured by the current diagnostic system. Longitudinal outcomes for personality subtypes have not been examined. METHOD: In this study, personality pathology was assessed by clinical interview in 213 individuals with anorexia nervosa and bulimia nervosa at baseline. Interview data on EDs, comorbid diagnoses, global functioning, and treatment utilization were collected at baseline and at 6-month follow-up intervals over a median of 9 years. RESULTS: Q-factor analysis of the participants based on personality items produced a 5-prototype system, including high-functioning, behaviorally dysregulated, emotionally dysregulated, avoidant-insecure, and obsessional-sensitive types. Dimensional prototype scores were associated with baseline functioning and longitudinal outcome. Avoidant-Insecure scores showed consistent associations with poor functioning and outcome, including failure to show ED improvement, poor global functioning after 5 years, and high treatment utilization after 5 years. Behavioral dysregulation was associated with poor baseline functioning but did not show strong associations with ED or global outcome when histories of major depression and substance use disorder were covaried. Emotional dysregulation and obsessional-sensitivity were not associated with negative outcomes. High-functioning prototype scores were consistently associated with positive outcomes. CONCLUSIONS: Longitudinal results support the importance of personality subtypes to ED classification.

Interactions between eating disorders and drug abuse.

To examine the relationship between drug abuse and eating disorders in a longitudinal sample. In a prospective study, women diagnosed with either DSM-IV anorexia nervosa (n = 136) or bulimia nervosa (n = 110) were interviewed and assessed for research diagnostic criteria drug use disorder (DUD) every 6-12 months over 8.6 years. Contrary to expectation, DUD did not influence recovery from either eating disorder. Multivariate analyses indicated that alcohol use and suicide attempts over the course of the study, as well as hospitalization for an affective disorder before the study, predicted DUD in anorexia nervosa. For bulimia nervosa, multivariate predictors included the severity of alcohol use and the severity of bulimic symptoms over the course of the study, and a hospitalization before study entry for a nonaffective disorder. Drug abuse in women with eating disorders is an area of clinical concern and should be monitored routinely.

Geometric determinants of functional tricuspid regurgitation: insights from 3-dimensional echocardiography.

BACKGROUND: Tricuspid regurgitation (TR) is an important predictor of morbidity and mortality in heart failure. We aimed to examine the 3D geometry of the tricuspid valve annulus (TVA) in patients with functional TR, comparing them with patients with normal tricuspid valve function and relating annular geometric changes to functional TR. METHODS AND RESULTS: TVA shape was examined by real-time 3D echocardiography in 75 patients: 35 with functional TR and 40 with normal tricuspid valve function (referent group). The 3D shape of the TVA was reconstructed from rotated 2D planes, and the annular plane was computed by least-squares fitting. Annular area and mediolateral, anteroposterior, and high (superior)-low (inferior) distances were calculated. TR was assessed by vena contracta width. The normal TVA has a bimodal pattern (high-low distance=7.23+/-1.05 mm). High points were located anteroposteriorly, and low points were located mediolaterally. With moderate or greater TR (vena contracta width 5.80+/-2.62 mm), the TVA became dilated (17.24+/-4.75 versus 9.83+/-2.18 cm2, P<0.0001, TR versus referent), more planar with decreased high-low distance (4.14+/-1.05 mm), and more circular with decreased ratio of mediolateral/anteroposterior (1.11+/-0.09 versus 1.32+/-0.09, P<0.0001, TR versus referent). CONCLUSIONS: The normal TVA has a bimodal shape with distinct high points located anteroposteriorly and low points located mediolaterally. With functional TR, the annulus becomes larger, more planar, and circular. These changes in annular shape with TR have potentially important mechanistic and therapeutic implications for tricuspid valve repair.

Single skeletal muscle fiber elastic and contractile characteristics in young and older men.

