Utilization of Rosuvastatin and Endogenous Biomarkers in Evaluating the Impact of Ritlecitinib on BCRP, OATP1B1, and OAT3 Transporter Activity.

PURPOSE: Ritlecitinib, an inhibitor of Janus kinase 3 and tyrosine kinase expressed in hepatocellular carcinoma family kinases, is in development for inflammatory diseases. This study assessed the impact of ritlecitinib on drug transporters using a probe drug and endogenous biomarkers. METHODS: In vitro transporter-mediated substrate uptake and inhibition by ritlecitinib and its major metabolite were evaluated. Subsequently, a clinical drug interaction study was conducted in 12 healthy adult participants to assess the effect of ritlecitinib on pharmacokinetics of rosuvastatin, a substrate of breast cancer resistance protein (BCRP), organic anion transporting polypeptide 1B1 (OATP1B1), and organic anion transporter 3 (OAT3). Plasma concentrations of coproporphyrin I (CP-I) and pyridoxic acid (PDA) were assessed as endogenous biomarkers for OATP1B1 and OAT1/3 function, respectively. RESULTS: In vitro studies suggested that ritlecitinib can potentially inhibit BCRP, OATP1B1 and OAT1/3 based on regulatory cutoffs. In the subsequent clinical study, coadministration of ritlecitinib decreased rosuvastatin plasma exposure area under the curve from time 0 to infinity (AUCinf) by ~ 13% and maximum concentration (Cmax) by ~ 27% relative to rosuvastatin administered alone. Renal clearance was comparable in the absence and presence of ritlecitinib coadministration. PK parameters of AUCinf and Cmax for CP-I and PDA were also similar regardless of ritlecitinib coadministration. CONCLUSION: Ritlecitinib does not inhibit BCRP, OATP1B1, and OAT3 and is unlikely to cause a clinically relevant interaction through these transporters. Furthermore, our findings add to the body of evidence supporting the utility of CP-I and PDA as endogenous biomarkers for assessment of OATP1B1 and OAT1/3 transporter activity.

Evaluation of the effect of ritlecitinib on the pharmacokinetics of caffeine in healthy participants.

AIMS: This clinical study was conducted to evaluate the impact of ritlecitinib on the pharmacokinetics of caffeine, a cytochrome P450 1A2 (CYP1A2) substrate. METHODS: In this single-centre, single-arm, open-label, fixed-sequence study, healthy participants received a single 100-mg dose of caffeine on 2 separate occasions: on Day 1 of Period 1 as monotherapy and on Day 8 of Period 2 after oral administration of ritlecitinib 200 mg once daily for 8 days. Serial blood samples were collected and analysed using a validated liquid chromatography-mass spectrometry assay. Pharmacokinetic parameters were estimated by using a noncompartmental method. Safety was monitored by physical examination, vital signs, electrocardiograms and laboratory assessments. RESULTS: Twelve participants were enrolled and completed the study. Coadministration of caffeine 100 mg in the presence of steady-state levels of ritlecitinib (200 mg once daily) increased caffeine exposure compared with caffeine given alone. Area under the curve to infinity and maximum concentration of caffeine increased by approximately 165 and 10%, respectively, when coadministered with ritlecitinib. The ratios of the adjusted geometric means (90% confidence interval) for caffeine area under the curve to infinity and maximum concentration were 265.14% (234.12-300.26%) and 109.74% (103.90-15.91%), respectively, when caffeine was coadministered with steady-state ritlecitinib (test) compared with its administration alone (reference). Multiple doses of ritlecitinib when coadministered with a single dose of caffeine were generally safe and well tolerated in healthy participants. CONCLUSION: Ritlecitinib is a moderate inhibitor of CYP1A2 and can increase systemic exposures of CYP1A2 substrates.

Evaluation of the Impact of Ritlecitinib on Organic Cation Transporters Using Sumatriptan and Biomarkers as Probes.

