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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]

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.