Assessing Participants' Experiences with Vitiligo from Patient Interviews.

INTRODUCTION: Vitiligo is an autoimmune disease, causing skin depigmentation. Individuals with vitiligo incur substantial psychosocial burden and have expressed frustration with their treatments. Here, we describe the burden of vitiligo and opinions on what constitutes meaningful change among participants of two qualitative interview studies. METHODS: Qualitative interviews were conducted with a subgroup of adolescent and adult participants with vitiligo from two pivotal phase 3 clinical trials of ruxolitinib cream (Study 1) and a real-world panel (Study 2). Participants were asked about their disease burden, treatment goals, importance of facial/body improvement (treatment satisfaction: scale range 0-10), and meaningfulness of change (yes/no). RESULTS: A total of 36 participants from Study 1 and 23 from Study 2 were interviewed. In Study 1, the highest degree of impact was on reduced self-esteem (facial lesions, 62.5%; body lesions, 55.6%), social inhibition (facial lesions, 65.6%; body lesions, 61.1%), and sun sensitivity (facial lesions, 31.3%; body lesions, 55.6%). Most participants (83.3%) reported that facial improvement was equally (36.1%) or more important (47.2%) than body improvement, with mean treatment satisfaction of 8.1 and 6.9, respectively. Meaningful change was reported by 83.3% and 92.9% of participants with 50-74% and ≥ 75% improvement per the facial Vitiligo Area Scoring Index, respectively, and by 82.6% of participants with ≥ 25% improvement per the total Vitiligo Area Scoring Index per Study 1 outcomes at Week 24. In Study 2, most (82.6%) participants felt that the noticeability of their vitiligo affected their behavior. Nearly all (87.0%) said that an ideal treatment would repigment or return natural color to their facial skin; 56.5% considered ≥ 50% facial repigmentation to be the smallest meaningful improvement. CONCLUSIONS: Participants from both qualitative interviews expressed substantial psychosocial burden. Repigmentation in both facial and body vitiligo were important, with meaningful change determined to be ≥ 50% facial repigmentation and ≥ 25% body repigmentation.

Vitiligo is an autoimmune disease that causes white patches to appear on the skin, affecting about 2% of people worldwide. People with vitiligo often have poor quality of life due to their disease and frequently do not believe that treatments work. We explored how people with vitiligo felt about their disease, and asked what hopes they had for treatment. Individual telephone interviews were conducted with 36 adolescents and adults with vitiligo from two clinical studies (Study 1) and 23 adolescents and adults with vitiligo from a real-world panel (Study 2) in the USA and Canada. Those from Study 1 said that their vitiligo caused them to have low self-esteem and to feel lonely. Most said that it was as important or more important to restore color to white patches on their face (i.e., repigmentation) than the body. Most achieving repigmentation of more than 50% on the face or more than 25% on the body were pleased with their treatment. In Study 2, most people said that their disease affected their behavior, and nearly all said that completely restoring color to their facial skin (i.e., 100% repigmentation) was important. Over half said that the smallest change they thought was important was more than 50% facial repigmentation. In short, people with vitiligo in two interview studies said that their vitiligo affected their quality of life. Most people with vitiligo in these studies reported that it was important to repigment more than 50% on the face and more than 25% on the body.

Psychometric Evaluation of the Facial and Total Vitiligo Area Scoring Index Instruments in the TRuE-V Phase 3 Studies.

