"Death Is a Possibility for Those without Shelter": A Thematic Analysis of News Coverage on Homelessness and the 2021 Heat Dome in Canada.

Among the most vulnerable to the health-harming effects of heat are people experiencing homelessness. However, during the 2021 Heat Dome, the deadliest extreme heat event (EHE) recorded in Canada to date, people experiencing homelessness represented the smallest proportion of decedents (n = 3, 0.5%)-despite the impacted region (British Columbia) having some of the highest rates of homelessness in the country. Thus, we sought to explore the 2021 Heat Dome as a media-based case study to identify potential actions or targeted strategies that were initiated by community support agencies, individuals and groups, and communicated in the news during this EHE that may have aided in the protection of this group or helped minimize the mortality impacts. Using media articles collated for a more extensive investigation into the effects of the 2021 Heat Dome (n = 2909), we identified a subset which included content on people experiencing homelessness in Canada (n = 274, 9%). These articles were thematically analysed using NVivo. Three main themes were identified: (i) public warnings issued during the 2021 Heat Dome directly addressed people experiencing homelessness, (ii) community support services explicitly targeting this population were activated during the heat event, and (iii) challenges and barriers faced by people experiencing homelessness during extreme heat were communicated. These findings suggest that mass-media messaging and dedicated on-the-ground initiatives led by various organizations explicitly initiated to support individuals experiencing homelessness during the 2021 Heat Dome may have assisted in limiting the harmful impacts of the heat on this community.

Assessment of the Effects of Abrocitinib on the Pharmacokinetics of Probe Substrates of Cytochrome P450 1A2, 2B6 and 2C19 Enzymes and Hormonal Oral Contraceptives in Healthy Individuals.

BACKGROUND AND OBJECTIVE: Abrocitinib is an oral small-molecule Janus kinase (JAK)-1 inhibitor approved for the treatment of moderate-to-severe atopic dermatitis. In vitro studies indicated that abrocitinib is a weak time-dependent inhibitor of cytochrome P450 (CYP) 2C19/3A and a weak inducer of CYP1A2/2B6/2C19/3A. To assess the potential effect of abrocitinib on concomitant medications, drug-drug interaction (DDI) studies were conducted for abrocitinib with sensitive probe substrates of these CYP enzymes. The impact of abrocitinib on hormonal oral contraceptives (ethinyl estradiol and levonorgestrel), as substrates of CYP3A and important concomitant medications for female patients, was also evaluated. METHODS: Three Phase 1 DDI studies were performed to assess the impact of abrocitinib 200 mg once daily (QD) on the probe substrates of: (1) 1A2 (caffeine), 2B6 (efavirenz) and 2C19 (omeprazole) in a cocktail study; (2) 3A (midazolam); and (3) 3A (oral contraceptives). RESULTS: After multiple doses of abrocitinib 200 mg QD, there is a lack of effect on the pharmacokinetics of midazolam, efavirenz and contraceptives. Abrocitinib increased the area under the concentration time curve from 0 to infinity (AUCinf) and the maximum concentration (Cmax) of omeprazole by approximately 189 and 134%, respectively. Abrocitinib increased the AUCinf of caffeine by 40% with lack of effect on Cmax. CONCLUSIONS: Based on the study results, abrocitinib is a moderate inhibitor of CYP2C19. Caution should be exercised when using abrocitinib concomitantly with narrow therapeutic index medicines that are primarily metabolized by CYP2C19 enzyme. Abrocitinib is a mild inhibitor of CYP1A2; however, the impact is not clinically relevant, and no general dose adjustment is recommended for CYP1A2 substrates. Abrocitinib does not inhibit CYP3A or induce CYP1A2/2B6/2C19/3A and does not affect the pharmacokinetics of contraceptives. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov registration IDs: NCT03647670, NCT05067439, NCT03662516.

"Breaking down in tears, soaked in sweat, and sick from the heat": Media-based composite narratives of first responders working during the 2021 Heat Dome.