Ritlecitinib, an inhibitor of Janus kinase 3 and hepatocellular carcinoma family kinases, is in development as potential treatment for several inflammatory diseases. In vitro studies presented ritlecitinib as an inhibitor of hepatic organic cation transporter (OCT) 1, renal transporters OCT2 and multidrug and toxin extrusion (MATE) proteins 1/2K using multiple substrates, and ritlecitinib's major inactive metabolite M2, as an inhibitor of OCT1. A clinical interaction study with an OCT1 drug probe (sumatriptan) and relevant probe biomarkers for OCT/MATE was conducted to assess the effect of ritlecitinib on these transporters in healthy adult participants. The selectivity of sumatriptan for OCT1 was confirmed through a series of in vitro uptake assays. A simple static model was used to help contextualize the observed changes in sumatriptan area under the plasma concentration-time curve (AUC). Coadministration of a single 400-mg dose of ritlecitinib increased sumatriptan AUC from time 0 to infinity (AUCinf ) by ≈30% relative to a single 25-mg sumatriptan administration alone. When administered 8 hours after a ritlecitinib dose, sumatriptan AUCinf increased by ≈50% relative to sumatriptan given alone. Consistent with OCT1 inhibition, the AUC from time 0 to 24 hours of isobutyryl-L-carnitine decreased by ≈15% after ritlecitinib. Based on the evaluation of the renal clearance of N1 -methylnicotinamide, ritlecitinib does not exert clinically meaningful inhibition on renal OCT2 or MATE1/2K. This study confirmed that ritlecitinib and M2 are inhibitors of OCT1 but not OCT2 or MATE1/2K in healthy adults.

Discovery and preclinical evaluation of anti-miR-17 oligonucleotide RGLS4326 for the treatment of polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations in either PKD1 or PKD2 genes, is one of the most common human monogenetic disorders and the leading genetic cause of end-stage renal disease. Unfortunately, treatment options for ADPKD are limited. Here we report the discovery and characterization of RGLS4326, a first-in-class, short oligonucleotide inhibitor of microRNA-17 (miR-17), as a potential treatment for ADPKD. RGLS4326 is discovered by screening a chemically diverse and rationally designed library of anti-miR-17 oligonucleotides for optimal pharmaceutical properties. RGLS4326 preferentially distributes to kidney and collecting duct-derived cysts, displaces miR-17 from translationally active polysomes, and de-represses multiple miR-17 mRNA targets including Pkd1 and Pkd2. Importantly, RGLS4326 demonstrates a favorable preclinical safety profile and attenuates cyst growth in human in vitro ADPKD models and multiple PKD mouse models after subcutaneous administration. The preclinical characteristics of RGLS4326 support its clinical development as a disease-modifying treatment for ADPKD.

Assessment of cumulative health risk in the World Trade Center general responder cohort.

BACKGROUND: Multiple comorbidities have been reported among rescue/recovery workers responding to the 9/11/2001 WTC disaster. In this study, we developed an index that quantifies the cumulative physiological burden of comorbidities and predicts life expectancy in this cohort. METHODS: A machine learning approach (gradient boosting) was used to model the relationship between mortality and several clinical parameters (laboratory test results, blood pressure, pulmonary function measures). This model was used to construct a risk index, which was validated by assessing its association with a number of health outcomes within the WTC general responder cohort. RESULTS: The risk index showed significant associations with mortality, self-assessed physical health, and onset of multiple chronic conditions, particularly COPD, hypertension, asthma, and sleep apnea. CONCLUSION: As an aggregate of several clinical parameters, this index serves as a cumulative measure of physiological dysregulation and could be utilized as a prognostic indicator of life expectancy and morbidity risk.

The association between body mass index and gastroesophageal reflux disease in the World Trade Center Health Program General Responder Cohort.

BACKGROUND: There is increasing concern about the obesity epidemic in the United States. Obesity is a potential risk factor for a number of chronic diseases, including gastroesophageal reflux disease (GERD). This analysis examined whether body mass index (BMI) was associated with physician-diagnosed GERD in World Trade Center (WTC) general responders. METHODS: 19,819 WTC general responders were included in the study. Cox proportional hazards regression models were used to compare time to GERD diagnosis among three BMI groups (normal (<25 kg/m(2) ), overweight (≥25 and <30 kg/m(2) ), and obese (≥30 kg/m(2) )). RESULTS: Among the responders, 43% were overweight and 42% were obese. The hazard ratio for normal versus overweight was 0.81 (95% Confidence Interval (CI), 0.75-0.88); normal versus obese 0.71 (95%CI, 0.66, 0.77); and overweight versus obese 0.88 (95%CI, 0.83-0.92). CONCLUSION: GERD diagnoses rates were higher in overweight and obese WTC responders. Am. J. Ind. Med. 59:761-766, 2016. © 2016 Wiley Periodicals, Inc.