INTRODUCTION: This study reports psychometric testing of the facial and total Vitiligo Area Scoring Index quantitative clinical instruments (F-VASI [range: 0-3], T-VASI [range: 0-100], respectively) using data from two phase 3 randomized, vehicle-controlled studies of ruxolitinib cream (TRuE-V1/TRuE-V2), the largest vitiligo trials conducted to date. Because VASI assessment is required by regulatory authorities, we evaluated the psychometric properties of the VASI instruments and confirmed thresholds for clinically meaningful change. METHODS: The TRuE-V1/TRuE-V2 full analysis set population included 652 patients (≥ 12 years old with nonsegmental vitiligo affecting ≤ 10% total body surface area, F-VASI ≥ 0.5, and T-VASI ≥ 3 at baseline). Data collected using the facial and total Patient Global Impression of Change-Vitiligo (PaGIC-V) and Physician's Global Vitiligo Assessment (PhGVA) scales were used as anchors to assess F-VASI and T-VASI for reliability, validity, sensitivity to change, and clinically meaningful change. RESULTS: Median F-VASI and T-VASI scores were 0.70 and 6.76, respectively, at baseline, decreasing to 0.48 and 4.80 at week 24. Test-retest reliability was excellent between screening and baseline for F-VASI (intraclass correlation coefficient [ICC]: 0.943) and T-VASI (ICC: 0.945). Among stable patients per PaGIC-V and PhGVA, reliability was moderate to good for both F-VASI (ICC: 0.891 and 0.739, respectively) and T-VASI (ICC: 0.768 and 0.686). F-VASI and T-VASI differentiated well among PhGVA categories mild/moderate/severe at baseline and week 24. Both VASI instruments detected changes assessed by correlations with PaGIC-V scores at week 24 (F-VASI, r = 0.610; T-VASI, r = 0.512) and changes in PhGVA scores from baseline to week 24 (F-VASI, r = 0.501; T-VASI, r = 0.344). Thresholds for clinically meaningful improvement per PaGIC-V and PhGVA were 0.38-0.60 for F-VASI and 1.69-3.88 for T-VASI. CONCLUSIONS: Data from the TRuE-V1/TRuE-V2 studies confirmed that F-VASI and T-VASI are reliable, valid, and responsive to change, with defined clinically meaningful change from baseline in patients with nonsegmental vitiligo. TRIAL REGISTRATION: The original studies were registered at ClinicalTrials.gov: NCT04052425/NCT04057573.

Vitiligo is a skin disease that causes patches of white (depigmented) skin and affects 0.5­2.0% of people worldwide. People with vitiligo often say that restoring color to white patches of skin (repigmentation) is important. Ruxolitinib cream is approved in the USA and Europe for topical treatment of vitiligo in adults and adolescents based on results from the phase 3 TRuE-V1 and TRuE-V2 studies. In these studies, applying ruxolitinib cream twice daily up to 52 weeks resulted in substantial repigmentation, as assessed by the facial and total Vitiligo Area Scoring Index (F-VASI/T-VASI). We aimed to confirm which changes in F-VASI/T-VASI scores represented meaningful improvement for doctors and people with vitiligo. We compared changes in VASI scores with results from two other tools used to assess vitiligo. One tool was based on doctor assessment (Physician's Global Vitiligo Assessment [PhGVA]); the other was based on patient assessment (Patient Global Impression of Change­Vitiligo [PaGIC-V]). The analysis included clinical trial data for 652 people with vitiligo. After 6 months of treatment, median F-VASI and T-VASI scores decreased considerably, indicating improvement in repigmentation. We saw higher VASI scores for disease considered more severe per the PhGVA and PaGIC-V. Changes in VASI scores largely aligned with changes in PhGVA and PaGIC-V scores. We found that F-VASI and T-VASI are reliable tools to assess vitiligo and confirmed that improvement of 0.38­0.60 for F-VASI and 1.69­3.88 for T-VASI scores represent meaningful repigmentation in people with vitiligo on up to 10% of their bodies.

Prebrief Time for Immersive Virtual and Augmented Reality Simulation: An Integrative Review.

BACKGROUND: Virtual reality and augmented technology are rapidly advancing and hold the potential to transform nursing education by offering a convenient, efficient, learner-centered way to educate students. A comprehensive and time-oriented prebrief is essential to the process. PURPOSE: This review analyzes the status of scientific exploration regarding the prebrief and time allotments for virtual and augmented reality simulation. METHODS: Whittemore and Knafl's 5-stage method guided this integrative review. The authors searched 6 databases and selected 7 articles based on inclusion criteria. RESULTS: The findings from this review demonstrated objectives, a safe learning environment, orientation, preparation materials, and time in the prebrief; yet, inconsistencies persist in the virtual and augmented reality prebrief. CONCLUSIONS: Defining a comprehensive and consistent prebrief is essential for high-quality simulation. A more standardized process, including time allotments, must be established for virtual and augmented reality.

Baseline Levels of Circulating Inflammatory Biomarkers Stratify Patients with Vitiligo Who Significantly Repigment after Treatment with Ruxolitinib Cream.