The current investigation was designed to: (a) assess the impact of aging on elastic characteristics of single skeletal muscle fibers from young (N = 6) and older men (N = 6); and (b) correlate the potential changes, with the fiber contractile properties. Chemically skinned single muscle fibers (n = 235) from vastus lateralis muscle were maximally activated. Maximal force and cross-sectional area were measured, and specific force calculated. The slack test was used to measure maximal unloaded shortening velocity. A quick release of 0.15% of fiber length was applied to determine instantaneous stiffness. The myosin heavy chain isoform composition of each single fiber was determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Aging induces changes in both fiber elasticity (i.e., increased instantaneous stiffness) and contractility (i.e., reduced specific force and unloaded shortening velocity) in type I and IIa fibers. However, the changes in fiber stiffness may not directly influence contractile characteristics alterations.

Predictors for the development of elevated anti-heparin/platelet factor 4 antibody titers in patients undergoing cardiac catheterization.

A substantial proportion of patients who undergo cardiac catheterization develop antibodies directed against the heparin/platelet factor 4 (PF4) complex after the procedure, which have been implicated in the pathogenesis of heparin-induced thrombocytopenia. This study attempted to identify factors that predicted the development of these antibodies in a prospective cohort study. Antiheparin/PF4 antibody titers were measured at baseline and again 5 +/- 2 days after cardiac catheterization by enzyme-linked immunosorbent assay. A total of 311 patients who underwent cardiac catheterization were included in the analysis. Of these, 25 (8.0%) developed positive antibody levels after catheterization. Patients who had positive antibody test results after catheterization had significantly greater baseline antiheparin/PF4 antibody titers compared with those whose titers remained low (optical density 0.227 vs 0.158, p < 0.001). In a logistic regression model, greater baseline antibody titers, a history of heparin exposure, and a lower platelet count at enrollment were the strongest predictors of conversion to positive antiheparin/PF4 antibody titers after cardiac catheterization. It is possible to identify patients at high risk for developing elevated titers of antiheparin/PF4 antibodies on the basis of their baseline clinical characteristics.

The relationship between human semen characteristics and sperm apoptosis: a pilot study.

This work was undertaken to explore the association between human semen characteristics and apoptosis in ejaculated sperm. We collected semen samples from 23 consecutive male patients who presented to the Andrology Laboratory at Massachusetts General Hospital (MGH) for routine semen analysis. Sperm concentration and motility were measured using computer-assisted sperm analysis. Morphology was assessed using Tygerberg strict criteria. The DNA diffusion assay was used to assess the percentage of apoptosis in ejaculated sperm. In this assay, cells were mixed with agarose and placed into a microgel on a microscopic slide. The cells were stained with YOYO-1 dye, and apoptotic cells were viewed under a fluorescent microscope. Among 23 men, the mean (SD) sperm concentration, percent motility, percent progressive motility, and normal morphology were 125.5 (92.3) million/mL, 45.6% (22.2), 28.4% (15.2), and 8.0 (4.6), respectively. The mean (SD) percent of apoptosis in ejaculated sperm was 8.3% (6.2) with a range from 1.1% to 20.1%. There were inverse associations between percent apoptosis and sperm motility (P = .0025), progressive motility (P = .0051), and morphology with a normal or good pattern of fertilization by Kruger strict criteria (P = .0045), and a positive relationship between percent apoptosis and sperm tail defects (P = .0053). In ejaculated semen, the percent sperm apoptosis was associated with several measures of semen quality.

The educational impact of ACGME limits on resident and fellow duty hours: a pre-post survey study.

