Datopotamab Deruxtecan, a Novel TROP2-directed Antibody-drug Conjugate, Demonstrates Potent Antitumor Activity by Efficient Drug Delivery to Tumor Cells.

Trophoblast cell surface antigen 2 (TROP2) is highly expressed on various epithelial tumors and correlates with poor prognosis. We developed the novel TROP2-directed antibody-drug conjugate (ADC), datopotamab deruxtecan (Dato-DXd, DS-1062a), with a potent DNA topoisomerase I inhibitor (DXd), and evaluated its antitumor activity and safety profiles in preclinical models.The pharmacologic activity and mechanism of action of Dato-DXd were investigated in several human cancer cell lines and xenograft mouse models including patient-derived xenograft (PDX) models. Safety profiles were also assessed in rats and cynomolgus monkeys.Dato-DXd bound specifically to TROP2 and was internalized into tumor cells followed by intracellular trafficking to lysosome and DXd release, which induced DNA damage and apoptosis in TROP2-expressing tumor cells in vitro. Dato-DXd exhibited in vivo antitumor activity with DNA damage induced by the accumulated DXd in TROP2-expressing xenograft tumors, but neither isotype control IgG-ADC nor anti-TROP2 antibody had this effect. Dato-DXd also showed potent antitumor activity with tumor regression in several TROP2-expressing xenograft tumors including NSCLC PDX models. Safety profiles of Dato-DXd in rats and cynomolgus monkeys were acceptable.Dato-DXd demonstrated potent antitumor activity against TROP2-expressing tumors by efficient payload delivery into tumors and acceptable safety profiles in preclinical models. These results suggest Dato-DXd could be a valuable treatment option for patients with TROP2-expressing tumors in the clinical setting.

In vitro and in vivo metabolism of a novel chymase inhibitor, SUN13834, and the predictability of human metabolism using mice with humanized liver.

1. A novel oral chymase inhibitor, SUN13834, is under clinical development for the treatment of atopic dermatitis (AD). In this study, in vitro and in vivo metabolic profiles of SUN13834 were compared between severe combined immunodeficiency (SCID) mice, chimeric mice with humanized liver and humans. 2. In in vitro experiments using liver microsomes, predominant metabolites of SUN13834 were glucuronide (MG-1) in SCID mice and hydroxylated metabolite (M-3) in chimeric mice and humans. 3. After a single oral dose of [(14)C]SUN13834 to SCID and chimeric mice, glucuronidation was the major metabolic pathway in SCID mice, while the parent compound, ring opening form (M-5), O-demethylated form of M-5 (M-6) and glucuronidation of M-6 (M-6G) were detected at higher levels in chimeric mice compared to SCID mice. 4. When AD patients were orally treated using SUN13834 for 28 days, the parent compound had the highest concentration in plasma, and M-6, M-6G, M-5 and MG-1 were identified as major metabolites. 5. This is the first report of SUN13834 metabolic information in human. In addition, based on similarities in metabolic profiles between chimeric mice and humans, it was concluded that chimeric mice are useful for predicting SUN13834 metabolism in humans during early stages of drug development.

Effect of renal impairment on the pharmacokinetics of memantine.

The effect of renal impairment on the pharmacokinetics of a single oral dose of memantine (10 mg) was determined in Japanese subjects. Subjects were assigned to four groups based on baseline creatinine clearance (CL(CR)): normal renal function (> 80 mL/min, n = 6), and mild (50 to ≤ 80 mL/min, n = 6), moderate (30 to < 50 mL/min, n = 6), and severe renal impairment (5 to < 30 mL/min, n = 7). Mean memantine maximum plasma concentration (C(max)) was similar in the groups (12.66, 17.25, 15.75, and 15.83 ng/mL, respectively), as was mean time to C(max) (6.2, 5.2, 4.3, and 5.4 h, respectively). However, exposure to memantine determined from mean area under the plasma concentration-time curve was 1.62-, 1.97-, and 2.33-times higher in subjects with mild, moderate, and severe renal impairment, respectively, as compared to controls with normal renal function. Mean memantine plasma elimination half-life increased according to increasing renal impairment (61.15, 83.00, 100.13, and 124.31 h, respectively), while mean cumulative urinary recovery of unchanged memantine in 72 h after dosing decreased according to increasing renal impairment (33.68%, 33.47%, 23.60%, and 16.17%, respectively). These results are the same as those in the previous study on caucasian individuals, when compared per body weight. It is suggested that the dose of memantine should be halved in patients with renal impairment.

Population pharmacokinetics of the selective serotonin 5-HT1A receptor partial agonist piclozotan.

BACKGROUND/AIMS: Serotonin (5-HT) and its receptors are known to play important roles in various physiological and pathophysiological processes. The 5-HT1A receptor subtype is thought to be involved in psychiatric disorders, immunomodulation, and in cerebral ischemic conditions. Piclozotan, a selective and potent partial agonist of 5-HT1A, has been shown to be neuroprotective against ischemic neuronal damage in animal models. Its pharmacokinetics (PK), tolerability, and safety have been evaluated in patients with acute ischemic stroke. The aim of the study was to describe piclozotan PK, using population PK modeling. METHODS: A total of 1308 plasma piclozotan concentration measurements from 84 healthy subjects and 412 plasma piclozotan measurements from 74 stroke patients were included in the analysis. Covariates considered during the model building process included disease status, age, weight, sex, smoking status, and alcohol consumption. Data were analyzed using nonlinear mixed-effects modeling with the NONMEM software system. The final model was qualified via predictive check and nonparametric bootstrap procedures. RESULTS: Piclozotan PK was well described using a 3-compartment model with first-order elimination. Parameter estimates (intersubject variability) were V1, central volume: 64.0 L (66.5%) and CL, systemic clearance: 18.0 L/h (31.4%). Peripheral volumes (V2, V3) were related to total body weight, whereas CL was related to ideal body weight. Clearance decreased with advancing age, yielding a decrease of 35%-65% in patients aged 70-90. There was no discernable difference in PK between healthy subjects and stroke patients. CONCLUSIONS: Piclozotan disposition was well described by the population model, and the intersubject variability around the estimated parameters was moderate in magnitude (<60%). The population PK analysis of piclozotan allows for characterization of piclozotan exposure in individual subjects based on their age and body weight. The availability of a population PK model will facilitate dose optimization and further clinical development of piclozotan.