BACKGROUND: During the summer of 2021, a deadly, unprecedented multiday Heat Dome engulfed western Canada. As a result of this extreme heat event (EHE), emergency dispatchers received an unparalleled increase in incoming 911 calls for ambulance, police, and fire (as first responders) services to attend to hundreds of heat-vulnerable community members succumbing to the heat. With 103 all-time heat records broken during this EHE and indoor temperatures of nearly 40°C, the first responders attending these calls faced extensive job demands and highly challenging operating conditions. Initial investigations have explored the health system-level impacts; however, little has been done to explore the impact on the first responders themselves. Therefore, this study aimed to improve our understanding of EHEs' impacts on the operational capabilities and health of first responders, specifically police, fire, ambulance, and dispatch services. METHODS: A systematized review and content analysis of media articles published on the 2021 Heat Dome in Canada was conducted (n = 2909), and four media-based composite narratives were developed highlighting police, fire, ambulance, and dispatch services. The Job Demands-Resources (JD-R) model was applied as a theoretical framework for occupational burnout. RESULTS: The media-based composite narratives highlighted that first responders faced record-breaking call volumes, increased mental-health-related claims, and exhaustive heat-related physiological stress. Using the JD-R model as a theoretical framework for occupational burnout, we identified three measures of stressful job demand: work overload (e.g., the surge in call volume, firefighters responding to medical emergencies), emotional demands (e.g., severe medical emergencies, sudden deaths, unresponsive patients, distraught family members), and physical demands (e.g., resuscitation in personal protective equipment, heat-related illness). CONCLUSION: The experiences described underscore the importance of supporting first responders during work in extreme heat conditions. These findings have important implications for addressing rising rates of burnout during and following public health crises, such as EHEs, a problem that is increasingly being recognized as a threat to the Canadian public healthcare system.

Reflections on a Century of Extreme Heat Event-Related Mortality Reporting in Canada.

Climate change is causing more frequent and severe extreme heat events (EHEs) in Canada, resulting in significant loss of life. However, patterns across mortality reporting for historical EHEs have not been analyzed. To address this gap, we studied deaths in Canadian EHEs from 1936 to 2021, identifying trends and challenges. Our analysis revealed inconsistencies in mortality data, discrepancies between vulnerable populations identified, difficulties in determining the cause of death, and inconsistent reporting on social vulnerability indicators. We provide some observations that could help inform solutions to address the gaps and challenges, by moving toward more consistent and comprehensive reporting to ensure no population is overlooked. Accurately accounting for affected populations could help better target evidence-based interventions, and reduce vulnerability to extreme heat.

Evaluation of the Effect of Lorlatinib on CYP2B6, CYP2C9, UGT, and P-Glycoprotein Substrates in Patients with Advanced Non-Small Cell Lung Cancer.

BACKGROUND AND OBJECTIVE: Lorlatinib is a tyrosine kinase inhibitor approved for the treatment of advanced anaplastic lymphoma kinase-positive non-small cell lung cancer. This study assessed the effect of steady-state lorlatinib on the metabolic enzymes cytochrome P450 (CYP) 2B6, CYP2C9, and uridine 5'-diphospho-glucuronosyltransferase (UGT) and the P-glycoprotein (P-gp) transporter. METHODS: Thirty-two patients received a single oral dose of a probe drug on Day - 2 to determine the pharmacokinetics of the probe drug alone. Starting on Day 1, patients received 100 mg oral lorlatinib daily. On Day 15, a single oral dose of the probe drug was administered concurrently with lorlatinib. Pharmacokinetic parameters for these probe substrates were assessed. RESULTS: Plasma exposures of all probe substrates were reduced by lorlatinib compared with the probe alone. The greatest reduction in area under the plasma concentration-time curve from time zero to infinity (AUC∞) and maximum (peak) plasma drug concentration (Cmax) (67% and 63% decrease, respectively) was observed with the P-gp probe substrate fexofenadine. Lorlatinib coadministration also decreased the AUC∞ and Cmax of bupropion (CYP2B6 probe substrate) by 25% and 27%, tolbutamide (CYP2C9 probe substrate) by 43% and 15%, and acetaminophen (UGT probe substrate) by 45% and 28%, respectively. CONCLUSIONS: Lorlatinib is a net moderate inducer of P-gp and a weak inducer of CYP2B6, CYP2C9, and UGT after steady state is achieved with daily dosing. Medications that are P-gp substrates with a narrow therapeutic window should be avoided in patients taking lorlatinib; no dose modifications are needed with substrates of CYP2B6, CYP2C9, or UGT. CLINICALTRIALS: gov: NCT01970865.

