Kyoko Matsuguma

Efficacy of a novel phosphodiesterase inhibitor, E6005, in patients with atopic dermatitis: An investigator-blinded, vehicle-controlled study

Abstract Introduction: Phosphodiesterase type 4 (PDE4) inhibition is a well-known anti-inflammatory mechanism. However, the clinical use of PDE4 inhibitors has been compromised by the occurrence of mechanism-associated adverse reactions, which often limit the maximum tolerated dose. To minimize systemic exposure, a topically active PDE4 inhibitor with low transdermal bioavailability could be clinically useful. The purpose of this study was to evaluate the efficacy of a novel topical PDE4 inhibitor, E6005, in patients with atopic dermatitis. Methods: This randomized, investigator-blinded, vehicle-controlled, multiple ascending dose study included 40 adult male patients with atopic dermatitis, who were randomly assigned to 10 days of treatment with either E6005 ointment (0.01, 0.03, 0.1 or 0.2%) or vehicle ointment. Results: Of 81 patients screened, 40 who had typical lesions on their posterior trunk were randomized into the study. One patient receiving 0.03% E6005 treatment discontinued because of acute gout and one receiving vehicle treatment discontinued because of progression of atopic dermatitis. The targeted lesion severity scores decreased in a concentration-dependent manner in patients treated with E6005. This drop was significant in the 0.2% E6005 ointment treatment group (mean percent change: −54.30%, p = 0.007). Conclusion: E6005 ointment showed anti-inflammatory efficacy in adult patients with atopic dermatitis.

Mechanisms of pharmacokinetic enhancement between ritonavir and saquinavir; micro/small dosing tests using midazolam (CYP3A4), fexofenadine (p-Glycoprotein), and pravastatin (OATP1B1) as probe drugs

We investigated the mechanisms of ritonavir‐mediated enhancement effect on the pharmacokinetics of saquinavir using in vivo probes for CYP3A4 (midazolam), p‐glycoprotein (fexofenadine), and OATP1B1 (pravastatin) following oral micro/small dosing. A cocktail of the drugs (2 mg of saquinavir, 100 µg of each probe) was administered to eight healthy volunteers (phase 1), and then coadministered with 20 mg (phase 2) and 100 mg (phase 3) of ritonavir. Plasma concentrations of the drugs were measured by validated LC–MS/MS methods. The mean plasma AUC0–24 (pg hour/mL) of saquinavir at phases 1, 2, and 3 was 101, 2 540, and 23 900 (P < .01), respectively. The relative area under the plasma concentration‐time curve (AUC)0–24 ratios of midazolam and fexofenadine at phases 1, 2, and 3 were 1:5.9:14.7 (P < .01), and 1:1.4:2.2 (P < .01–.05), respectively. In contrast, there was no difference in the pharmacokinetics of pravastatin. Inhibition of intestinal and hepatic CYP3A‐mediated metabolism, and intestinal p‐glycoprotein‐mediated efflux of saquinavir, but not OATP1B1, is involved in the enhancement mechanism. Micro/small dosing is useful for examining the mechanism of drug interactions without safety concern.

Pharmacogenomic/pharmacokinetic assessment of a four-probe cocktail for CYPs and OATPs following oral microdosing.

OBJECTIVES To test whether the multiple phenotype and genotype relationships established using therapeutic dose, can be reproduced following oral microdosing using substrates of CYP2C9 (warfarin and glibenclamide), CYP2C19 (lansoprazole), CYP2D6 (dextromethorphan), and OATPs (glibenclamide). METHODS A cocktail of test drugs was administered orally under the microdose in liquid or capsule form, and then a therapeutic dose of dextromethorphan was administered to 17 healthy subjects whose genotypes for CYPs and OATPs had been prescreened. Concentrations of the drugs and their metabolites were measured by LC-MS/MS. RESULTS The AUC and t1/2 of glibenclamide following the microdosing tended to be higher and longer, respectively, in CYP2C9*1/*3 than CYP2C9*1/*1 subjects. In contrast, there were no significant differences in any of the pharmacokinetic parameters for warfarin between the two genotypes. For CYP2D6 following the therapeutic dose, there was good concordance between genotype and phenotype; however, such relationships disappeared after microdosing. For CYP2C19 following the microdosing, there were significant differences between EMs and PMs in the pharmacokinetic parameters of lansoprazole. The relative AUC0-12 ratio of lansoprazole in EMs and PMs was 1:3.3 - 4.3. Among test drugs, phenotypic measurements of lansoprazole accorded well with the CYP2C19 genotype at the microdose as well as therapeutic dose. CONCLUSIONS The present study suggests that 1) the sampling strategy should be optimized according to pharmacokinetic profiles of the test drugs following oral microdosing, and 2) microdosing can be applied to the pharmacogenomic study of CYP-specific drugs.

