non-Asian Subjects Research Articles

Asia-Inclusive Global Development of Enpatoran: Results of an Ethno-Bridging Study, Intrinsic/Extrinsic Factor Assessments and Disease Trajectory Modeling to Inform Design of a Phase II Multiregional Clinical Trial.

Enpatoran is a novel, highly selective, and potent dual toll-like receptor (TLR)7 and TLR8 inhibitor currently under development for the treatment of autoimmune disorders including systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), and myositis. The ongoing phase II study (WILLOW; NCT05162586) is evaluating enpatoran for 24 weeks in patients with active SLE or CLE and is currently recruiting. To support development of WILLOW as an Asia-inclusive multiregional clinical trial (MRCT) according to International Conference on Harmonisation E5 and E17 principles, we have evaluated ethnic sensitivity to enpatoran based on clinical pharmacokinetic (PK), pharmacodynamic (PD), and safety data from an ethno-bridging study (NCT04880213), supplemented by relevant quantitative PK, PD, and disease trajectory modeling (DTM) results, and drug metabolism/disease knowledge. A single-center, open-label, sequential dose group study in White and Japanese subjects matched by body weight, height, and sex demonstrated comparable PK and PD properties for enpatoran in Asian vs. non-Asian (White and other) subjects across single 100, 200, and 300 mg orally administered doses. DTM suggested no significant differences in SLE disease trajectory for Asian vs. non-Asian individuals. Aldehyde oxidase (AOX) is considered to be a key contributor to enpatoran metabolism, and a literature review indicated no relevant ethnic differences in AOX function based on in vitro and clinical PK data from marketed drugs metabolized by AOX, supporting the conclusion of low ethnic sensitivity for enpatoran. Taken together, the inclusion of Asian patients in MRCTs including WILLOW was informed based on a Totality of Evidence approach.

Comparisons of effectiveness and safety between different dosage strategy in patients with atrial fibrillation treated with rivaroxaban: a systemic review and meta-analysis

Abstract Background Limited real world data show that rivaroxaban following dosage criteria from either ROCKET AF (15mg/day or 10mg/day if creatinine clearance (CrCl)<50ml/min) or J-ROCKET AF (15mg/day or 10mg/day if CrCl<50ml/min) are associated with comparable risks of thromboembolism and bleeding with each other in patients with non-valvular atrial fibrillation (NVAF). We aimed to study whether these observations differ between Asian and non-Asian subjects. Methods Databases were searched for adjusted observational study that compared relevant clinical outcomes of NVAF patients receiving off-label under-dosing rivaroxaban (10mg/day if CrCl>50ml/min), on-label dose rivaroxaban eligible for ROCKET AF or J-ROCKET AF, and off-label over-dosing rivaroxaban (20mg/day if CrCl<50ml/min). Results Eighteen studies were included. Rivaroxaban following J-ROCKET AF criteria (n=19,513) was associated with comparable risks of thromboembolism in the Asian subgroup (n=43,076), whereas rivaroxaban following J-ROCKET AF criteria (n=8555) was associated with higher risks of thromboembolism (hazard ratio (HR):1.27;[95% confidential interval (CI):1.05–1.53]) and all-cause mortality (HR:1.30;[95%CI:1.05–1.60]) compared with that of ROCKET AF criteria (n=23,139) in the non-Asian subgroup (n=31,694)(Figure). There was no differences in risks of major bleeding between rivaroxaban following J-ROCKET AF versus ROCKET AF criteria either in the Asian or non-Asian subgroup (Figure). Off-label underdosed rivaroxaban 10mg (n=6305) was associated with a higher risk of thromboembolism (HR:1.64;[95%CI:1.28–2.11]) but lower risk of major bleeding (HR:0.72;[95%CI:0.57–0.90]) compared with eligible dosage criteria (n=11,673). Off-label overdosed rivaroxaban 20mg (n=7572) was associated with worse clinical outcomes in the risks of thromboembolism (HR:1.42;[95%CI:1.14–1.79]), mortality (HR:1.41;[95%CI:1.15–1.73]) and major bleeding (HR:1.27; 95%CI:1.05–1.54; N=7 with I2=25%) compared with eligible dosage criteria (n=39,097). Conclusions Rivaroxaban dosing regimen following J-ROCKET criteria may serve as an alternative to ROCKET-AF criteria for the Asian population with NVAF, whereas the dosing regimen following ROCKET AF criteria was more favorable for the non-Asian population. Off-label underdosed rivaroxaban 10mg was associated with a higher risk of thromboembolism but a lower risk of major bleeding, while off-label overdosed rivaroxaban 20mg was associated with worse outcome in most clinical events.