Hot Topic: A Systematic Review and Content Analysis of Heat-Related Messages During the 2021 Heat Dome in Canada.

CONTEXT: During the summer of 2021, western Canada experienced a deadly heat event. From the first heat alert to postevent reporting, thousands of media articles were published that reference the heat event. However, a gap remains in understanding how this communication chain-from the release of a public heat alert to information shared through media outlets to the public-currently operates to disseminate heat-related messaging across Canada. OBJECTIVE: To understand the role of digital media in delivering heat-health messaging during an extreme heat event in Canada. DESIGN: A qualitative content analysis was conducted using Canadian news articles published on the 2021 Heat Dome between June 2021 and February 2022 (n = 2909). The coding frame was designed to align with the basic framework for information gathering used in journalism (who, what, where, when, and how) and included both concept-driven and data-driven codes. RESULTS: Overall, 2909 unique media articles discussing the 2021 Heat Dome were identified, with the majority (74%) published by online news agencies (how). The highest article count was on June 29, 2021 (n = 159), representing 5% of the total data set (n = 2909) spanning 260 days (when); 57% of the identified locations were in British Columbia (where). Although we found that the top voices providing media-based heat-health messages are government officials (who), only 23% of articles included heat-health messaging that aligns with the government health alert bulletins released during extreme heat. In addition, heat-health messaging frequently included contradictory content, inconsistent language, or incorrect advice (what). CONCLUSION: The findings demonstrate clear opportunities to improve health communication related to extreme heat, perhaps most importantly, including updates to mass media messaging educating the public on heat-protective behaviors.

Working under the 2021 Heat Dome: A Content Analysis of Occupational Impacts Mentioned in the Canadian Media.

Extreme heat events directly impact worker health and cause additional cascading and transitional workplace impacts. However, current investigations on these impacts often rely on specific datasets (e.g., compensation claims, hospitalizations). Thus, to continue to work towards preventing and mitigating the occupational risks posed by extreme heat events, this study aimed to explore the occupational impacts of the 2021 Heat Dome in Canada using a qualitative content analysis method on a news-based dataset. A systematized review of news articles published before, during, and after the 2021 Heat Dome was conducted on academic (n = 8) and news (n = 5) databases, along with targeted grey literature. Two researchers qualitatively coded the articles in NVivo for occupational impacts or references mentioned within the articles. Overall, 52 different occupations were identified as being impacted by the 2021 Heat Dome. Impacts were diverse and ranged from work cancellations or delays to work modifications and reports of heat-related illnesses. The 2021 Heat Dome impacted the health and safety of many occupational groups and provided new insights into the expanding impacts that extreme heat events can have on the Canadian workforce. With climate projections showing a growing trend of more hot days and intense heat waves in Canada, addressing these concerns should be a critical priority.

The Intersection of the COVID-19 Pandemic and the 2021 Heat Dome in Canadian Digital News Media: A Content Analysis.

During the 2021 Heat Dome, 619 people in British Columbia died due to the heat. This public health disaster was made worse by the ongoing COVID-19 pandemic. Few studies have explored the intersection of heat with COVID-19, and none in Canada. Considering that climate change is expected to increase the frequency of extreme heat events, it is important to improve our understanding of intersecting public health crises. Thus, this study aimed to explore media-based public health communication in Canada during the COVID-19 pandemic and the 2021 Heat Dome. A qualitative content analysis was conducted on a subset of media articles (n = 520) related to the COVID-19 pandemic which were identified through a previous media analysis on the 2021 Heat Dome (n = 2909). Many of the articles provided conflicting health messages that may have confused the public about which health protective actions to take. The articles also showed how the COVID-19 pandemic may have exacerbated the health impacts of the 2021 Heat Dome, as pandemic-related public health measures may have deterred people away from protecting themselves from heat. This study, which provides novel insight into the prioritization of public health messaging when an extreme heat event occurs concurrently with a pandemic, supports the need for consistent heat health guidance.