BACE1 Inhibitor Lanabecestat (AZD3293) in a Phase 1 Study of Healthy Japanese Subjects: Pharmacokinetics and Effects on Plasma and Cerebrospinal Fluid Aβ Peptides

Lanabecestat (AZD3293; LY3314814) is an orally active potent inhibitor of human β‐secretase 1 in clinical development for the treatment of Alzheimer disease. In this first Japanese clinical study for an Alzheimer disease intervention to include cerebrospinal fluid (CSF) sampling in Japanese elderly healthy subjects, we report the pharmacokinetics and effects on plasma and CSF amyloid‐β (Aβ) peptides of lanabecestat in a phase 1 study involving 40 healthy Japanese subjects (NCT02005211). No safety and tolerability concerns were identified in healthy Japanese subjects exposed to lanabecestat up to the highest doses given, which is consistent with observations in a US phase 1 study of lanabecestat. Exposure to lanabecestat was similar for young and elderly subjects and increased in a dose‐dependent manner. For elderly subjects, plasma lanabecestat half‐life after multiple dosing was 12 to 17 hours (on days 10 and 14). Robust plasma and CSF Aβ peptide reductions were also seen at all doses, with CSF Aβ42 concentrations reduced by 63% and 79% in the 15‐ and 50‐mg lanabecestat groups, respectively. CSF soluble amyloid‐β precursor protein β also decreased following lanabecestat treatment. Suppression of CSF Aβ peptides was similar in elderly healthy Japanese subjects and US patients with mild to moderate Alzheimer disease. Lanabecestat is a promising potentially disease‐modifying treatment in phase 3 development for patients with early Alzheimer disease.

Recapitulation of Clinical Individual Susceptibility to Drug-Induced QT Prolongation in Healthy Subjects Using iPSC-Derived Cardiomyocytes

Summary To predict drug-induced serious adverse events (SAE) in clinical trials, a model using a panel of cells derived from human induced pluripotent stem cells (hiPSCs) of individuals with different susceptibilities could facilitate major advancements in translational research in terms of safety and pharmaco-economics. However, it is unclear whether hiPSC-derived cells can recapitulate interindividual differences in drug-induced SAE susceptibility in populations not having genetic disorders such as healthy subjects. Here, we evaluated individual differences in SAE susceptibility based on an in vitro model using hiPSC-derived cardiomyocytes (hiPSC-CMs) as a pilot study. hiPSCs were generated from blood samples of ten healthy volunteers with different susceptibilities to moxifloxacin (Mox)-induced QT prolongation. Different Mox-induced field potential duration (FPD) prolongation values were observed in the hiPSC-CMs from each individual. Interestingly, the QT interval was significantly positively correlated with FPD at clinically relevant concentrations (r > 0.66) in multiple analyses including concentration-QT analysis. Genomic analysis showed no interindividual significant differences in known target-binding sites for Mox and other drugs such as the hERG channel subunit, and baseline QT ranges were normal. The results suggest that hiPSC-CMs from healthy subjects recapitulate susceptibility to Mox-induced QT prolongation and provide proof of concept for in vitro preclinical trials.