Oral anticoagulant use and outcomes in Asian patients with atrial fibrillation in the GLORIA-AF Registry

Abstract Background Ethnic differences in the management and outcomes of patients with atrial fibrillation (AF) have been shown in previous studies, but available data is still limited, although urgently needed. Purpose to analyse oral anticoagulant (OAC) prescription, OAC discontinuation, and long-term risk of major outcomes in Asian patients with AF, using data from a global prospective cohort study. Methods Using data from the GLORIA-AF Registry Phase II and III, we analysed patients according to their self-reported ethnicity (Asian vs. Non-Asian), and according to Asian ethnic subgroup (i.e. Chinese, Japanese, Korean and other Asian). Odds of OAC prescription were analysed through multivariable logistic regression, while the risk of OAC discontinuation and adverse outcomes were analysed through multivariable Cox-regression model. Primary outcome of this analysis was defined as the composite of all-cause death and major adverse cardiovascular events (MACE). Results 34,421 AF patients were included (70.0±10.5 years, 45.1% females, 6,900 (20.0%) Asian). Compared to Non-Asian subjects, prescription of OAC and non-vitamin K antagonist oral anticoagulant (NOAC) was lower in Asian subjects (Odds Ratio [OR] and 95% Confidence Intervals (CI): 0.23 [0.22-0.25] and 0.66 [0.61-0.71], respectively; Figure 1), but higher in the Japanese subgroup. Asian ethnicity was also associated with OAC discontinuation (Hazard Ratio [HR] and [95%CI]: 1.79 [1.67-1.92]), and lower risk of the primary composite outcome (HR [95%CI]: 0.86 [0.76-0.96]; Figure 2). Among the secondary outcomes, Asian patients had also higher risk of thromboembolism and intracranial haemorrhage, and lower risk of major bleeding events. Conclusions In this large, contemporary cohort of patients with AF, Asian subjects received suboptimal management of thromboembolic risk, and showed a peculiar long-term risk of adverse outcomes. Integrated and appropriate treatment of these patients is crucial to improve their prognosis.Figure 1Figure 2

Comparisons of Effectiveness and Safety between On-label Dosing, Off-label Underdosing and Off-label Overdosing in Asian and Non-Asian Atrial Fibrillation Patients Treated with Rivaroxaban: A Systematic Review and Meta-analysis of Observational Studies.

