Ensitrelvir is a novel selective inhibitor of the 3C-like protease of SARS-CoV-2, which is essential for viral replication. This phase 1 study of ensitrelvir assessed its safety, tolerability, and pharmacokinetics of single (part 1, n  = 50) and multiple (part 2, n  = 33) ascending oral doses.

Direct compression is a faster, simpler, and easier technique for tablet manufacturing compared to other processes such as wet and dry granulation techniques because it only requires mixing and compression. In addition to mixing and compression, wet granulation requires granulation, drying, and milling. Each additional step generates variability in the process and increases the risk of out-of-specification products. Fewer steps in the manufacturing process are advantageous for pharmaceutical industries; however, the application of direct compression has been limited due to issues of powder flowability, content uniformity and tabletability. A failure of powder flow often leads to abandon direct compression and adopt granulation process during formulation and process development trials. Flow has a direct impact on decision of whether to start out developing direct compression. Additionally, flowability and tabletability often develop into critical quality factors of high-dose tablets, while content uniformity causes the major concern in low-dose tablets. 1)Therefore, unfavorable powder flow is the fundamental and serious bottleneck to be first eliminated in the direct compression processing.Glidants are usually incorporated in direct compression formulations to improve powder flow and control tablet weight. Specifically, silica has been reported to be the most efficient glidant because of its small particle size and extremely low-density.2) Moreover, direct compression vehicles, such as spray-dried lactose and agglomerated lactose instead of fine-powder lactose, are commonly used to remedy flow properties. Several studies have reported that powder flowability can be significantly enhanced with the optimum concentration of porous or nonporous silica, 3) appropriate mixing time, 4) correct mixer type 5,6) and hydrophilic or hydrophobic silica properties.7) However, most of the studies have focused only on the relationships between the glidant and the direct compression vehicles and have excluded an active pharmaceutical ingredient (API), even though API powder properties are quite different from these excipients for direct compression. Generally, APIs are micronized to improve solubility and bioavailability, and consequently tend to be cohesive. In contrast, the direct compression vehicles are usually agglomerated and enlarged to become free flowing. Therefore, micronized API and enlarged direct compression vehicles are the most interesting and noteworthy factors to comprehensively improve the flow properties of a direct compression formulation. Shear mixing plays a critical role in blending for direct compression, particularly for low-dose drug products containing lubricants (e.g., magnesium stearate and calcium stearate). The homogeneity of the low-dose API requires sufficient mixing and results in excessive shear on magnesium stearate. The excessive shear mixing of the lubricant reduces the mechanical strength of the direct compression tablets by producing a surplus coating of the finely divided magnesium stearat...

Background Management of drug–drug interactions (DDIs) for ensitrelvir, a novel 3-chymotrypsin-like protease inhibitor of SARS-CoV-2 infection is crucial. A previous clinical DDI study of ensitrelvir with midazolam, a clinical index cytochrome P450 (CYP) 3A substrate, demonstrated that ensitrelvir given for 5 days orally with a loading/maintenance dose of 750/250 mg acted as a strong CYP3A inhibitor. Objectives The objectives of this study were to investigate the effect of ensitrelvir on the pharmacokinetics of CYP3A substrates, dexamethasone, prednisolone and midazolam, and to assess the pharmacokinetics, safety, and tolerability of ensitrelvir following multiple-dose administration of ensitrelvir. Methods This was a Phase 1, multicenter, single-arm, open-label study in healthy Japanese adult participants. The effects of multiple doses of ensitrelvir in the fasted state on the pharmacokinetics of dexamethasone, prednisolone, and midazolam were investigated. Ensitrelvir was administered from Day 1 through Day 5, with a loading/maintenance dose of 750/250 mg for the dexamethasone and prednisolone cohorts whereas 375/125 mg for the midazolam cohort. Either dexamethasone, prednisolone, or midazolam was administered alone (Day − 2) or in combination with ensitrelvir (Day 5) in each of the cohorts. Additionally, dexamethasone or prednisolone was administered on Days 9 and 14. The pharmacokinetic parameters of ensitrelvir, dexamethasone, prednisolone, and midazolam were calculated based on their plasma concentration data with non-compartmental analysis. In safety assessments, the nature, frequency, and severity of treatment-emergent adverse events were evaluated and recorded. Results The area under the concentration-time curve (AUC) ratio of dexamethasone on Day 5 was 3.47-fold compared with the corresponding values for dexamethasone alone on Day − 2 and the effect diminished over time after the last dose of ensitrelvir. No clinically meaningful effect was observed for prednisolone. The AUC ratio of midazolam was 6.77-fold with ensitrelvir 375/125 mg suggesting ensitrelvir at 375/125 mg strongly inhibits CYP3A similar to that at 750/250 mg. No new safety signals with ensitrelvir were reported during the study. Conclusion The inhibitory effect for CYP3A was confirmed after the last dose of ensitrelvir, and the effect diminished over time. In addition, ensitrelvir at 375/125 mg showed CYP3A inhibitory potential similar to that at 750/250 mg. These findings can be used as a clinical recommendation for prescribing ensitrelvir with regard to concomitant medications. Clinical Trial Registration Japan Registry of Clinical Trials identifier: jRCT2031210202. Supplementary Information The online version contains supplementary material available at 10.1007/s40261-023-01265-8.

Drug‐drug interaction potentials of ensitrelvir, a novel oral inhibitor of 3C‐like protease of severe acute respiratory syndrome coronavirus 2, for drug transporters were evaluated by in vitro and clinical studies. The target drug transporters assessed were P‐glycoprotein (P‐gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, and multidrug and toxin extrusion 1 and 2K. In vitro study revealed that ensitrelvir is a substrate for P‐gp and BCRP and inhibits P‐gp, BCRP, OATP1B1, OATP1B3, OCT1, and OAT3. Based on these results, a clinical drug‐drug interaction study to evaluate the effect of ensitrelvir on the pharmacokinetics of P‐gp, BCRP, OATP1B1, OATP1B3, and OCT1 substrates was conducted with a cocktail approach using digoxin (P‐gp substrate), rosuvastatin (BCRP, OATP1B1, and OATP1B3 substrate), and metformin (OCT1 substrate). The cocktail was administered first, and after the washout period, the cocktail was coadministered with 500 mg of ensitrelvir. No treatment‐emergent adverse events were observed. Pharmacokinetic analyses demonstrated that the ratios (90% confidence intervals) of “cocktail with ensitrelvir” to “cocktail without ensitrelvir” for maximum plasma concentration and area under the plasma concentration–time curve were, respectively, 2.17 (1.72‐2.73) and 1.31 (1.13‐1.52) for digoxin, 1.97 (1.73‐2.25) and 1.65 (1.47‐1.84) for rosuvastatin, and 1.03 (0.91‐1.16) and 1.02 (0.94‐1.11) for metformin. The results indicate that the exposure levels of digoxin and rosuvastatin increased when coadministered with ensitrelvir, but those of metformin were not changed. In conclusion, ensitrelvir has an impact on the exposure levels of P‐gp, BCRP, OATP1B1, and OATP1B3 substrates.