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.

Assessment of the Effects of Inhibition or Induction of CYP2C19 and CYP2C9 Enzymes, or Inhibition of OAT3, on the Pharmacokinetics of Abrocitinib and Its Metabolites in Healthy Individuals.

BACKGROUND AND OBJECTIVE: Abrocitinib is a Janus kinase 1-selective inhibitor for the treatment of moderate-to-severe atopic dermatitis. Abrocitinib is eliminated primarily by metabolism involving cytochrome P450 (CYP) enzymes. Abrocitinib pharmacologic activity is attributable to the unbound concentrations of the parent molecule and 2 active metabolites, which are substrates of organic anion transporter 3 (OAT3). The sum of potency-adjusted unbound exposures of abrocitinib and its 2 active metabolites is termed the abrocitinib active moiety. We evaluated effects of CYP inhibition, CYP induction, and OAT3 inhibition on the pharmacokinetics of abrocitinib, its metabolites, and active moiety. METHODS: Three fixed-sequence, open-label, phase I studies in healthy adult volunteers examined the drug-drug interactions (DDIs) of oral abrocitinib with fluvoxamine and fluconazole, rifampin, and probenecid. RESULTS: Co-administration of abrocitinib with fluvoxamine or fluconazole increased the area under the plasma concentration-time curve from time 0 to infinity (AUCinf) of the unbound active moiety of abrocitinib by 91% and 155%, respectively. Co-administration with rifampin decreased the unbound active moiety AUCinf by 56%. The OAT3 inhibitor probenecid increased the AUCinf of the unbound active moiety by 66%. CONCLUSIONS: It is important to consider the effects of DDIs on the abrocitinib active moiety when making dosing recommendations. Co-administration of strong CYP2C19/2C9 inhibitors or CYP inducers impacted exposure to the abrocitinib active moiety. A dose reduction by half is recommended if abrocitinib is co-administered with strong CYP2C19 inhibitors, whereas co-administration with strong CYP2C19/2C9 inducers is not recommended. No dose adjustment is required when abrocitinib is administered with OAT3 inhibitors. CLINICAL TRIALS REGISTRATION IDS: NCT03634345, NCT03637790, NCT03937258.

Conservative management of Jones fractures with immediate weight-bearing in a walking boot demonstrates healing.

Jones fractures, or proximal metatarsal fractures at the level of the fourth and fifth intermetatarsal junction, have a high risk for nonunion due to a vascular watershed region. Classically, treatment consists of weight bearing restrictions in a cast or surgical fixation. Some studies have assessed immediate weight bearing following a Jones fracture. Due to conflicting results, the most appropriate treatment method remains unclear. This study analyzes outcomes after treating adults with acute Jones fractures non-operatively without weight bearing restrictions in a walking boot. This study hypothesizes that patients will not require future operative intervention following functional treatment. A retrospective review of 55 adult patients who sustained acute, closed Jones fractures was conducted. 47 were treated weight bearing as tolerated (WBAT) in a walking boot and eight were treated non-weight bearing (NWB) in a cast. They were followed radiographically by an orthopedic surgeon for an average of 6.4 and 15.5 months, respectively. Three patients in each group (6.4% WBAT, 37.5% NWB) developed painful nonunion leading to surgical fixation. Thirty (66.7%) patients in the WBAT group demonstrated radiographic union on final radiographs. Only two (13.3%) of the 15 patients with partial union were seen at least six months from time of injury, one of whom had ongoing pain but declined surgery. The remaining 13 patients were asymptomatic at their final clinic appointment. Controversy still exists as to the best treatment methodology for acute Jones fractures. Due to a lack of clear guidelines, it can be difficult for the multiple medical specialties involved to evaluate and treat this injury. Our study suggests that non-operative management of minimally displaced Jones fractures, in the adult, low demand population, without weight bearing restrictions in a walking boot offers similar outcomes to cast immobilization with weight bearing restrictions, resulting in bony union or asymptomatic fibrous nonunion.

Evaluation of the absolute oral bioavailability of the anaplastic lymphoma kinase/c-ROS oncogene 1 kinase inhibitor lorlatinib in healthy participants.