Limited real-world data show that rivaroxaban following dosage criteria from either ROCKET AF (20mg/day or 15mg/day if creatinine clearance [CrCl]<50ml/min) or J-ROCKET AF (15mg/day or 10mg/day if CrCl<50ml/min) are associated with comparable risks of thromboembolism and bleeding with each other in patients with non-valvular atrial fibrillation (NVAF). We are aimed to study whether these observations differ between Asian and non-Asian subjects. A systematic review and meta-analysis with random effects was conducted to estimate the aggregate hazard ratio (HR) and 95% confidence interval (CI) using PubMed and MEDLINE databases from September 8, 2011 to December 31, 2022 searched for adjusted observational studies that reported relevant clinical outcomes of NVAF patients receiving rivaroxaban 10mg/day if CrCl>50ml/min, on-label dose rivaroxaban eligible for ROCKET AF or J-ROCKET AF, and rivaroxaban 20mg/day if CrCl<50ml/min. Effectiveness and safety endpoints were compared between ROCKET AF and J-ROCKET AF dosing regimen in Asian and non-Asian subjects, separately. Also, risks of events of rivaroxaban 10mg/day despite of CrCl>50ml/min and rivaroxaban 20mg/day despite of CrCl<50ml/min were compared to that of "ROCKET AF/J-ROCKET AF dosing". Sensitivity analyses were performed by sequential elimination of each study from the pool. The meta-regression analysis was performed to explore the influence of potential factors on the effectiveness and safety outcomes. Eighteen studies involving 67,571 Asian and 54,882 non-Asian patients were included. Rivaroxaban following J-ROCKET AF criteria was associated with comparable risks of thromboembolism in the Asian subgroup, whereas rivaroxaban following J-ROCKET AF criteria was associated with higher risks of all-cause mortality (HR:1.30; 95%CI:1.05-1.60) compared with that of ROCKET AF criteria in the non-Asian population. There were no differences in risks of major bleeding between rivaroxaban following J-ROCKET AF versus ROCKET AF criteria either in the Asian or non-Asian population. Use of rivaroxaban 10mg despite of CrCl>50ml/min was associated with a higher risk of thromboembolism (HR:1.64; 95%CI:1.28-2.11) but lower risk of major bleeding (HR:0.72; 95%CI:0.57-0.90) compared with eligible dosage criteria. Use of rivaroxaban 20mg despite of CrCl<50ml/min was associated with worse clinical outcomes in the risks of thromboembolism (HR:1.32; 95%CI:1.09-1.59), mortality (HR:1.33; 95%CI:1.10-1.59) and major bleeding (HR:1.26; 95%CI:1.03-1.53) compared with eligible dosage criteria. The pooled results were generally in line with the primary effectiveness and safety outcomes by removing a single study at one time. Meta-regression analyses failed to detect the bias in most potential patient characteristics associated with the clinical outcomes. Rivaroxaban dosing regimen following J-ROCKET criteria may serve as an alternative to ROCKET-AF criteria for the Asian population with NVAF, whereas the dosing regimen following ROCKET AF criteria was more favorable for the non-Asian population. Use of rivaroxaban 10mg despite of CrCl>50ml/min was associated with a higher risk of thromboembolism but a lower risk of major bleeding, while use of rivaroxaban 20mg despite of CrCl<50ml/min was associated with worse outcome in most clinical events.

Does Decision Making for Others Close the Gender Gap in Competition?

We examine whether the gender gap in competitiveness in stereotypically male tasks persists when the decision to compete is made by someone else. In a within-subject laboratory experiment, decision makers make competition entry decisions for both themselves and a randomly selected other. Although we replicate the standard gender gap in decisions for oneself, we do not find a gender gap when the decision to compete is made by someone else. This is driven by men being significantly more willing to enter themselves than others into competitions. Men’s and women’s willingness to enter others into competitions is statistically indistinguishable from women’s willingness to enter themselves into competitions. Subgroup analyses reveal that competitive preferences are significantly greater for Asian than non-Asian subjects. Our results have implications for the effectiveness of nominations and mentorship to close gender gaps in labor market outcomes that are affected by competitive preferences. This paper was accepted by Yan Chen, behavioral economics and decision analysis. Funding: This work was supported by the Russell Sage Foundation [Grant G-5602]. Supplemental Material: The data files and online appendix are available at https://doi.org/10.1287/mnsc.2023.4861 .

Thyrotoxic periodic paralysis associated with lactic metabolic acidosis: Case report of an African man and review of literature