BACKGROUND: Efficacy of ruxolitinib cream, a topical Jak1/Jak2 inhibitor, was demonstrated in a phase 2 trial in patients with vitiligo. OBJECTIVE: This study aimed to characterize circulating inflammatory biomarker profiles in patients who demonstrated ≥50% improvement in facial Vitiligo Area Scoring Index scores by week 24 (group 1) and those who did not (group 2). DESIGN: This was a posthoc analysis of a multicenter, randomized, double-blind, vehicle-controlled, phase 2 study in which screening was conducted between June 7, 2017 and March 21, 2018. POPULATION: Patients aged between 18 and 75 years with vitiligo, including depigmentation affecting ≥0.5% of body surface area on the face and ≥3% of body surface area on nonfacial areas, were eligible. INTERVENTION: Patients applied 1.5% ruxolitinib cream to lesions once or twice daily for 52 weeks. MAIN OUTCOMES AND MEASURES: Patients were grouped by achievement of ≥50% improvement in facial Vitiligo Area Scoring Index at week 24. Proteomic analysis was performed on baseline serum samples. RESULTS: Mean ± standard error facial Vitiligo Area Scoring Index in group 1 (n = 30) versus group 2 (n = 27) improved by 79.9 ± 4.0% versus 1.1 ± 7.3% and 91.9 ± 1.5% versus 25.1 ± 13.4% at weeks 24 and 52, respectively. Broad proteomic analysis revealed 76 proteins (of 1,104 tested) that were differentially expressed between groups 1 and 2 at baseline (P < 0.05). Ten distinct proteins were upregulated in group 1; 64 were elevated in group 2. CONCLUSION: This analysis identified potential differences between patients who achieved ≥50% improvement in facial Vitiligo Area Scoring Index at 24 weeks and those who did not that require deeper scientific interrogation and may be important in stratifying therapeutic benefit for patients with vitiligo. TRIAL REGISTRATION: The original study was registered at ClinicalTrials.gov, NCT03099304.

Two Phase 3, Randomized, Controlled Trials of Ruxolitinib Cream for Vitiligo.

BACKGROUND: Vitiligo is a chronic autoimmune disease that causes skin depigmentation. A cream formulation of ruxolitinib (an inhibitor of Janus kinase 1 and 2) resulted in repigmentation in a phase 2 trial involving adults with vitiligo. METHODS: We conducted two phase 3, double-blind, vehicle-controlled trials (Topical Ruxolitinib Evaluation in Vitiligo Study 1 [TRuE-V1] and 2 [TRuE-V2]) in North America and Europe that involved patients 12 years of age or older who had nonsegmental vitiligo with depigmentation covering 10% or less of total body-surface area. Patients were randomly assigned in a 2:1 ratio to apply 1.5% ruxolitinib cream or vehicle control twice daily for 24 weeks to all vitiligo areas on the face and body, after which all patients could apply 1.5% ruxolitinib cream through week 52. The primary end point was a decrease (improvement) of at least 75% from baseline in the facial Vitiligo Area Scoring Index (F-VASI; range, 0 to 3, with higher scores indicating a greater area of facial depigmentation), or F-VASI75 response, at week 24. There were five key secondary end points, including improved responses on the Vitiligo Noticeability Scale. RESULTS: A total of 674 patients were enrolled, 330 in TRuE-V1 and 344 in TRuE-V2. In TRuE-V1, the percentage of patients with an F-VASI75 response at week 24 was 29.8% in the ruxolitinib-cream group and 7.4% in the vehicle group (relative risk, 4.0; 95% confidence interval [CI], 1.9 to 8.4; P<0.001). In TRuE-V2, the percentages were 30.9% and 11.4%, respectively (relative risk, 2.7; 95% CI, 1.5 to 4.9; P<0.001). The results for key secondary end points showed superiority of ruxolitinib cream over vehicle control. Among patients who applied ruxolitinib cream throughout 52 weeks, adverse events occurred in 54.8% in TRuE-V1 and 62.3% in TRuE-V2; the most common adverse events were application-site acne (6.3% and 6.6%, respectively), nasopharyngitis (5.4% and 6.1%), and application-site pruritus (5.4% and 5.3%). CONCLUSIONS: In two phase 3 trials, application of ruxolitinib cream resulted in greater repigmentation of vitiligo lesions than vehicle control through 52 weeks, but it was associated with acne and pruritus at the application site. Larger and longer trials are required to determine the effect and safety of ruxolitinib cream in patients with vitiligo. (Funded by Incyte; TRuE-V1 and TRuE-V2 ClinicalTrials.gov numbers, NCT04052425 and NCT04057573.).

The Effect of Infectious Complications During Ventricular Assist Device Use on Outcomes of Pediatric Heart Transplantation.