A comparative pharmacokinetic and pharmacodynamic study of FSK0808 versus reference filgrastim after repeated subcutaneous administration in healthy Japanese men

FSK0808, a biosimilar of filgrastim, is a recombinant human granulocyte colony‐stimulating factor developed by Fuji Pharmaceuticals and Mochida Pharmaceutical Co., Ltd. We conducted a double‐blind, randomized, crossover study in healthy Japanese men, comparing the number of CD34‐positive cells (CD34+ cells) after repeated subcutaneous administration of either FSK0808 or the reference filgrastim (Gran®). As primary endpoints, we compared the maximum number of CD34+ cells (CD34+ Cmax) and the time to reach CD34+ Cmax (CD34+ tmax). As secondary endpoints, we compared the area under the curve for the number of CD34+ cells over time at the 410 hours time point (CD34+ AUC0–410), the parameters used to calculate the pharmacodynamic index of the absolute neutrophil count, and the pharmacokinetic parameters. Regarding the CD34+ Cmax and the CD34+ AUC0–410 values, the 95% confidence interval (CI) of the differences between the mean values for each drug was within the range of log(0.8)–log(1.25). With respect to the differences in the median values between drugs, the ratio against the reference filgrastim median value in the 95% CI was within the range of ± 0.2 for the CD34+ tmax value. From these results, we considered that these drugs display equivalent pharmacodynamic and pharmacokinetic properties.

Pharmacokinetics and pharmacodynamics of FSK0808 and Gran after single intravenous drip administration or single subcutaneous administration: comparative study in healthy Japanese adult male subjects.

Abstract FSK0808 is a recombinant human granulocyte colony-stimulating factor developed by Fuji Pharma Co., Ltd and Mochida Pharmaceutical Co., Ltd. as a biosimilar product of Gran®. We verified the pharmacokinetic/pharmacodynamic equivalence of FSK0808 and commercially available Gran® by a randomized crossover study of single intravenous dose (200 µg/m2) and single subcutaneous dose (400 µg/m2) in healthy Japanese adult male subjects. According to the bioequivalence guidelines, the area under the blood concentration – time curve by 48 hours after administration (AUC0–48) in a single intravenous drip (IVD) study, and AUC0–48 and maximum blood concentration (Cmax) in a single subcutaneous (SC) dose study were used as primary endpoints, and the pharmacodynamic parameters including absolute neutrophil count (ANC) or number of CD34 positive cells (CD34+ cells) as secondary endpoints. The safety was evaluated based on the characteristics and incidence of adverse reactions. As a result, the 90% confidence interval (CI) of the difference in mean value for AUC0–48 among drugs ranged from log(0.8) to log(1.25), in the IVD study, and those for Cmax and AUC0–48 were within the range of log(0.8)–log(1.25) in the SC study. Those for secondary endpoints were all within the range of log(0.8)–log(1.25). Thus, the pharmacokinetics/pharmacodynamics of both drugs were considered equivalent for all routes of administration, and the profiles of adverse reactions were also very similar.

Evaluation of Assay Sensitivity and the Concentration-Effect Relationship of Moxifloxacin in a QT/QTc Study in Japan

To investigate the potential for a QT/QTc study in Japan, a randomized, single-blind, crossover study was conducted using moxifloxacin in 64 healthy Japanese male volunteers. A 12-lead Holter electrocardiogram was used to test a relatively small population at each of 4 incorporated clinical research units to confirm the assay sensitivity and efficiency. Moxifloxacin (400 mg) significantly prolonged QT intervals, as previously reported, with small variations in this study. In addition, the placebo-adjusted mean QTcF changes from predose baseline showed that the lower bounds of the 1-sided 95% confidence interval exceeded 5 milliseconds at all of the clinical research units. The data also indicated statistically significant concentration-QT relationships in 3 of the 4 research units by separate analysis. These findings and the small amount of variability in this study suggest the feasibility of conducting a high-quality QT/QTc study in Japan.

ASSESSMENT OF THE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND EFFECTS ON PLASMA AND CEREBROSPINAL FLUID AB PEPTIDES OF AZD3293, A NOVEL BACE1 INHIBITOR, IN HEALTHY JAPANESE ADULTS

POSTER PRESENTATIONS P2 P2-001 A PHARMACODYNAMIC STUDY (54861911ALZ1008)WITHABACE INHIBITOR, JNJ54861911 IN JAPANESE ASYMPTOMATIC SUBJECTS AT RISK FOR ALZHEIMER’S DEMENTIA Masayoshi Takahashi, Luc Tritsmans, Hiroko Shimizu, Tomoko Santoh, Ayako Shiraishi, Yushin Tominaga, Johannes Streffer, 1 Janssen Pharm KK Japan, Tokyo, Japan; 2 Janssen Research & Development, Beerse, Belgium. Contact e-mail: MTAKAHA4@its.jnj.com