BackgroundThyrotoxic periodic paralysis (TPP) is a rare and most often acquired subtype of hypokalemic periodic paralysis. The association of varying degrees of muscle weakness, hyperthyroidism and hypokalemia characterizes it. The treatment requires potassium supplementation, control of hyperthyroidism and prevention measures. It is a frequent disease in Asian men, but much rare in Caucasian or African populations. This is the first report of TPP associated with lactic metabolic acidosis in an African man. Case presentationA 23 year-old African man, native from Morocco, with recurrent episodes of tetraparesis for eleven months, and abdominal pain, was referred for evaluation. Biochemical investigations showed severe hypokalemia associated with hyperthyroidism and lactic metabolic acidosis. His EKG showed signs of hypokalemia such as sinus tachycardia and U waves. After potassium supplementation, neurological recuperation was quick and complete. Thyroid ultrasound identified a hypoechogenic and hypervascularized goiter, associated with high levels of thyroid antibodies, in favor of Grave's disease. With antithyroid drugs and life-style changes, the patient did not have any other attack. Review of literatureIn addition to the case report, this article presents an extended review of literature, from the first large study reporting the diagnosis and incidence of TPP in 1957 to nowadays. Are reported here the latest information concerning epidemiology, clinical manifestations, complementary examinations, management and genetic finding. The lactic acidosis observed initially is exceptional, never described in TPP. TPP is a diagnostic and therapeutic emergency, requiring careful potassium supplementation, in order to avoid the risk of the onset of rebound hyperkalemia, to be maintained until the etiological treatment is effective. Paraclinical assessment with emergency EKG and electromyogram are essential to assess the impact. DiscussionIt is essential in the face of any hypokalaemic periodic paralysis, including in non-Asian subjects, to search hyperthyroidism. ConclusionsThis report demonstrates the importance of thyroid testing in case of acute muscle weakness, even in non-Asian patients in order to diagnose TPP. This is a rare but possible etiology, to be distinguished from the familial form of hypokalemic periodic paralysis. It also questions on the impact of TPP on energetic metabolism, in particular on lactic metabolism.

Geographic Atrophy Phenotypes in Subjects of Different Ethnicity: Asia–Pacific Ocular Imaging Society Work Group Report 3

To characterize geographic atrophy (GA) and evaluate differences between Asians and non-Asians. Multicenter, retrospective case series. Subjects aged ≥ 50 years with GA secondary to age-related macular degeneration in the absence of neovascularization in the study eye and follow-up of ≥ 2 years. The GA lesion characterized at baseline and last follow-up based on multimodal imaging (fundus autofluorescence [FAF], near infrared [NIR], and spectral domain-OCT). Patients were grouped as either Asian or non-Asian. Comparison of (1) phenotypes of GA lesions (size, foveal involvement, number of foci, drusen background, and choroid background) and (2) growth rates of GA. A total of 144 patients (169 eyes) with distribution of 50.9% Asians and 49.1% non-Asians. The age and sex were similar between Asians and non-Asians (Asians: mean age, 77.2 ± 10.1 years, 47.9% female; non-Asians: mean age, 79.7 ± 8.4 years, 58.7% female). Asians exhibited thicker choroids (167 ± 74 versus [vs.] 134 ± 56 μm; P < 0.01) and lower prevalence of drusen (40.7% vs. 66.3%; P < 0.01). At baseline, the GA area was smaller in Asians vs. non-Asians (NIR, 3.7 ± 4.6 vs. 6.3 ± 6.8 mm2; P= 0.01: FAF, 2.4 ± 3.4 vs. 8.4 ± 9.6 mm2; P< 0.01). Asians had fewer GA foci (1.7 ± 1.3 vs. 2.7 ± 2.2; P < 0.01) compared to non-Asians. The proportion with diffused or banded FAF junctional zone pattern was similar between Asians and non-Asians (44.2% vs. 60.2%; P= 0.20). Asians had a slower GA lesion growth rate than non-Asians (NIR, 0.7 vs. 1.9 mm2/year; P<0.01: FAF, 0.3 vs. 2.0 mm2/year; P < 0.01: NIR, 0.2 vs. 0.4 mm/year; P < 0.01 square root transformed: FAF, 0.1 vs. 0.3 mm/year; P < 0.01 square root transformed). The factors associated with GA lesion growth rate are (from the highest effect size) ethnicity, junctional zone FAF pattern, baseline GA area, and number of GA foci. Higher GA lesion growth rate was observed in both Asian and non-Asian subgroups, with drusen or lesion size and FAF patterns meeting inclusion criteria of recent therapeutic trials, but growth rate remained significantly slower in Asians. Eyes with baseline lesion ≥ 5 mm2 showed the highest growth rate, and the difference between ethnicities was no longer significant (2.6 vs. 3.3 mm2/year; P= 0.14). There are differences in GA lesion phenotype, associated features, and growth rate between Asians and non-Asian subjects. Proprietary or commercial disclosure may be found after the references.

Treatment decision-making among Asian Americans with chronic rhinosinusitis.

Treatment decision-making among Asian Americans with chronic rhinosinusitis.

Asian Ethnicity and Femoral Geometry in Atypical Femur Fractures: Independent or Interdependent Risk Factors?

