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Aims: The aim of this study was to characterize the population pharmacokinetics of AZD8233, an antisense oligonucleotide (ASO) that targets the PCSK9 transcript to reduce hepatocyte PCSK9 protein production and plasma levels. AZD8233 utilizes generation 2.5 S‐constrained ethyl motif (cET) chemistry and is conjugated to a triantennary N‐acetylgalactosamine (GalNAc3) ligand for targeted hepatocyte uptake. Methods: A non‐linear mixed‐effect modelling approach utilizing NONMEM software was applied to AZD8233 concentration–time data from 3416 samples in 219 participants from four phase 1–2 studies, one in healthy volunteers (NCT03593785) and three in patients with dyslipidaemia (NCT04155645, NCT04641299 and NCT04823611). Results: The final model described the AZD8233 plasma concentration–time profile from four phase 1–2 studies in healthy volunteers or participants with dyslipidaemia, covering a dose range of 4 to 120 mg. The pharmacokinetics of AZD8233 were adequately described by a two‐compartment model with first‐order absorption. The supra‐proportional increase in maximum plasma concentration (Cmax) across the observed dose range was described by non‐linear Michaelis–Menten elimination (maximum elimination rate, 9.9 mg/h [12% relative standard error]; concentration yielding half‐maximal elimination rate, 4.8 mg/L [18% relative standard error]). Body weight, sex, estimated glomerular filtration rate and disease status (healthy participant vs. patient with dyslipidaemia) were identified as factors affecting exposure to AZD8233. Conclusions: Covariate analysis showed body weight to be the main factor affecting exposure to AZD8233, which largely explained the higher Cmax observed in the Asian population relative to non‐Asians. [ABSTRACT FROM AUTHOR]

In this survey, 4 such cases were identified; for 3 drugs (oral to intravenous, oral to intramuscular, and oral to ocular injection) J-PhI study waivers were accepted, but for 1 drug (subcutaneous to intravenous) the waiver was not accepted. For small-molecule drugs, 5 drugs were successfully waived (dosing route: inhalation, ocular instillation, intramuscular, intravenous or subcutaneous injection) due to at least 1 reason in Table 1. Keywords: ethnic sensitivity/difference; dosage regimen; drug dose; Japanese; phase I study; regulatory science EN ethnic sensitivity/difference dosage regimen drug dose Japanese phase I study regulatory science 1410 1418 9 12/13/21 20211201 NES 211201 The pharmacokinetic (PK) and the pharmacodynamic (PD) properties of a drug and correlations of PK and PD with clinical efficacy and safety are important to assess the sensitivity of a drug to potential differences between ethnic groups. [Extracted from the article]

What is known and objective: Esomeprazole, the S‐isomer of omeprazole, is a proton pump inhibitor which has been approved by over 125 countries, also known as NEXIUM®. Esomeprazole was developed to provide further improvement on efficacy for acid‐related diseases with higher systemic bioavailability due to the less first‐pass metabolism and lower plasma clearance. Esomeprazole is primarily metabolized by CYP2C19. Approximately <1% of Caucasians and 5%‐10% of Asians have absent CYP2C19 enzyme activity. Although the influence of various CYP2C19 phenotypes on esomeprazole pharmacokinetics has been studied, this is the first report in the Japanese population where 27 low CYP2C19 metabolizers were included. Methods: In this study, a population PK model describing the PK of esomeprazole was developed to understand the difference of CYP2C19 phenotypes on clearance in the Japanese population. The model quantitatively assessed the influence of CYP2C19 phenotype on esomeprazole PK in healthy Japanese male subjects after receiving repeated oral dosing. The inhibition mechanism of esomeprazole on CYP2C19 activity was also included in the model. Results and discussion: CYP2C19 phenotype and dose were found as statistically significant covariates on esomeprazole clearance. The apparent clearance at 10‐mg dose was 17.32, 9.77 and 7.37 (L/h) for homozygous extensive metabolizer, heterozygous extensive metabolizer and poor metabolizer subjects, respectively. And the apparent clearance decreased as dose increased. What is new and conclusion: The established population PK model well described the esomeprazole PK and model‐predicted esomeprazole PK was in good agreement with external clinical data, suggesting the robustness and applicability of the current model for predicting esomeprazole PK. [ABSTRACT FROM AUTHOR]