PURPOSE: Lorlatinib is a third-generation tyrosine kinase inhibitor currently approved for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer. This open-label, phase 1, randomized two-sequence, two-treatment, two-period, crossover study investigated the absolute oral bioavailability of lorlatinib in healthy participants. METHODS: Eligible participants were randomized to receive two treatments in one of two sequences: lorlatinib 100 mg single oral dose followed by lorlatinib 50 mg intravenous (IV) dose, or lorlatinib IV dose followed by lorlatinib oral dose, each with at least a 10-day washout between successive lorlatinib doses. Blood samples for pharmacokinetics were collected for up to 144 hours (h) after dosing. Validated liquid chromatographic-tandem mass spectrometry was used to determine plasma concentrations of lorlatinib and its benzoic acid metabolite PF-06895751. RESULTS: In total, 11 participants were enrolled (mean age 37.6 years, all male). The adjusted geometric mean (90% confidence interval) for the absolute oral bioavailability was 80.78% (75.73-86.16%). Using non-compartmental analysis, the estimated arithmetic mean elimination plasma half-life of lorlatinib was 25.5 and 27.0 h after the oral and IV doses, respectively. No deaths, serious adverse events (AEs), or severe AEs were reported, and most treatment-emergent AEs were mild in severity, with two events of transaminase increase of moderate severity. All treatment-emergent AEs were resolved by the end of the study. CONCLUSION: Both oral and IV lorlatinib were well-tolerated in healthy participants and oral lorlatinib is highly bioavailable after oral administration.

Evaluation of Proton Pump Inhibitor Esomeprazole on Crizotinib Pharmacokinetics in Healthy Participants.

Crizotinib is a small-molecule, multitargeted tyrosine kinase inhibitor that exhibits decreased aqueous solubility at a higher pH. This open-label, randomized, phase 1 study (NCT01549574) evaluated the effect of multiple doses of the proton pump inhibitor esomeprazole on the pharmacokinetics (PK) of crizotinib and the safety of crizotinib with or without esomeprazole in healthy adults. Participants received a single 250-mg crizotinib dose after overnight fast or a single 250-mg crizotinib dose following esomeprazole 40 mg/day for 5 days. After a washout of ≥14 days, participants crossed over to the alternate treatment. Blood samples for plasma analysis were taken up to 144 hours after crizotinib dosing and relevant PK parameters estimated. Safety was assessed in all participants receiving ≥1 dose of study medication. Fifteen participants were evaluable for PK and safety for each treatment. Coadministration with esomeprazole resulted in a slight decrease (≈10%) in the crizotinib geometric mean area under the plasma concentration-time profile from time 0 to infinity (adjusted geometric mean ratio, 89.81% [90% confidence interval, 79.05-102.03]). Coadministration of esomeprazole did not affect peak crizotinib exposure. Adverse events (AEs) occurred in similar numbers between treatments; no serious or severe AEs occurred. The most common AE was diarrhea. Although esomeprazole decreased total exposure of crizotinib, it is not considered clinically meaningful, and dose modification is not required when crizotinib is coadministered with agents that affect gastric pH.

Pediatric Resuscitation.

This article describes evidence-based nursing practices for detecting pediatric decompensation and prevention of cardiopulmonary arrest and outlines the process for effective and high-quality pediatric resuscitation and postresuscitation care. Primary concepts include pediatric decompensation signs and symptoms, pediatric resuscitation essential practices, and postresuscitation care, monitoring, and outcomes. Pediatric-specific considerations for family presence during resuscitation, ensuring good outcomes for medically complex children in community settings, and the role of targeted temperature management, continuous electroencephalography, and the use of extracorporeal membrane oxygenation in pediatric resuscitation are also discussed.

Phase 1 Study Evaluating the Effects of the Proton Pump Inhibitor Rabeprazole and Food on the Pharmacokinetics of Lorlatinib in Healthy Participants.