PURPOSE: To assess the educational impact of Accreditation Council for Graduate Medical Education resident work-hour limits implemented in July 2003. METHOD: All trainees in all 76 accredited programs at two large teaching hospitals were surveyed between May and June 2003 (before work-hour reductions) and then between May and June 2004 (after work-hour reductions) about hours, education, and fatigue. Based on changes in weekly duty hours, 13 programs experiencing substantial reduction in hours were classified into a reduced-hours group. Differences in assessments of educational endpoints before and after policy implementation by trainees in the reduced-hours group were compared with those in other programs to control for potential temporal trends, using two-way ANOVA with interaction. RESULTS: The number of respondents was 1,770 (60% response rate). The reduced-hours group reported a significant decrease in time spent directly caring for patients (from 48.5 to 42.3 mean h/wk, P = 0.03), but the volume of important clinical experiences, including procedures, was preserved, as was the sense of clinical preparedness. On 22 questions related to educational quality and adequacy, only three differences in differences were significant, with the reduced-hours group reporting a relative increase in opportunities for research, decrease in quality of faculty teaching, and decrease in educational satisfaction. The percentage of trainees reporting frequent negative effects of fatigue dropped more in the reduced-hours programs than in the other programs (P < 0.05). CONCLUSION: This study shows that it may be possible to reduce residents' hours--and the perceived adverse impact of fatigue--while generally preserving the self-assessed quality, quantity, and outcomes of graduate medical education.

Sex differences in single muscle fiber power in older adults.

PURPOSE: This study was conducted to determine whether differences in power at the single muscle fiber level contribute to sex differences in whole muscle power production in the elderly. METHODS: A total of 16 sedentary older persons (10 women, 6 men), mean age 72 yr, had percutaneous needle biopsy of musculus vastus lateralis. Chemically skinned single muscle fibers were activated with Ca for maximal isometric force measurement (Po). The slack test was performed to determine maximal unloaded shortening velocity (Vo). Force-velocity and power curves were generated via a series of isotonic contractions, allowing measurement of peak power and specific power. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) was used to determine myosin heavy chain composition of single muscle fibers. Whole muscle strength, velocity, and power were measured for knee extension and double leg press. RESULTS: Men had greater whole muscle strength, power, and velocity compared with women. Studied were 274 type I and 33 type IIa single fibers. No significant sex differences were found for fiber size, Po, specific force, Vo, power, or specific power in type I or IIa fibers. CONCLUSIONS: Single muscle fiber quality in older women is equivalent to that in older men and can not explain the differences seen in whole muscle strength, power, or function.

Impact of dose intensity of ponatinib on selected adverse events: Multivariate analyses from a pooled population of clinical trial patients.

Ponatinib is approved for adults with refractory chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia, including those with the T315I BCR-ABL1 mutation. We pooled data from 3 clinical trials (N=671) to determine the impact of ponatinib dose intensity on the following adverse events: arterial occlusive events (cardiovascular, cerebrovascular, and peripheral vascular events), venous thromboembolic events, cardiac failure, thrombocytopenia, neutropenia, hypertension, pancreatitis, increased lipase, increased alanine aminotransferase, increased aspartate aminotransferase, rash, arthralgia, and hypertriglyceridemia. Multivariate analyses allowed adjustment for covariates potentially related to changes in dosing or an event. Logistic regression analysis identified significant associations between dose intensity and most events after adjusting for covariates. Pancreatitis, rash, and cardiac failure had the strongest associations with dose intensity (odds ratios >2). Time-to-event analyses showed significant associations between dose intensity and risk of arterial occlusive events and each subcategory. Further, these analyses suggested that a lag exists between a change in dose and the resulting change in event risk. No significant association between dose intensity and risk of venous thromboembolic events was evident. Collectively, these findings suggest a potential causal relationship between ponatinib dose and certain adverse events and support prospective investigations of approaches to lower average ponatinib dose intensity.

Postremission predictors of relapse in women with eating disorders.

OBJECTIVE: The authors sought to evaluate patterns and predictors of relapse among women with eating disorders. METHOD: Interviews were conducted biannually to annually to assess symptoms of eating disorders, axis I disorders, treatment, and psychosocial function on a weekly basis for women diagnosed with anorexia nervosa (N=136) or bulimia nervosa (N=110) and prospectively followed for 9 years. At the last follow-up, 229 (93%) of the subjects had been retained in the study group. RESULTS: Relapse occurred in 36% of the women with anorexia nervosa and 35% of the women with bulimia nervosa. Women with intake diagnoses of anorexia nervosa, restricting subtype, tended to develop bulimic symptoms during relapse, whereas women with intake diagnoses of anorexia nervosa, binge-purge subtype, or bulimia nervosa tended to return to bulimic patterns during relapse. Greater body image disturbance contributed to a risk of relapse in both eating disorders, and worse psychosocial function increased the risk of relapse in bulimia nervosa. CONCLUSIONS: These results may explain the long-term efficacy of interpersonal therapy for bulimia nervosa and suggest that focused body image work during relapse prevention may enhance long-term recovery from eating disorders.