ABSTRACTThe earliest reports of atypical femur fractures (AFF) emerged from Asia. In the West, epidemiologic studies report a greater incidence of AFFs among subjects of Asian background. Asian ethnicity is an established risk factor for AFF, but clear mechanisms to explain this risk and implications for the general development of AFF are open questions. Ethno‐specific differences in bisphosphonate action and femoral geometry have been proposed as hypotheses. In a retrospective cohort of 163 female patients presenting with AFFs or typical femur fractures (TFF), relative contributions of Asian ethnicity, proximal femoral geometry, and bisphosphonate use in AFF status were examined. There was a fourfold higher proportion of Asian subjects in the AFF compared with TFF groups (31.6%, 30/95 versus 7.4%, 5/68). Asian subjects had smaller femurs in femoral head, neck, and axial dimensions. A multiple logistic regression model for AFF status was fitted adding Asian ethnicity to three previously reported independent predictors of AFF including femoral geometry, which together comprise the Sydney AFF Score (age ≤80 years, femoral neck width <37 mm than non‐Asian, lateral cortical width at lesser trochanter ≥5 mm). Asian ethnicity was a robust independent predictor of AFF, imparting sevenfold increase in the odds of AFF after adjusting for all three variables (95% confidence interval [CI] 2.2–23.2, p = 0.001) or for overall AFF score (95% CI 2.2–22.3 p = 0.001). Overall Asian subjects had higher rates of bisphosphonate use than non‐Asian subjects (67.6% versus 47.2%, p = 0.034). Among AFF bisphosphonate users, Asian subjects had lower AFF scores than non‐Asians (Sydney AFF Score ≤1, 45.5% Asian subjects versus 22.2% non‐Asian subjects, p = 0.05). Asian ethnicity is a strong independent risk factor for AFF, unaccounted for by ethno‐specific differences in proximal femoral geometry. Bisphosphonate use may be associated with a greater predisposition for AFF in Asian subjects compared with non‐Asian subjects. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Dupilumab pharmacokinetics in Chinese healthy subjects and patients with atopic dermatitis: Results of two randomized, double-blind, placebo-controlled studies

BackgroundDupilumab, a fully human monoclonal antibody targeting IL-4Rα, has demonstrated rapid and sustained improvements in clinical outcomes in patients with atopic dermatitis (AD), asthma, and chronic rhinosinusitis with nasal polyps. MethodsIn a phase 1, double-blind, ascending-dose study, 30 healthy Chinese adults were randomized to single subcutaneous doses of dupilumab 200, 300, 600 mg, or placebo. In a phase 3, double-blind study, 165 Chinese adults with AD were randomized to dupilumab 300 mg or placebo every 2 weeks. ResultsFollowing single doses of dupilumab 200, 300, and 600 mg in the phase 1 study, mean serum maximum concentrations (Cmax) were 25.4 ± 4.0, 37.2 ± 14.5, and 77.3 ± 19.0 mg/L, respectively. For a 1.5-fold increase in dupilumab dose, 1.31-, 1.73-, and 1.66-fold increases in Cmax, area under the curve to real time (AUClast), and extrapolated to infinity (AUC) were observed, respectively, while a 2-fold dose increase resulted in 2.17-, 2.81-, and 2.80-fold increases, respectively. In the phase 3 study, mean dupilumab trough concentrations were 78.8 ± 32.0 and 86.4 ± 33.6 mg/L at weeks 12 and 16, respectively. ConclusionsCmax increased approximately proportionally to dose, while AUC and AUClast increased greater than proportionally. Dupilumab pharmacokinetics were generally comparable between Chinese and non-Asian healthy subjects (single dose) and between Chinese and non-Asian AD patients (repeated doses), with differences accounted for by body weight. As differences in exposure by weight are unlikely to be clinically relevant based on late-stage study results, no dose adjustment by ethnic origin or weight is required.

Population Pharmacokinetic Analyses of Ertugliflozin in Select Ethnic Populations.

