Minimally invasive quantification of cerebral P2X7R occupancy using dynamic [F]JNJ-64413739 PET and MRA-driven image derived input function.

[F]JNJ-64413739 has been evaluated as PET-ligand for in vivo quantification of purinergic receptor subtype 7 receptor (P2X7R) using Logan graphical analysis with a metabolite-corrected arterial plasma input function. In the context of a P2X7R PET dose occupancy study, we evaluated a minimally invasive approach by limiting arterial sampling to baseline conditions. Meanwhile, post dose distribution volumes (V) under blocking conditions were estimated by combining baseline blood to plasma ratios and metabolite fractions with an MR angiography driven image derived input function (IDIF).

Translational Model-Informed Dose Selection for a Human Positron Emission Tomography Imaging Study of JNJ-54175446, a P2X7 Receptor Antagonist.

Positron emission tomography (PET) provides useful information in target engagement or receptor occupancy in the brain for central nervous system (CNS) drug development, however, dose selection for human PET studies is challenging and largely empirical. Here, we describe a translational pharmacokinetic/pharmacodynamic (PK/PD) modeling work to inform dose selection for a human PET study of JNJ-54175446, a CNS-penetrating P2X7 receptor antagonist. Models were developed using data on monkey brain occupancy and plasma drug exposures from a monkey PET study and early human clinical studies that provided data on drug exposures and human ex vivo-stimulated peripheral interleukin (IL)-1β release.

Bioequivalence of the Once-Daily Single-Tablet Regimen of Darunavir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide Compared to Combined Intake of the Separate Agents and the Effect of Food on Bioavailability.

The effect of food on the bioavailability of the components of the once-daily, single-tablet human immunodeficiency virus (HIV) type 1 regimen containing darunavir (DRV 800 mg), cobicistat (COBI 150 mg), emtricitabine (FTC 200 mg), and tenofovir alafenamide (TAF 10 mg) (D/C/F/TAF) (NCT02475135) and the bioequivalence of D/C/F/TAF versus combined intake of the separate agents (NCT02578550) were evaluated. These were 2 phase 1, open-label, randomized, 2-period crossover studies (7-day washout between treatments) in HIV-negative healthy volunteers. Twenty-four participants each received a single dose of D/C/F/TAF in fasted conditions (test) or after a standardized high-fat breakfast (reference).

Zoledronic acid treatment of 5T2MM-bearing mice inhibits the development of myeloma bone disease: evidence for decreased osteolysis, tumor burden and angiogenesis, and increased survival.

Multiple myeloma is characterized by the growth of plasma cells in the bone marrow and the development of osteolytic bone disease. Myeloma cells are found closely associated with bone, and targeting this environment may therefore affect both the bone disease and the growth of myeloma cells. We have investigated the effect of the potent bisphosphonate, zoledronic acid, on the development of bone disease, tumor burden, and disease-free survival in the 5T2MM model of myeloma.