RESUMO
Sotatercept is a breakthrough, first-in-class biologic, that is FDA-approved for the treatment of pulmonary arterial hypertension (PAH). A population pharmacokinetic (PopPK) model was developed using data from two phase 1 studies in healthy participants, and two phase 2 studies and one phase 3 study in participants with PAH. The pooled sotatercept PK data encompassed single intravenous (IV) or subcutaneous (SC) doses ranging from 0.01 to 3.0 mg/kg, as well as multiple SC doses ranging from 0.03 to 1.0 mg/kg, with PK samples collected up to a maximum of ~150 weeks following Q3W and Q4W dosing regimens. The final PopPK analysis included 350 participants, with 30 and 320 participants receiving sotatercept IV and SC, respectively. A two-compartment model with a first-order absorption rate constant and a linear disposition from central compartment well-described sotatercept PK. The estimated bioavailability is ~66%; bioavailability, clearance (CL), and central volume (VC) have low to moderate inter-individual variability. Time-varying body weight and baseline albumin concentration were statistically significant predictors of PK; CL and VC were predicted to increase with increasing body weight, while CL was predicted to decrease with increasing baseline albumin concentration. However, the magnitude of covariate effects is not predicted to meaningfully alter the disposition of sotatercept. Altogether, the PopPK modeling results demonstrate favorable PK characteristics (low to moderate variability and typical bioavailability), supporting sotatercept as a SC biological agent for the treatment of patients with PAH.
RESUMO
The objective of this research was to investigate the presence of a specialized carrier-mediated system for biotin and delineate uptake mechanism and intracellular trafficking of biotin in the human derived retinoblastoma cell line (Y-79). Human derived retinoblastoma cell line, Y-79, was used for uptake studies. Uptake of [3H]Biotin was determined at various concentrations, pH, temperatures, in the absence of sodium and in the presence of other vitamins and metabolic inhibitors to delineate the mechanism of uptake. Uptake was determined in the presence of various intracellular regulatory pathways (protein kinase A & C, protein tyrosine kinase and calcium-calmodulin) modulators. Reverse transcription polymerase chain reaction (RT-PCR) was performed to confirm the molecular identity of human sodium-dependent multivitamin transporter (hSMVT). Uptake of [3H]Biotin in Y-79 cells were found to be saturable at micromolar concentration range, with apparent Km of 8.53 microM and Vmax of 14.12 pmol/min/mg protein, but linear at nanomolar concentration range. Uptake was sodium, pH, temperature and energy-dependent, but chloride independent; inhibited by the structural analogue desthiobiotin, pantothenic acid and lipoic acid at milimolar concentrations and not at nanomolar concentrations. Uptake of [3H]Biotin was trans-stimulated by the intracellular biotin. Ca2+/calmodulin pathways appeared to play important roles in the regulation of riboflavin uptake in Y-79 cells via significant reduction in Vmax (66%) and Km (28%) of the uptake process. A human sodium-dependant multivitamin transporter, hSMVT, was identified by RT-PCR in Y-79. These studies demonstrated for the first time the existence of a human sodium dependant multivitamin transporter (hSMVT), a specialized carrier-mediated system for biotin uptake, in human derived retinoblastoma cells.