Predictors of mortality in eating disorders.

BACKGROUND: Anorexia nervosa, but not bulimia nervosa, has one of the highest mortality rates among psychiatric disorders. However, potential predictors of mortality, such as comorbid psychiatric illnesses, remain unclear. We sought to determine mortality ratios and predictors of fatal outcome in women diagnosed as having anorexia or bulimia nervosa. METHODS: Women (N = 246) diagnosed as having either DSM-IV anorexia nervosa (n = 136) or bulimia nervosa (n = 110) between January 1, 1987, and December 31, 1991, participated in a prospective longitudinal study. Vital status was determined by ongoing contact and a National Death Index search as of December 1998 (overall ascertainment, 99.8%) and telephone contact as of October 2000 (ascertainment, 95.0%). RESULTS: Eleven women died. Standardized mortality ratios were elevated for all causes of mortality (11.6; 95% confidence interval, 5.5-21.3) and suicide (56.9; 95% confidence interval, 15.3-145.7) in anorexia nervosa but not for death (1.3; 95% confidence interval, 0.0-7.2) in bulimia nervosa. Predictors of mortality in anorexia nervosa included severity of alcohol use disorder during follow-up (P<.001). Hospitalization for an affective disorder before baseline assessment seemed to protect women from a fatal outcome (P<.001). CONCLUSIONS: Physicians treating patients with anorexia nervosa should carefully assess patterns of alcohol use during the course of care because one third of women who had alcoholism and died had no history of alcohol use disorder at intake.

Evaluation of the effect of multiple doses of rifampin on the pharmacokinetics and safety of ponatinib in healthy subjects.

Ponatinib, an oral tyrosine kinase inhibitor with significant activity in heavily pretreated patients with chronic myeloid leukemia, is a CYP3A4 substrate. This open-label, nonrandomized, fixed-order crossover study evaluated the effect of multiple oral doses of rifampin, a strong CYP3A4 inducer, on the pharmacokinetics of ponatinib (45 mg, single dose). Twenty healthy adults received ponatinib on day 1, rifampin 600 mg alone on days 8-13, 15, and 16, and rifampin 600 mg with ponatinib on day 14. Rifampin decreased maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) from time zero to time of last measurable concentration (AUC0-t ) and from time zero to infinity (AUC0-∞ ) of ponatinib by 42%, 59%, and 63%, respectively, with no effect on time to Cmax . The limits of the 90% confidence intervals of the estimated geometric mean ratios of ponatinib Cmax , AUC0-t , and AUC0-∞ did not fall within the 80-125% margins for equivalence, suggesting a statistically significant interaction. Coadministration of ponatinib with strong CYP3A4 inducers should be avoided unless the benefit outweighs the possible risk of ponatinib underexposure, because the safety of ponatinib dose increases has not been studied in this context.

Diagnostic errors after inferior petrosal sinus sampling.