Lorlatinib is approved worldwide as treatment for anaplastic lymphoma kinase-positive and c-ros oncogene 1-positive non-small cell lung cancer. The objectives of this phase 1, open-label crossover study (NCT02569554) in healthy adult participants were to determine (1) the effects of the proton pump inhibitor (PPI) rabeprazole on lorlatinib pharmacokinetics (PK), (2) the effects of a high-fat meal on lorlatinib PK, and (3) the relative bioavailability of an oral solution to tablet formulation of lorlatinib under fasted conditions. Participants were followed on-study for ≥50 days after the first dose of lorlatinib. Participants received treatments over 4 periods, with a washout of ≥10 days between consecutive lorlatinib doses. Twenty-seven participants were enrolled and received lorlatinib, and all were assessed for PK and safety. Results showed no effect of multiple doses of rabeprazole on the total plasma exposure of a single oral dose of lorlatinib 100-mg tablets. The results also indicated that a high-fat meal had no effect on lorlatinib PK after a single 100-mg oral dose. In addition, the relative bioavailability of lorlatinib oral solution compared with lorlatinib tablets was complete (approximately 108%). The safety profile of lorlatinib was consistent with that reported in previous studies, and most treatment-related adverse events were mild to moderate. These data indicate that lorlatinib can be administered with drugs that modify gastric acid, including PPIs, without restriction. These results also confirm that lorlatinib can be administered regardless of food intake.

Pharmacokinetics of Lorlatinib After Single and Multiple Dosing in Patients with Anaplastic Lymphoma Kinase (ALK)-Positive Non-Small Cell Lung Cancer: Results from a Global Phase I/II Study.

BACKGROUND: Lorlatinib demonstrated efficacy (including intracranial activity) in patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) in a phase I/II study (NCT01970865). BACKGROUND AND OBJECTIVE: This analysis describes the pharmacokinetics (PK) of lorlatinib following single and multiple dosing. METHODS: This ongoing, multicenter, open-label, single-arm, phase I/II trial enrolled patients with ALK-positive or c-ros oncogene 1 (ROS1)-positive advanced NSCLC. In phase I, patients received escalating doses of lorlatinib (10-200 mg orally once daily) and twice-daily doses of 35, 75, and 100 mg in continuous 21-day cycles. In phase II, lorlatinib was administered at a starting dose of 100 mg once daily in continuous 21-day cycles. Parameters investigated included the potential for lorlatinib to inhibit/induce cytochrome P450 (CYP) 3A; the absorption/metabolism of lorlatinib and its major metabolite PF-06895751; and differences in these parameters between Asian and non-Asian patients. RESULTS: Data were available for 54 patients from phase I and 275 patients from phase II. Lorlatinib plasma exposure increased dose proportionally after single doses of 10-200 mg, and slightly less than dose proportionally after multiple doses. Lorlatinib clearance increased following multiple dosing compared with single dosing, indicating autoinduction. The area under the concentration-time curve from time zero to time τ (the dosing interval; AUCτ) of PF-06895751 was approximately 80% higher than that of lorlatinib after multiple dosing. Lorlatinib exhibited brain penetration. Furthermore, no overt differences in single- and multiple-dose PK parameters between the Asian and non-Asian patients were observed. CONCLUSIONS: Lorlatinib is highly brain penetrant and exhibits autoinduction after multiple dosing. There appears to be no inherent differences in lorlatinib PK between healthy subjects and cancer patients, or between Asian and non-Asian patients. ClinicalTrials.gov NCT01970865.

Effects of Hepatic Impairment on the Pharmacokinetics of Abrocitinib and Its Metabolites.