To describe the impact of infectious adverse events (IAEs) during ventricular assist device (VAD) support on graft loss, infection, and rejection after pediatric heart transplant (HT). Pedimacs data were linked to Pediatric Heart Transplant Society (PHTS) data for patients receiving a VAD followed by HT between September 2012 and December 2016. Linked patients were categorized into IAE on VAD (group A) and no IAE on VAD (group B). Infectious adverse event locations included nondevice, device (external or internal), and sepsis. Post-HT outcomes for analysis were graft loss, infection, and rejection. Time-dependent analysis included Kaplan-Meier and multiphase parametric hazard function analysis. We linked 207 patients (age 9.4 ± 6.3 years). Post-HT follow-up was 19.4 patient-months (<8 days-4.1 years). Group A included 42 patients (20%) with 62 IAEs. Group B included 165 patients without an IAE. Group A patients were younger (7.4 ± 6.1 vs. 9.5 ± 6.3 years; p = 0.03), waited longer for HT (5.3 ± 4.1 vs. 2.9 ± 2.5 months; p = 0.0005), and were hospitalized longer post-HT (42 ± 59 vs. 23 ± 22 days; p = 0.05). VAD-related IAEs were rare (N = 11). Groups A and B had similar freedom from first post-HT infection, rejection, and graft loss (all p > 0.1). However, patients with VAD-related IAE were somewhat more likely to experience rejection (p = 0.03) and graft loss (p = 0.01). Children with an IAE on VAD who survive to HT are younger, wait longer for HT, and remain hospitalized longer than those without an IAE on VAD. Overall, IAE on VAD did not impact post-HT outcomes, but VAD-related IAE may be associated with graft loss and rejection.

Ruxolitinib cream for treatment of vitiligo: a randomised, controlled, phase 2 trial.

BACKGROUND: Vitiligo is a chronic autoimmune disease resulting in skin depigmentation and reduced quality of life. There is no approved treatment for vitiligo repigmentation and current off-label therapies have limited efficacy, emphasising the need for improved treatment options. We investigated the therapeutic potential of ruxolitinib cream in patients with vitiligo and report the efficacy and safety results up to 52 weeks of double-blind treatment. METHODS: We did a multicentre, randomised, double-blind, phase 2 study for adult patients with vitiligo in 26 US hospitals and medical centres in 18 states. Patients with depigmentation of 0·5% or more of their facial body surface area (BSA) and 3% or more of their non-facial BSA were randomly assigned (1:1:1:1:1) by use of an interactive response technology system to receive ruxolitinib cream (1·5% twice daily, 1·5% once daily, 0·5% once daily, or 0·15% once daily) or vehicle (control group) twice daily on lesions constituting 20% or less of their total BSA for 24 weeks. Patients in the control group in addition to patients in the 0·15% once daily group who did not show a 25% or higher improvement from baseline in facial Vitiligo Area Scoring Index (F-VASI) at week 24 were re-randomised to one of three higher ruxolitinib cream doses (0·5% once daily, 1·5% once daily, 1·5% twice daily). Patients in the 0·5% once daily, 1·5% once daily, or 1·5% twice daily groups remained at their original dose up to week 52. Patients, investigators, and the study sponsor (except members of the interim analysis and primary endpoint analysis data monitoring teams) remained masked to treatment assignment throughout the study. The primary endpoint was the proportion of patients achieving a 50% or higher improvement from baseline in F-VASI (F-VASI50) at week 24, assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03099304. FINDINGS: Between June 7, 2017, and March 21, 2018, 205 patients were screened for eligibility, 48 were excluded and 157 patients (mean age, 48·3 years [SD 12·9]; 73 [46%] male and 84 [54%] female) were randomly assigned to either an intervention group or the control group. 32 (20%) of 157 were assigned to the control group, 31 (20%) to the 0·15% once daily group, 31 (20%) to the 0·5% once daily group, 30 (19%) to the 1·5% once daily group, and 33 (21%) to the 1·5% twice daily group. F-VASI50 at week 24 was reached by significantly more patients given ruxolitinib cream at 1·5% twice daily (15 [45%] of 33) and 1·5% once daily (15 [50%] of 30) than were treated with vehicle (one [3%] of 32). Four patients had serious treatment-emergent adverse events (one patient in the 1·5% twice daily group developed subdural haematoma; one patient in the 1·5% once daily group had a seizure; one patient in the 0·5% once daily group had coronary artery occlusion; and one patient in the 0·5% once daily group had oesophageal achalasia), all of which were unrelated to study treatment. Application site pruritus was the most common treatment-related adverse event among patients given ruxolitinib cream (one [3%] of 33 in the 1·5% twice daily group; three [10%] of 30 in the 1·5% once daily group; three [10%] of 31 in the 0·5% once daily group; and six [19%] of 31 in the 0·15% once daily group)with three [9%] of 32 patients showing application site pruritis in the control group. Acne was noted as a treatment-related adverse event in 13 (10%) of 125 patients who received ruxolitinib cream and one (3%) of 32 patients who received vehicle cream. All treatment-related adverse events were mild or moderate in severity and similar across treatment groups. INTERPRETATION: Treatment with ruxolitinib cream was associated with substantial repigmentation of vitiligo lesions up to 52 weeks of treatment, and all doses were well tolerated. These data suggest that ruxolitinib cream might be an effective treatment option for patients with vitiligo. FUNDING: Incyte.