Sex differences in asthma and gastroesophageal reflux disease incidence among the World Trade Center Health Program General Responder Cohort.

BACKGROUND: Asthma and gastroesophageal reflux disease (GERD) are two common conditions among the responders to the WTC attacks. This study examined whether the cumulative incidence rates of asthma and GERD differed by sex among 24,022 and 23,557 WTC responders, respectively. METHODS: Cox proportional hazards regression was used to examine the sex difference in the rate of onset of physician-diagnosed asthma or GERD, from 9/12/2001 through 12/31/2015. RESULTS: The cumulative incidence of asthma reached 23% for women and 17% for men by the end of 2015, and the cumulative incidence of GERD reached 45% for women and 38% for men. Comparing women to men, the hazard ratio was 1.48 (95% confidence interval (CI): 1.27, 1.74) for asthma, and 1.25 (95% CI: 1.13, 1.38) for GERD. CONCLUSIONS: WTC general responders have a substantial burden of asthma and GERD, with higher incidence in women. Am. J. Ind. Med. 59:815-822, 2016. © 2016 Wiley Periodicals, Inc.

Posttraumatic stress symptoms and smoking among World Trade Center disaster responders: A longitudinal investigation.

PURPOSE: The current longitudinal study examined posttraumatic stress disorder (PTSD) symptom severity in relation to smoking abstinence and reduction over time among responders to the World Trade Center (WTC) disaster. METHOD: Participants were 763 police and 1881 non-traditional (e.g., construction workers) WTC responders who reported being smokers at an initial examination obtained between July 2002 and July 2011 at the WTC Health Program (WTC-HP). WTC responders were reassessed, on average, 2.5 years later. RESULTS: For police WTC responders, higher levels of WTC-related PTSD symptoms at the initial visit were associated with a decreased likelihood of smoking abstinence (OR=0.98, p=.002) and with decreased smoking reduction (ß=-.06, p=.012) at the follow-up visit. WTC-related PTSD symptom severity was not related to likelihood of smoking abstinence or change in number of cigarettes smoked among non-traditional responders. Post hoc analyses suggested that for police, hyperarousal PTSD symptoms were predictive of decreased abstinence likelihood at the follow-up visit (OR=0.56, p=.006). DISCUSSION: The present findings suggest that PTSD symptoms may be differentially related to smoking behavior among police and non-traditional WTC responders in a naturalistic, longitudinal investigation. Future work may benefit from exploring further which aspects of PTSD (as compared to each other and to common variance) explain smoking maintenance.

Posttraumatic stress disorder and the risk of respiratory problems in World Trade Center responders: longitudinal test of a pathway.

OBJECTIVE: Posttraumatic stress disorder (PTSD) is associated with high medical morbidity, but the nature of this association remains unclear. Among responders to the World Trade Center (WTC) disaster, PTSD is highly comorbid with lower respiratory symptoms (LRS), which cannot be explained by exposure alone. We sought to examine this association longitudinally to establish the direction of the effects and evaluate potential pathways to comorbidity. METHODS: 18,896 responders (8466 police and 10,430 nontraditional responders) participating in the WTC-Health Program were first evaluated between 2002 and 2010 and assessed again 2.5 years later. LRS were ascertained by medical staff, abnormal pulmonary function by spirometry, and probable WTC-related PTSD with a symptom inventory. RESULTS: In both groups of responders, initial PTSD (standardized regression coefficient: ß = 0.20 and 0.23) and abnormal pulmonary function (ß = 0.12 and 0.12) predicted LRS 2.5 years later after controlling for initial LRS and covariates. At follow-up, LRS onset was 2.0 times more likely and remission 1.8 times less likely in responders with initial PTSD than in responders without. Moreover, PTSD mediated, in part, the association between WTC exposures and development of LRS (p < .0001). Initial LRS and abnormal pulmonary function did not consistently predict PTSD onset. CONCLUSIONS: These analyses provide further evidence that PTSD is a risk factor for respiratory symptoms and are consistent with evidence implicating physiological dysregulation associated with PTSD in the development of medical conditions. If these effects are verified experimentally, treatment of PTSD may prove helpful in managing physical and mental health of disaster responders.

World Trade Center disaster and sensitization to subsequent life stress: A longitudinal study of disaster responders.