Ertugliflozin, a sodium‐glucose cotransporter 2 inhibitor, is approved for treatment of type 2 diabetes. Two population pharmacokinetic (PK) analyses were conducted, using data from up to 17 phase 1 to 3 studies, to characterize ertugliflozin PK parameters in select ethnic subgroups: (1) East/Southeast (E/SE) Asian vs non‐E/SE Asian subjects; (2) Asian subjects from mainland China vs Asian subjects from the rest of the world and non‐Asian subjects. A 2‐compartment model with first‐order absorption, lag time, and first‐order elimination was fitted to the observed data. For the E/SE Asian vs non‐E/SE Asian analysis (13 692 PK observations from 2276 subjects), E/SE Asian subjects exhibited a 17% increase in apparent clearance (CL/F) and 148% increase in apparent central volume of distribution (Vc/F) vs non‐E/SE Asian subjects. However, individual post hoc CL/F values were similar between groups when body weight differences were considered. For the second analysis (16 018 PK observations from 2620 subjects), compared with non‐Asian subjects, CL/F was similar while Vc/F increased by 44% in Asian subjects from mainland China and both CL/F and Vc/F increased in Asian subjects from the rest of the world (8% and 115%, respectively) vs non‐Asian subjects. Increases in Vc/F would decrease the ertugliflozin maximum concentration but would not impact area under the concentration‐time curve. Therefore, the differences in CL/F (area under the concentration‐time curve) and Vc/F were not considered clinically relevant or likely to result in meaningful ethnic differences in the PK of ertugliflozin.

Revisiting Anchor Epicanthoplasty in Mild to Moderate Asian Epicanthal Folds: A Clinicopathological Study.

To assess the epicanthal fold (EF), eyelid, eyebrow, scar, and patients' satisfaction after anchor epicanthoplasty and upper blepharoplasty and histopathologically compare Asian epicanthal fold skin with non-Asian counterpart. Asian Iranians with grade 2 and 3 EF were included. Photographs were taken before and at least 12months after the surgery. Photoanalysis included EF grade, inter-canthal distance (ICD), margin reflex distance 1 (MRD1), tarsal plate show (TPS), brow fat span (BFS), and eyebrow height. Manchester scar scale score (5-28) and patients' satisfaction score (0-100) were documented. The most medial skin of 5 Asian and 5 non-Asian subjects was histologically compared for the thickness and elastic fiber density and morphology. Included were 89 patients (178 eyelids) with a mean age of 31.6years and follow-up of 13.1months. Mean ICD significantly decreased by 3.5mm (shortening ratio of 9.7%). All grade 2 and almost half of the grade 3 EF disappeared. Significant postoperative increase in mean MRD1 (0.3mm) and TPS (1.1-1.4mm) and decrease in BFS (3.3-3.6mm) and eyebrow height (1.7-3.4mm) were observed. Revision rate of epicanthoplasty was 7.3%. Mean satisfaction and scar scores were 97.1 and 5.4, respectively. Histopathologically, Asian and non-Asian medial upper eyelid skin was not significantly different. Anchor epicanthoplasty eliminated grade 2 and improved grade 3 EF with a high satisfaction and negligible scar. Simultaneous upper blepharoplasty significantly increased MRD1 and TPS and decreased eyebrow height. EF skin was not histologically different from non-Asians. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Is Endoscopic Balloon Dilation Still Associated With Higher Rates of Pancreatitis?: A Systematic Review and Meta-Analysis.

The objective of this study was to compare the efficacy and safety of endoscopic papillary balloon dilation (EPBD), endoscopic sphincterotomy (ES), and the combination of large balloon dilation and ES (ES + EPLBD) in the treatment of common bile duct stones, with a special focus on postendoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). Individualized search strategies were developed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We included randomized controlled trials (RCTs) which evaluated at least one of the following outcomes: PEP, complete stone removal in the first ERCP, need for mechanical lithotripsy, recurrence of common bile duct stones, bleeding, and cholangitis. Twenty-five RCTs were selected for analysis. Pancreatitis rates were higher for EPBD than for ES (P = 0.003), as were severe pancreatitis rates (P = 0.04). However, in the 10-mm or greater balloon subgroup analysis, this difference was not shown (P = 0.82). Rates of PEP were higher in the subgroup of non-Asian subjects (P = 0.02), and the results were not robust when RCTs that used endoscopic nasobiliary drainage were omitted. The incidence of pancreatitis was comparable between EPLBD and ES + EPLBD. All 3 approaches were equally efficacious. Nevertheless, the results should be interpreted with caution, because pancreatitis is a multifactorial pathology, and RCTs can have limited generalizability.