Assessment of the Pharmacokinetics, Pharmacodynamics, and Safety of Single Doses of TV-1106, a Long-Acting Growth Hormone, in Healthy Japanese and Caucasian Subjects.

TV-1106 is a human serum albumin genetically fused to recombinant human growth hormone, designed to provide a long-acting alternative to daily growth hormone (GH) injections in patients with GH deficiency. This study investigated the pharmacokinetics, pharmacodynamics, and safety of single subcutaneous doses of TV-1106 (7.5, 15, 50, and 100 mg) in Japanese (n = 44) and caucasian (n = 44) healthy subjects. TV-1106 pharmacokinetics and pharmacodynamics were comparable in Japanese and caucasian populations. TV-1106 demonstrated relatively slow absorption (median tmax , 10-30 hours) and a mean elimination half-life of 26-36 hours. Apparent clearance and volume of distribution decreased with increasing TV-1106 doses in both populations and appeared to increase more than dose proportionality across the tested doses. Insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 (IGFBP-3) increased in a dose-related manner, with maximum responses observed at 33-96 and 42-109 hours, respectively. IGF-1 and IGFBP-3 returned to baseline values at 168 hours following 7.5 and 15 mg of TV-1106, and 336 hours following 50 and 100 mg of TV-1106. TV-1106 appeared safe in both populations. There was no evidence of differences in pharmacokinetics, pharmacodynamics, or safety of TV-1106 between Japanese and caucasian populations. The data also demonstrate long-acting growth hormone properties of TV-1106 and support its potential for once-weekly dosing.

The effect of quinidine, a strong P-glycoprotein inhibitor, on the pharmacokinetics and central nervous system distribution of naloxegol.

Naloxegol is a PEGylated, oral, peripherally acting µ-opioid receptor antagonist approved in the United States for treatment of opioid-induced constipation in patients with noncancer pain. Naloxegol is metabolized by CYP3A, and its properties as a substrate for the P-glycoprotein (PGP) transporter limit its central nervous system (CNS) permeability. This double-blind, randomized, 2-part, crossover study in healthy volunteers evaluated the effect of quinidine (600 mg PO), a CYP3A/PGP transporter inhibitor, on the pharmacokinetics and CNS distribution of naloxegol (25 mg PO). In addition, the effects of quinidine on morphine (5 mg/70 kg IV)-induced miosis and exposure to naloxegol were assessed. Coadministration of quinidine and naloxegol increased naloxegol's AUC 1.4-fold and Cmax 2.5-fold but did not antagonize morphine-induced miosis, suggesting that PGP inhibition does not increase the CNS penetration of naloxegol. Naloxegol pharmacokinetics was unaltered by coadministration of morphine and either quinidine or placebo; conversely, pharmacokinetics of morphine and its metabolites (in the presence of quinidine) were unaltered by coadministration of naloxegol. Naloxegol was safe and well tolerated, alone or in combination with quinidine, morphine, or both. The observed increase in exposure to naloxegol in the presence of quinidine is primarily attributed to quinidine's properties as a weak CYP3A inhibitor.

Safety, tolerability, pharmacokinetics, and pharmacodynamic effects of naloxegol at peripheral and central nervous system receptors in healthy male subjects: A single ascending-dose study.