PURPOSE: The current study examined the role of World Trade Center (WTC) disaster exposure (hours spent working on the site, dust cloud exposure, and losing friend/loved one) in exacerbating the effects of post-disaster life stress on posttraumatic stress disorder (PTSD) symptoms and overall functioning among WTC responders. METHOD: Participants were 18,896 responders (8466 police officers and 10,430 non-traditional responders) participating in the WTC Health Program who completed an initial examination between July, 2002 and April, 2010 and were reassessed an average of two years later. RESULTS: Among police responders, there was a significant interaction, such that the effect of post-disaster life stress on later PTSD symptoms and overall functioning was stronger among police responders who had greater WTC disaster exposure (ß's=.029 and .054, respectively, for PTSD symptoms and overall functioning). This moderating effect was absent in non-traditional responders. Across both groups, post-disaster life stress also consistently was related to the dependent variables in a more robust manner than WTC exposure. DISCUSSION: The present findings suggest that WTC exposure may compound post-disaster life stress, thereby resulting in a more chronic course of PTSD symptoms and reduced functioning among police responders.

Post-disaster stressful life events and WTC-related posttraumatic stress, depressive symptoms, and overall functioning among responders to the World Trade Center disaster.

BACKGROUND: The current study examined contributions of post-disaster stressful life events in relation to the maintenance of WTC-related posttraumatic stress, depressive symptoms, and overall functioning among rescue, recovery, and clean-up workers who responded to the September 11, 2001 World Trade Center (WTC) terrorist attacks. METHODS: Participants were 18,896 WTC responders, including 8466 police officers and 10,430 non-traditional responders (85.8% male; 86.4% Caucasian; M(age) = 39.5, SD = 8.8) participating in the WTC Health Program who completed an initial examination between July, 2002 and April, 2010 and who were reassessed, on average, 2.5 years later. RESULTS: Path analyses were conducted to evaluate contributions of life events to the maintenance of WTC-related posttraumatic stress, depressive symptoms, and overall functioning. These analyses were stratified by police and non-traditional responder groups and adjusted for age, sex, time from 9/11 to initial visit, WTC exposures (three WTC contextual exposures: co-worker, friend, or a relative died in the disaster; co-worker, friend, or a relative injured in the disaster; and responder was exposed to the dust cloud on 9/11), and interval from initial to first follow-up visit. In both groups, WTC-related posttraumatic stress, depressive symptoms, and overall functioning were stable over the follow-up period. WTC exposures were related to these three outcomes at the initial assessment. WTC-related posttraumatic stress, depressive symptoms, and overall functioning, at the initial assessment each predicted the occurrence of post-disaster stressful life events, as measured by Disaster Supplement of the Diagnostic Interview Schedule. Post-disaster stressful life events, in turn, were associated with subsequent mental health, indicating partial mediation of the stability of observed mental health. CONCLUSIONS: The present findings suggest a dynamic interplay between exposure, post-disaster stressful life events, and WTC-related posttraumatic stress, depressive symptoms, and overall functioning among WTC disaster responders.

Cancer incidence in world trade center rescue and recovery workers, 2001-2008.

BACKGROUND: World Trade Center (WTC) rescue and recovery workers were exposed to a complex mix of pollutants and carcinogens. OBJECTIVE: The purpose of this investigation was to evaluate cancer incidence in responders during the first 7 years after 11 September 2001. METHODS: Cancers among 20,984 consented participants in the WTC Health Program were identified through linkage to state tumor registries in New York, New Jersey, Connecticut, and Pennsylvania. Standardized incidence ratios (SIRs) were calculated to compare cancers diagnosed in responders to predicted numbers for the general population. Multivariate regression models were used to estimate associations with degree of exposure. RESULTS: A total of 575 cancers were diagnosed in 552 individuals. Increases above registry-based expectations were noted for all cancer sites combined (SIR = 1.15; 95% CI: 1.06, 1.25), thyroid cancer (SIR = 2.39; 95% CI: 1.70, 3.27), prostate cancer (SIR = 1.21; 95% CI: 1.01, 1.44), combined hematopoietic and lymphoid cancers (SIR = 1.36; 95% CI: 1.07, 1.71), and soft tissue cancers (SIR = 2.26; 95% CI: 1.13, 4.05). When restricted to 302 cancers diagnosed ≥ 6 months after enrollment, the SIR for all cancers decreased to 1.06 (95% CI: 0.94, 1.18), but thyroid and prostate cancer diagnoses remained greater than expected. All cancers combined were increased in very highly exposed responders and among those exposed to significant amounts of dust, compared with responders who reported lower levels of exposure. CONCLUSION: Estimates should be interpreted with caution given the short follow-up and long latency period for most cancers, the intensive medical surveillance of this cohort, and the small numbers of cancers at specific sites. However, our findings highlight the need for continued follow-up and surveillance of WTC responders.

