Model-Based Analysis of the Influence of Alcohol Use and Age on Pharmacokinetics-Pharmacodynamics of Oral Oxycodone in Middle-Age and Older Community-Dwelling Adults.

Little is known about how opioid responses vary by age and in the presence of alcohol consumption. This model-based pharmacokinetic (PK)-pharmacodynamic (PD) analysis quantified the impact of age and alcohol use on pupillometry and cold pressor test (CPT) PD based on data from an open-label study of a single, immediate-release 10-mg oral oxycodone in middle-age and older adults (aged 35-85) without severe functional limitations. PK and pupillometry assessments were obtained on 11 occasions over 8 hours. Cold pressor test was administered at 1.5, 5, and 8 hours after oxycodone dosing. The study population consisted of 62 older adults (aged ≥60) and 66 middle-aged adults (aged 35-59), with 82% meeting the unhealthy drinking criteria. Oral oxycodone PK were well described using a 1-compartment model with a sequential 0 to first-order absorption process. Inhibitory maximum effect and linear direct effect PD models described the respective pupillometry and cold pressor test data using simultaneous PK-PD analysis in MONOLIX. Recent alcohol use measures were selected a priori as covariates. This analysis demonstrated an influence of age on clearance and body weight on the distribution volume of oxycodone; alcohol consumption was not noted to alter oxycodone PK. Oxycodone pupillometry PD were influenced by the level of subject-reported alcohol consumption (Alcohol Use Disorders Identification Test for Consumption), alcohol use biomarker-blood phosphatidylethanol, previous cannabis use, and age. Over the opioid exposure range of the study, none of the covariables including alcohol and age were noted to affect cold pressor test pharmacodynamics. Additional clinical studies are needed to further investigate the clinical consequences of opioid-alcohol-age interaction.

Kinetics of B, CD4 T, and CD8 T cells infused into humans: estimates of intravascular:extravascular ratios and total body counts.

Little is known about the rate of T and B cell traffic from blood to extravascular compartments or about the steady-state distribution of T and B cells between intravascular and extravascular compartments in humans. We quantitated circulating T and B cell subsets before and during the first 24 h after the infusion of an allogeneic or syngeneic peripheral blood stem cell graft (containing approximately 10(10) lymphocytes) into 10 patients conditioned with chemotherapy and/or total body irradiation. For all lymphocyte subsets measured, <15% of the infused cells were present in the blood at the end of the 0.5-h infusion and <3% of the infused cells were present in the blood 1 h later. Thereafter, CD4 T cell counts plateaued at approximately 1% and CD8 T cell counts at < or = 0.4% of the infused cells, whereas B cell counts declined slowly (1.5% of the infused B cells were present in the blood at 2 h and 0.3% at 24 h postinfusion). We conclude that the rate of lymphocyte traffic from blood to extravascular spaces can be extraordinary (approximately 10(10) lymphocytes can leave blood within 0.5 h) and that at steady state the blood contains approximately 1% total body CD4 T cells, < or = 0.4% total body CD8 T cells, and approximately 1.4% total body B cells. By inference, an average-size person may carry a total of approximately 4.1 x 10(11) CD4 T cells, > or = 4.5 x 10(11) CD8 T cells, and approximately 1.0 x 10(11) B cells.