This randomized, double-blind, placebo-controlled, ascending-dose, crossover study evaluated single oral doses of naloxegol (NKTR-118; 8, 15, 30, 60, 125, 250, 500, and 1000 mg), a PEGylated derivative of naloxone, for safety and tolerability, antagonism of peripheral and central nervous system (CNS) effects of intravenous morphine, and pharmacokinetics. Healthy men were randomized 1:1 to naloxegol or naloxegol-matching placebo administered with morphine and lactulose in a 2-period crossover design. Periods were separated by a 5- to 7-day washout. Assessments included safety, tolerability, orocecal transit time (OCTT), pupillary miosis, and pharmacokinetics. The study was completed by 46 subjects. The most common adverse events were somnolence, dizziness, headache, and nausea. Greater reversal of morphine-induced delay in OCTT occurred with increasing naloxegol dose, demonstrating dose-ordered antagonism of morphine's peripheral gastrointestinal effects. Forty-four subjects showed no reversal of pupillary miosis; 2 showed potential partial reversal at 250 and 1000 mg, indicating negligible antagonism of morphine's CNS effects at doses ≤ 125 mg. Rapid absorption, linear pharmacokinetics up to 1000 mg, and low to moderate between-subject pharmacokinetic variability was observed. The pharmacokinetics of morphine or its glucuronide metabolites were unaltered by concurrent naloxegol administration. Naloxegol was generally safe and well tolerated at single doses up to 1000 mg.

Safety, tolerability, and pharmacokinetics of multiple ascending doses of naloxegol.

Opioid-induced constipation (OIC) is the most common and often a treatment-limiting adverse event (AE) of opioid therapy for chronic pain. Naloxegol (previously NKTR-118), a PEGylated derivative of naloxone that has minimal penetration of the central nervous system, has received regulatory approval as an oral therapy for OIC. This randomized, double-blind, placebo-controlled, multiple-dose, dose-escalation study was performed to assess safety, tolerability, and pharmacokinetics of multiple doses of naloxegol in healthy volunteers. Four cohorts, each with 4 male and 4 female volunteers, were randomized 3:1 to a twice-daily naloxegol solution (25, 60, 125, and 250 mg) or matching placebo solution. Doses were given every 12 hours for 7 days, with a single final dose on the morning of day 8. All 32 subjects completed the study. The incidence of most AEs was similar in the naloxegol and placebo groups; no AE led to study discontinuation. Naloxegol was rapidly absorbed. Plasma naloxegol pharmacokinetics showed dose proportionality, negligible accumulation at steady state, and no sex differences. Naloxegol in doses up to 250 mg every 12 hours was generally safe and well tolerated in this healthy volunteer population.

Pharmacokinetics, pharmacodynamics, and tolerability of single and multiple doses of ticagrelor in Japanese and Caucasian volunteers.

OBJECTIVES: Two studies assessing ticagrelor pharmacokinetics, pharmacodynamics, and tolerability in healthy Japanese and Caucasian volunteers. MATERIALS AND METHODS: Single-ascending dose (SAD) study: Japanese (n = 20) and Caucasians (n = 20) received single doses of ticagrelor (50, 100, 200, 300, 400, and 600 mg) or placebo. Multiple-ascending dose (MAD) study: Japanese (n = 36) and Caucasians (n = 36) received single doses of 100 mg or 300 mg ticagrelor (day 1), twice-daily 100 mg or 300 mg ticagrelor, or placebo (days 4 – 9), and single doses of 100 mg or 300 mg ticagrelor (day 10). RESULTS: Exposure to ticagrelor and its active metabolite, AR-C124910XX, was generally higher in Japanese vs. Caucasians. In the SAD study, area under the plasma concentration-time curve (AUC) values were 33% (ticagrelor) and 55% (AR-C124910XX) greater in Japanese vs. Caucasians following 600 mg ticagrelor. In the MAD study, AUC values of ticagrelor and AR-C124910XX following multiple doses of ticagrelor 100 mg and 300 mg were statistically significantly greater (33 - 48%) in Japanese vs. Caucasians. In both groups, mean peak inhibition of platelet aggregation was > 86% after single doses (>= 100 mg ticagrelor) and > 84% after multiple doses. Bleeding times were >= 60 minutes in more Japanese than Caucasians with multiple dosing of 100 mg and 300 mg ticagrelor Adverse events were similar between groups (mild-to-moderate intensity). CONCLUSIONS: The pharmacokinetics and tolerability of ticagrelor were broadly similar in Japanese and Caucasians, although exposure was slightly greater in Japanese volunteers. Ticagrelor was generally well tolerated.

Safety, tolerability, pharmacokinetics and pharmacodynamics of high single-ascending doses of ticagrelor in healthy volunteers.