Although inferior petrosal sinus sampling (IPSS) is useful in the evaluation of Cushing's syndrome, false negative cases have been described, and many patients presumed to have ectopic tumors based upon negative IPSS remain without a final diagnosis. These patients are often managed as if they have as yet undiscovered ectopic tumors. To test this assumption, we conducted a retrospective review of our results to determine the ultimate diagnoses after IPSS. Between 1986 and 2002, 179 patients underwent 185 IPSS procedures as part of their evaluation for Cushing's syndrome. Confirmed diagnoses were available for 149 patients (83%): 139 patients had pituitary adenomas (94%), eight had bronchial carcinoids (5%), and two had adrenal tumors (1%). Threshold criteria for a pituitary source were defined as an inferior petrosal sinus to peripheral (IPS:P) basal ratio of 2:1 or greater without CRH or an IPS:P ratio of 3:1 or greater after CRH stimulation. There were nine patients in whom the IPS:P ratio failed to meet threshold criteria after successful sampling, but were nonetheless found to have pituitary tumors after transsphenoidal exploration (false negatives). Eight of these had received CRH and had a significant rise (>35%) in peripheral ACTH levels after CRH treatment, even though the IPS:P ratio did not reach the threshold. There were two patients in whom the IPS:P ratio reached threshold criteria, and ectopic tumors were demonstrated as the source of ACTH overproduction (false positives). The sensitivity after CRH stimulation was 90% (95% confidence interval, 80.8-95.5%) with a specificity of 67% (95% confidence interval, 11.4-94.5%). The positive and negative predictive values were 99 and 20%, respectively. Our data show that patients with an IPS:P ratio suggestive of a nonpituitary source of ACTH overproduction may still have Cushing's disease. Analyzing the CRH-stimulated peripheral ACTH levels in addition to the standard IPS:P ratios may provide improved diagnostic accuracy. Transsphenoidal exploration should be considered in all cases of unsuccessful sampling and in those cases for which no ectopic source can be identified after further body imaging, even if the IPSS is negative, and especially if peripheral ACTH levels rise significantly with CRH stimulation.

Predictors of treatment utilization among women with anorexia and bulimia nervosa.

OBJECTIVE: The authors sought predictors of treatment utilization among women with eating disorders. METHOD: Women diagnosed with either anorexia or bulimia nervosa (N=246) completed prospective evaluations of eating disorder status, comorbid disorders, global assessment of functioning, and treatment utilization. RESULTS: Women with anorexia nervosa received significantly more inpatient treatment than did women with bulimia nervosa. Predictors of treatment utilization included lower global assessment of functioning scores and presence of personality disorders. CONCLUSIONS: Women with more severe pathology have higher treatment utilization rates. This pattern may explain the seeming lack of treatment efficacy for eating disorders outside of randomized controlled studies.

Evaluation of the effect of multiple doses of lansoprazole on the pharmacokinetics and safety of ponatinib in healthy subjects.

BACKGROUND: In vitro studies have demonstrated that the aqueous solubility of the tyrosine kinase inhibitor ponatinib decreases as pH increases. OBJECTIVES: The primary aim of this study was to assess the effects of the gastric proton pump inhibitor lansoprazole on the pharmacokinetics of ponatinib. The single-dose safety profile of ponatinib with and without coadministration of lansoprazole was also characterized. METHODS: This was a phase I, open-label, non-randomized, two-period crossover study in 20 healthy subjects aged 18-55 years. Subjects received a single oral dose of ponatinib 45 mg alone on day 1, an oral dose of lansoprazole 60 mg on day 14, and ponatinib 45 mg plus lansoprazole 60 mg on day 15. RESULTS: Lansoprazole coadministration resulted in a 1-h increase in the time to maximum plasma concentration (t max) of ponatinib (6 vs. 5 h post-dose; P < 0.001). A corresponding 25 % decrease in the geometric mean maximum plasma concentration (C max) of ponatinib was observed for ponatinib + lansoprazole versus ponatinib alone (40.67 vs. 53.96 ng/mL). Importantly, lansoprazole did not decrease the overall ponatinib systemic exposure as assessed by the ponatinib area under the plasma concentration-time curve from time zero to infinity (AUC∞ 1,153 ng·h/mL for lansoprazole + ponatinib vs. 1,222 ng·h/mL for ponatinib alone). The safety profile was considered acceptable when ponatinib was administered alone or with lansoprazole. CONCLUSIONS: Although coadministration of lansoprazole led to a modest, albeit statistically significant, reduction in ponatinib C max, overall systemic exposure to ponatinib did not change. The findings suggest that no dose adjustment is necessary when ponatinib is administered with drugs that increase gastric pH.