Persistence of multiple illnesses in World Trade Center rescue and recovery workers: a cohort study.

BACKGROUND: More than 50,000 people participated in the rescue and recovery work that followed the Sept 11, 2001 (9/11) attacks on the World Trade Center (WTC). Multiple health problems in these workers were reported in the early years after the disaster. We report incidence and prevalence rates of physical and mental health disorders during the 9 years since the attacks, examine their associations with occupational exposures, and quantify physical and mental health comorbidities. METHODS: In this longitudinal study of a large cohort of WTC rescue and recovery workers, we gathered data from 27,449 participants in the WTC Screening, Monitoring, and Treatment Program. The study population included police officers, firefighters, construction workers, and municipal workers. We used the Kaplan-Meier procedure to estimate cumulative and annual incidence of physical disorders (asthma, sinusitis, and gastro-oesophageal reflux disease), mental health disorders (depression, post-traumatic stress disorder [PTSD], and panic disorder), and spirometric abnormalities. Incidence rates were assessed also by level of exposure (days worked at the WTC site and exposure to the dust cloud). FINDINGS: 9-year cumulative incidence of asthma was 27·6% (number at risk: 7027), sinusitis 42·3% (5870), and gastro-oesophageal reflux disease 39·3% (5650). In police officers, cumulative incidence of depression was 7·0% (number at risk: 3648), PTSD 9·3% (3761), and panic disorder 8·4% (3780). In other rescue and recovery workers, cumulative incidence of depression was 27·5% (number at risk: 4200), PTSD 31·9% (4342), and panic disorder 21·2% (4953). 9-year cumulative incidence for spirometric abnormalities was 41·8% (number at risk: 5769); three-quarters of these abnormalities were low forced vital capacity. Incidence of most disorders was highest in workers with greatest WTC exposure. Extensive comorbidity was reported within and between physical and mental health disorders. INTERPRETATION: 9 years after the 9/11 WTC attacks, rescue and recovery workers continue to have a substantial burden of physical and mental health problems. These findings emphasise the need for continued monitoring and treatment of the WTC rescue and recovery population. FUNDING: Centers for Disease Control and Prevention and National Institute for Occupational Safety and Health.

Development of methods to monitor ionization modification from dosing vehicles and phospholipids in study samples.

Two approaches to monitor the matrix effect on ionization in study samples were described. One approach is the addition of multiple reaction monitoring transitions to the bioanalytical methods to monitor the presence of known ionization modification-causing components of the matrix, for example, m/z 184→125 (or m/z 184→184) and m/z 133→89 may be used for phospholipids and polyethylene oxide containing surfactants, respectively. This approach requires no additional equipment and can be readily adapted for most method. The approach detects only the intended interfering compounds and provides little quantitative indication if the matrix effect is within the tolerable range (±15%). The other approach requires the addition of an infusion pump and identifies an appropriate surrogate of the analyte to be infused for the determination of modification on the ionization of the analyte. The second approach detects interferences in the sample regardless of the sources (i.e., dosing vehicle components, co-administrated drugs, their metabolites, phospholipids, plasticizers and endogenous components introduced due to disease stage).

The effect of one versus two nights of in-laboratory continuous positive airway pressure titration on continuous positive airway pressure compliance.

OBJECTIVE: To investigate continuous positive airway pressure (CPAP) compliance after one versus two nights of CPAP titration. METHOD: A chart review and a telephone questionnaire interview were conducted in 110 sleep apnea patients who received one or two nights of CPAP titration. Of these patients, 78 followed through with phone interview. RESULTS: There was no difference in CPAP compliance between those who had one or two nights of CPAP titration. The titration pressures on the first and second nights were not significantly different. But there was significant improvement in sleep efficiency from the first to the second diagnostic night. CONCLUSION: One versus two nights of CPAP titration did not affect CPAP compliance, but sleep efficiency improved on the second diagnostic night and an extra titration study may be necessary for some patients, especially those with only one diagnostic night.