Effect of rifampin and itraconazole on the pharmacokinetics of zanubrutinib (a Bruton's tyrosine kinase inhibitor) in Asian and non-Asian healthy subjects

PurposeZanubrutinib (BGB-3111) is a potent Bruton’s tyrosine kinase inhibitor with promising clinical activity in B-cell malignancies. Zanubrutinib was shown to be mainly metabolized through cytochrome P450 3A (CYP3A) in vitro. We evaluated the effect of steady-state rifampin (a strong CYP3A inducer) and steady-state itraconazole (a strong CYP3A inhibitor) on the pharmacokinetics (PK), safety, and tolerability of zanubrutinib in healthy Asian and non-Asian subjects.MethodsIn this open-label, two-part clinical study, 20 participants received a single oral dose of zanubrutinib (320 mg) and oral rifampin (600 mg) in Part A, and 18 participants received a single oral dose of zanubrutinib (20 mg) and oral itraconazole (200 mg) in Part B. Serial blood samples were collected after administration of zanubrutinib alone and zanubrutinib in combination with rifampin or itraconazole for the measurement of PK parameters.ResultsCoadministration with rifampin decreased AUC0–∞ of zanubrutinib by 13.5-fold and Cmax by 12.6-fold. Coadministration with itraconazole increased the AUC0–∞ of zanubrutinib by 3.8-fold and Cmax by 2.6-fold. The PK of zanubrutinib was consistent between Asian and non-Asian subjects, and zanubrutinib was well tolerated in this study.ConclusionsThese results confirm that zanubrutinib is primarily metabolized by CYP3A in humans. The PK of zanubrutinib was comparable between Asian and non-Asian subjects and, therefore, no dose modifications are necessary for zanubrutinib in these ethnic populations.

Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of ASP1617 in Healthy Adult Non-Asian and Japanese Subjects Including Assessment of a Food Effect

Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of ASP1617 in Healthy Adult Non-Asian and Japanese Subjects Including Assessment of a Food Effect

Increased sensitivity of 2015 Neuromyelitis Optica Spectrum Disorder (NMOSD) diagnostic criteria in older, non-Asian subjects (P2.332)

Increased sensitivity of 2015 Neuromyelitis Optica Spectrum Disorder (NMOSD) diagnostic criteria in older, non-Asian subjects (P2.332)

Clinical Pharmacokinetics of Ombitasvir.

Ombitasvir is a potent, nonstructural protein 5A inhibitor of the hepatitis C virus (HCV) that is used in combination with other direct-acting antivirals for the treatment of chronic HCV infection. Ombitasvir is predominantly metabolized by amide hydrolysis followed by oxidative metabolism and is a substrate of P-glycoprotein. Ombitasvir displays linear pharmacokinetics with minimal accumulation and is eliminated via metabolism and biliary excretion. A negligible amount of unchanged drug is excreted in urine. Exposures are comparable across Chinese, Japanese, and non-Asian subjects. The pharmacokinetic characteristics of ombitasvir are similar in healthy subjects and HCV-infected patients, and are not appreciably altered by hepatic or renal impairment. Results from several drug interaction studies demonstrated that ombitasvir has a low potential for drug interactions.

Pharmacokinetics and pharmacodynamics of two different landiolol formulations in a healthy Caucasian group