OBJECTIVE: Previous studies have indicated that ticagrelor is well tolerated and exhibits linear pharmacokinetics up to doses of 600 mg/day. The safety, tolerability, pharmacokinetics and pharmacodynamics (bleeding times and pulmonary function tests) of high single-ascending doses of ticagrelor were assessed to determine the maximum tolerated dose of ticagrelor. MATERIALS AND METHODS: This was a randomized, double-blind, placebo-controlled study. Eight healthy volunteers were planned for enrollment in each of 3 dose groups, ticagrelor 900 mg, 1,260 mg, and 1,620 mg (6 : 2 ratio ticagrelor : placebo). RESULTS: The study stopping criteria were met when 3 of the 6 volunteers receiving ticagrelor 1,260 mg experienced moderate gastrointestinal adverse events (AE); none were observed with placebo. One volunteer receiving ticagrelor 1,260 mg had a serious AE - sinus arrest, high-grade atrioventricular block, and ventricular escape rhythm with syncope - and another volunteer had brief, mild dyspnea. Ticagrelor 900 mg was well tolerated. Total exposure to ticagrelor increased dose proportionally. Peak plasma concentration (Cmax) for ticagrelor did not increase much, most likely due to delayed absorption. There were no relevant changes in respiratory parameters. Bleeding times were prolonged in those receiving ticagrelor with respect to placebo, with longer bleeding times in volunteers receiving ticagrelor 1,260 mg than in volunteers receiving 900 mg; no bleeding events were reported. CONCLUSION: These results indicate that the maximum tolerated single dose of ticagrelor is 900 mg in healthy volunteers.

The effect of ticagrelor on the metabolism of midazolam in healthy volunteers.

BACKGROUND: In vitro studies have demonstrated that ticagrelor, an oral antiplatelet agent, is a substrate, activator, and inhibitor of cytochrome P450 (CYP) 3A. Thus, potential CYP3A-mediated drug-drug interactions may occur. OBJECTIVES: The goal of this article was to report study results on the effect of ticagrelor on the pharmacokinetics of oral midazolam (oral midazolam study) and oral versus intravenous (IV) midazolam (oral/IV midazolam study). Secondary objectives included assessing the effect of midazolam on ticagrelor pharmacokinetic parameters, and the safety and tolerability of ticagrelor/midazolam coadministration. METHODS: Two randomized crossover studies were conducted in healthy volunteers (n = 28 in each) with ticagrelor and midazolam. In the first study, volunteers received oral ticagrelor (400 mg daily) or placebo for 6 days, then oral midazolam (7.5 mg). The second study regimen was a single dose of ticagrelor 270 mg, then ticagrelor 180 mg BID for 6 days with a single oral (7.5 mg) or IV (2.5 mg) dose of midazolam. RESULTS: After oral midazolam administration, ticagrelor significantly reduced the AUC(0-∞) of midazolam (30%-32%) and 4-hydroxymidazolam (42%-47%) but not 1-hydroxymidazolam. After administration of IV midazolam, ticagrelor reduced the AUC(0-∞) of midazolam (12%) and 4-hydroxymidazolam (23%) but not 1-hydroxymidazolam. CONCLUSIONS: These results indicate that ticagrelor can weakly activate the metabolism of midazolam to its major 1'-hydroxy metabolite, and at the same time, seems to weakly inhibit midazolam 4'-hydroxylation. Furthermore, ticagrelor affects both hepatic and intestinal CYP3A activity.

A pharmacokinetic interaction study of ticagrelor and digoxin in healthy volunteers.

PURPOSE: Ticagrelor is a reversibly binding P2Y12 receptor antagonist for the prevention of atherothrombotic events in patients with acute coronary syndrome. Previous in vitro studies showed that ticagrelor is a substrate and inhibitor of P-glycoprotein (ABCB1). Therefore, we examined the potential interaction between digoxin, a P-glycoprotein substrate, and ticagrelor by evaluating the pharmacokinetics, safety, and tolerability. METHODS: This was a randomized, double-blind, two-period crossover study in healthy volunteers (n = 20). Pharmacokinetic parameters of digoxin and ticagrelor were evaluated following co-administration of ticagrelor 400 mg qd or placebo on days 1-16, and digoxin (0.25 mg bid on day 6 and 0.25 mg qd on days 7-14). RESULTS: Co-administration of ticagrelor increased the digoxin maximum plasma concentration by 75 %, from 1.8 ng/ml to 3.0 ng/ml (Gmean ratio [GMR] 1.75 [95 % CI, 1.52-2.01]); minimum plasma concentration by 31 %, from 0.5 ng/ml to 0.7 ng/ml (GMR 1.31, 1.13-1.52); and mean area under the curve by 28 %, from 16.8 ng · h/ml to 21.0 ng · h/ml (GMR 1.28, 1.12-1.46), compared with placebo. Renal clearance of digoxin was unaffected by the presence of ticagrelor. Digoxin had no effect on the pharmacokinetics of ticagrelor or its active metabolite, AR-C124910XX. Co-administration of ticagrelor and digoxin was well tolerated. CONCLUSIONS: Collectively, these results indicate that ticagrelor is a weak inhibitor of the P-glycoprotein transporter. Based on these findings, it is recommended that serum concentrations of drugs like digoxin (P-glycoprotein transporter substrates with a narrow therapeutic range) are monitored when initiating or changing ticagrelor therapy.