As described in the ICH E5 guidelines, a bridging study is an additional study executed in a new geographical region or subpopulation to link or "build a bridge" from global clinical trial outcomes to the new region. The regulatory and scientific goals of a bridging study is to evaluate potential subpopulation differences while minimizing duplication of studies and meeting unmet medical needs expeditiously. Use of historical data (borrowing) from global studies is an attractive approach to meet these conflicting goals. Here, we propose a practical and relevant approach to guide the optimal borrowing rate (percent of subjects in earlier studies) and the number of subjects in the new regional bridging study. We address the limitations in global/regional exchangeability through use of a Bayesian power prior method and then optimize bridging study design with a return on investment viewpoint. The method is demonstrated using clinical data from global and Japanese trials in dapagliflozin for type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background: Plexiform neurofibromas (PN) are a manifestation of neurofibromatosis type 1 (NF1) that may cause morbidity and impact health-related quality of life (HRQoL). Selumetinib (ARRY-142886, AZD6244) is an orally available, selective, mitogen-activated protein kinase kinase 1/2 inhibitor approved for children with NF1 and symptomatic, inoperable PN in regions including the USA (aged ≥2 years), EU (≥3 years), and Japan (≥3 years). This open-label, single-arm, phase I study evaluated selumetinib in Japanese children with NF1 and symptomatic, inoperable PN., Methods: Eligible patients (aged 3-18 years) received oral selumetinib (25 mg/m 2 twice daily) continuously in 28-day cycles in a fasted state. Primary objectives were safety and tolerability. Secondary objectives included pharmacokinetics, efficacy, PN-related morbidities, and HRQoL., Results: Twelve patients (median age 13.3 years) were enrolled, received ≥1 selumetinib dose (data cutoff: cycle 13 day 1) with median follow-up of 11.5 months. All patients had baseline PN-related morbidities, most commonly disfigurement (91.7%) and pain (58.3%). Most frequently reported any-grade adverse events were dermatologic and gastrointestinal. Objective response rate was 33.3%; median duration of response was not reached. Most patients (83.3%) had target PN volume reduction versus baseline. No patients reported worsening of PN-related morbidities. Selumetinib was rapidly absorbed with moderate-to-high inter-patient variability in maximum plasma concentration and area under the concentration-time curve from time 0-6 hours., Conclusions: Consistent with results of the phase II SPRINT trial, 25 mg/m 2 selumetinib twice daily was well tolerated with a manageable safety profile in Japanese children with NF1 and symptomatic, inoperable PN., Competing Interests: SS’s institution received funding from AstraZeneca and received grants from Osaka University and ARTham Therapeutics. SS has also received grants for an endowed course from OITA City (Division of General Pediatrics and Emergency Medicine). SS is also a committee member of The Japanese Society of Hematology/Oncology and the Japan Children’s Cancer Group. KT has received grants or contracts from AstraZeneca, Novartis, and Ohara. KT has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Chugai Pharmaceutical and Bayer. KT has also received payment for participating on an advisory board or Data Safety Monitoring Board from AstraZeneca and Bayer. KT holds a leadership or fiduciary role in the Japan Children’s Cancer Group and the Japan Society for Neuro-Oncology. MA reports no conflicts of interest. TO, AW, MS, MH, and KS report employment at AstraZeneca and own stock at AstraZeneca. YN has received consulting fees from AstraZeneca and has received payment or honoraria for lectures from AstraZeneca., (© The Author(s) 2023. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Andexanet alfa is a modified recombinant human factor Xa (FXa) that was designed to serve as a binding target for FXa inhibitors as decoy protein. It sequesters FXa inhibitors from binding to endogenous FXa, thereby reversing anticoagulant effect of FXa inhibitors. Andexanet alfa has been approved in March 2022 in Japan for patients with life-threatening or uncontrolled bleeding while on treatment with a FXa inhibitor, apixaban, rivaroxaban, or edoxaban tosilate hydrate. It is administered via two dosing regimens, based on the type of FXa inhibitor, dose, and time since the last dose. In nonclinical studies, andexanet alfa significantly inhibited bleeding induced by FXa inhibitors in animal bleeding models. In the development for Japanese patients, the following two clinical studies have been conducted to confirm the efficacy and safety. First, safety and the reversal effect of andexanet alfa on the FXa inhibitor-mediated anticoagulant activity in healthy adults were confirmed in the overseas phase 2 study including Japanese subjects. Next, the reversal effect of andexanet alfa on the anticoagulation activity and the hemostasis were demonstrated in patients with acute major bleeding while on FXa inhibitor treatment in the global phase 3b/4 study (ANNEXA-4 study). The subgroup analysis of Japanese population showed that the efficacy and safety results were consistent with those of overall population. Andexanet alfa is the first approved reversal agent for FXa inhibitors in Japan and is expected to contribute to the improvement of prognosis in patients with fatal and/or uncontrolled bleeding by timely reversing anticoagulant effect of FXa inhibitors.