Abrocitinib, an oral once-daily Janus kinase 1 selective inhibitor, is under development for treatment of atopic dermatitis. This phase 1, nonrandomized, open-label, single-dose study (NCT03626415) investigated the effect of hepatic impairment on pharmacokinetics (PK), safety, and tolerability of abrocitinib and its metabolites after a 200-mg oral dose. Twenty-four subjects with varying degrees of hepatic function (normal, mild, and moderate impairment) were enrolled (N = 8/group). Active moiety PK parameters were calculated as the sum of unbound PK parameters for abrocitinib and its active metabolites. For abrocitinib, the ratios (percentages) of adjusted geometric means for area under the concentration-time curve from time 0 extrapolated to infinite time (AUCinf ) and maximum plasma concentration (Cmax ) were 133.33 (90% confidence interval [CI], 86.17-206.28) and 94.40 (90%CI, 62.96-141.55), respectively, for subjects with mild hepatic impairment vs normal hepatic function. The corresponding comparisons of ratios (percentages) for AUCinf and Cmax were 153.99 (90%CI, 99.52-238.25) and 105.53 (90%CI, 70.38-158.24), respectively, for subjects with moderate hepatic impairment. Exposures of the metabolites were generally lower in subjects with hepatic impairment. For abrocitinib active moiety, the ratios (percentages) of adjusted geometric means of unbound AUCinf were 95.74 (90%CI, 72.71-126.08) and 114.82 (90%CI, 87.19-151.20) in subjects with mild and moderate impairment vs normal hepatic function, respectively. Abrocitinib was generally safe and well tolerated. Hepatic impairment had no clinically relevant effect on the PK and safety of abrocitinib and the exposure of abrocitinib active moiety. These results support the use of abrocitinib without dose adjustment in subjects with mild or moderate hepatic impairment.

Palbociclib (PD-0332991) pharmacokinetics in subjects with impaired renal function.

PURPOSE: This publication describes an evaluation of the impact of different degrees of renal impairment on the pharmacokinetics and safety of palbociclib after a single 125-mg oral dose. METHODS: Thirty-one subjects were assigned to different renal function groups. Serial blood sampling for pharmacokinetics was performed up to 120 h and 168 h post-palbociclib dose for subjects with normal and impaired renal function, respectively. A separate blood sample was collected at pre-dose and 8 h after dosing to measure plasma protein binding. Plasma palbociclib was measured using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Plasma protein binding samples were processed by equilibrium dialysis and measured by a validated LC-MS/MS method. RESULTS: Plasma palbociclib exposure was higher in subjects with renal impairment than in subjects with normal renal function; however, there were no marked differences in exposure across subjects with mild, moderate, and severe renal impairment. Total plasma exposure AUCinf increased by 39%, 42%, and 31% with mild, moderate, and severe renal impairment, respectively, relative to subjects with normal renal function. Peak exposure Cmax increased by 17%, 12%, and 15% for mild, moderate, and severe impairment, respectively. There was no obvious trend in the mean fu with worsening renal function. The PBPK model adequately described palbociclib exposure observed in subjects with moderate or severe renal impairment from this study. CONCLUSION: Palbociclib was safe and well-tolerated in a small population of subjects with normal and impaired renal function after a single oral 125 mg dose. No dose adjustment is required in patients with renal impairment.

The Bioequivalence of Tafamidis 61-mg Free Acid Capsules and Tafamidis Meglumine 4 × 20-mg Capsules in Healthy Volunteers.

Tafamidis, a non-nonsteroidal anti-inflammatory benzoxazole derivative, acts as a transthyretin (TTR) stabilizer to slow progression of TTR amyloidosis (ATTR). Tafamidis meglumine, available as 20-mg capsules, is approved in more than 40 countries worldwide for the treatment of adults with early-stage symptomatic ATTR polyneuropathy. This agent, administered as an 80-mg, once-daily dose (4 × 20-mg capsules), is approved in the United States, Japan, Canada, and Brazil for the treatment of hereditary and wild-type ATTR cardiomyopathy in adults. An alternative single solid oral dosage formulation (tafamidis 61-mg free acid capsules) was developed and introduced for patient convenience (approved in the United States, United Arab Emirates, and European Union). In this single-center, open-label, randomized, 2-period, 2-sequence, crossover, multiple-dose phase 1 study, the rate and extent of absorption were compared between tafamidis 61-mg free acid capsules (test) and tafamidis meglumine 80-mg (4 × 20-mg) capsules (reference) after 7 days of repeated oral dosing under fasted conditions in 30 healthy volunteers. Ratios of adjusted geometric means (90%CI) for the test/reference formulations were 102.3 (98.0-106.8) for area under the concentration-time profile over the dosing interval and 94.1 (89.1-99.4) for the maximum observed concentration, satisfying prespecified bioequivalence acceptance criteria (90%CI, 80-125). Both tafamidis regimens had an acceptable safety/tolerability profile in this population.