Effect of ticagrelor on pulmonary function in healthy elderly volunteers and asthma or chronic obstructive pulmonary disease patients.

BACKGROUND: Ticagrelor is a direct-acting, reversibly binding, oral P2Y12 platelet inhibitor that reduces thrombotic cardiovascular events in patients with acute coronary syndrome. Dyspnea is one of the most commonly reported adverse events associated with ticagrelor. OBJECTIVE: To determine the effect of ticagrelor on pulmonary function in healthy elderly volunteers and asthma or chronic obstructive pulmonary disease (COPD) patients. METHODS: Two randomized, double-blind, placebo-controlled, two-way crossover, single-center studies were conducted: 1) healthy elderly volunteers (55-75 years; n = 12); 2) patients with mild asthma (n = 11) or mild-to-moderate COPD (n = 7). Subjects were randomized to receive ticagrelor (a single 450 mg dose, 180 mg 12 hours later, twice daily for 2 days, and once on day 4) or placebo, with a 7 day washout. Pulmonary function at rest and during exercise was monitored using similar schedules and assessments across the two studies. RESULTS: Resting pulmonary function parameters, including respiratory rate, minute ventilation, or tidal volume, were similar between ticagrelor and placebo in any cohort. Furthermore, bronchospasm (as determined by spirometry and pulse oximetry), was not observed with either ticagrelor or placebo in any cohort. Perception of breathing was generally similar following ticagrelor or placebo. Exercise performance was not affected, and no clinically relevant differences were seen in pulmonary parameters during exercise for ticagrelor or placebo. There was no apparent relationship between plasma concentrations of ticagrelor and its main metabolite and pulmonary function. Ticagrelor was well tolerated in all cohorts. Study limitations include the use of relatively few subjects without documented coronary artery disease. CONCLUSIONS: Short-term administration of high doses of ticagrelor did not appear to alter pulmonary function at rest and during exercise in subjects at risk of (healthy elderly) or with respiratory impairment (mild asthma or mild-to-moderate COPD).

Evaluation of the pharmacokinetic interaction between ticagrelor and tolbutamide, a cytochrome P450 2C9 substrate, in healthy volunteers.

OBJECTIVES: To assess the effect of ticagrelor on the pharmacokinetics of tolbutamide (a CYP2C9 substrate), and the effect of tolbutamide on ticagrelor pharmacokinetics. METHODS: In this randomized, double-blind, two-period, crossover study, 23 healthy volunteers received either placebo or ticagrelor 180 mg twice daily (b.i.d.) for 9 days, with a single open-label oral dose of tolbutamide 500 mg on Day 5. After washout (14 days), volunteers received the alternate treatment. Plasma concentrations of tolbutamide, 4-hydroxytolbutamide, ticagrelor, and AR-C124910XX were determined for pharmacokinetic analyses. RESULTS: Ticagrelor had no effect on tolbutamide or 4-hydroxytolbutamide pharmacokinetic parameters. The geometric least square mean ratios for maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from Time 0 to infinity (AUC0-∞) were lose to unity, and the 90% confidence intervals (CI) were within the range 0.80 - 1.25 for both tolbutamide and 4-hydroxytolbutamide. The terminal elimination half-life (t1/2), and time to maximal plasma concentrations (tmax) for tolbutamide and its metabolite were unaffected by ticagrelor coadministration. Tolbutamide had no effect on the Cmax, area under the concentration curve over the 2-hour dosing interval (AUC0-τ), t1/2 or tmax of either ticagrelor or AR-C124910XX. Coadministration of ticagrelor and tolbutamide was well tolerated. CONCLUSIONS: These results suggest that ticagrelor does not affect tolbutamide metabolism and is therefore unlikely to affect CYP2C9-mediated metabolism of drugs.