BackgroundTo date, no data have been reported on the pharmacokinetic and pharmacodynamic properties of landiolol, a fast-acting cardioselective β1-adrenergic antagonist, in non-Asian subjects. The aim of this study was to compare two landiolol formulations in healthy Caucasian subjects. Materials and methodsWe conducted a single-center, prospective, double-blinded, randomized study in two cross-over periods with 12 healthy subjects (7 women and 5 men) each receiving three doses (0.1, 0.2, and 0.3mg/kg BW) of Onoact® 50 Lyophilized powder (50mg) or Rapibloc® concentrate IV (20mg/2mL) to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of the two landiolol formulations. ResultsFor both formulations, maximum blood concentrations of landiolol were rapidly reached (median tmax 2.3±0.65 and 2.8±1.13min for the high dose of each formulation). The compounds had a short half-life (t1/2=3.2±1.2min and 3.0±1.1min for the low dose of the concentrate formulation and the lyophilized powder, respectively). The results showed no statistically significant differences between both formulations of landiolol for any PK parameters, at study doses. Both formulations dose-dependently and significantly decreased the heart rate values from 62.2bpm at baseline to minimum values of 55–56, 52–53, and 50–52bpm after 0.1, 0.2, and 0.3mg/kg respectively. This bradycardic effect was achieved within 1 to 3min. The decrease in systolic blood pressure (baseline: 107mmHg, minimum values were around 99mmHg) was significant but not dose dependent, and occurred within 3 to 12min. Seven mild to moderate AEs occurred after administration of the concentrate formulation. No SAEs were reported in this study. ConclusionIn Caucasians, both landiolol formulations showed similar pharmacokinetic behaviours, displaying very short half-lives (3.0 to 3.6min). In addition, after administration of both formulations, the landiolol-induced heart rate reduction showed fast onset and dose dependence, whilst the decrease of systolic blood pressure occurred more slowly, was less pronounced, and dose independent. In summary, both landiolol formulations delivered comparable plasma concentration profiles and showed good local tolerability. Overall, the pharmacokinetic and pharmacodynamic reactions observed in Caucasians were comparable to those described in Japanese subjects.

Diabetic striatopathy—Does it exist in non-Asian subjects?

BackgroundDiabetic striatopathy (DS) is a rare complication of diabetes mellitus (DM). The syndrome appears in patients with uncontrolled DM and is characterized by abrupt onset of movement disorder, mainly hemichorea and accompanied by specific findings on brain imaging. It is believed that DS is unique to the Asian population and affects mainly elderly women with uncontrolled DM. MethodsIn order to define existence and characterization of DS in Western population, we reviewed the medical records of all patients admitted to the Chaim Sheba Medical Center between 2004 and 2014 and identified those with documented elevated HbA1c (>10%). The charts and imaging studies of those with elevated HbA1c and undiagnosed neurological symptoms were reviewed to diagnose DS. ResultsOut of 697 patients with HbA1c>10%, 328 patients had unknown neurological diagnosis. Among them, we identified 4 patients (3 women, mean age 73 and mean HbA1c of 14.8%) with hemichorea or choreoathetosis and brain imaging findings compatible with the diagnosis of DS. Only one out of the 4 patients was diagnosed during hospitalization with DS. All patients were treated with insulin with improvement of their symptoms during hospitalization. However, there was a recurrence in 2 of them and 1 died during the second episode. ConclusionDiabetic striatopathy exists but underdiagnosed in the Western population. It is important to increase the awareness for this clinical syndrome in order to treat those patients properly.

Axitinib plasma pharmacokinetics and ethnic differences

Axitinib, a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, showed improved progression-free survival over sorafenib in patients previously treated for advanced renal cell carcinoma in the AXIS trial. Although a few studies had established the efficacy and safety of axitinib in Asian patients, additional evaluation was necessary to obtain regulatory approval in several Asian countries, especially in light of ethnic differences that are known to exist in genetic polymorphisms for metabolizing enzymes such as cytochrome P450 (CYP) 3A5, CYP2C19 anduridine diphosphate glucuronosyltransferase (UGT) 1A1, which are involved in axitinib metabolism. Axitinib plasma pharmacokinetics following single or multiple administration of oral axitinib in Asian (Japanese or Chinese) healthy subjects as well as Asian patients with advanced solid tumors was compared with that obtained in Caucasians. Upon review, the data demonstrated that axitinib can be characterized as not sensitive to ethnic factors based on its pharmacokinetic and pharmacodynamic properties. Axitinib exhibited similar pharmacokinetics in Asian and non-Asian subjects. A pooled population pharmacokinetic analysis indicated lack of a clinically meaningful effect of ethnicity on axitinib disposition. Therefore, dose adjustment for axitinib on the basis of ethnicity is not currently warranted.