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Clinical Pharmacology and Therapeutics May 2024In this study, we aimed to improve upon a published population pharmacokinetic (PK) model for venlafaxine (VEN) in the treatment of depression in older adults, then...
In this study, we aimed to improve upon a published population pharmacokinetic (PK) model for venlafaxine (VEN) in the treatment of depression in older adults, then investigate whether CYP2D6 metabolizer status affected model-estimated PK parameters of VEN and its active metabolite O-desmethylvenlafaxine. The model included 325 participants from a clinical trial in which older adults with depression were treated with open-label VEN (maximum 300 mg/day) for 12 weeks and plasma levels of VEN and O-desmethylvenlafaxine were assessed at weeks 4 and 12. We fitted a nonlinear mixed-effect PK model using NONMEM to estimate PK parameters for VEN and O-desmethylvenlafaxine adjusted for CYP2D6 metabolizer status and age. At both lower doses (up to 150 mg/day) and higher doses (up to 300 mg/day), CYP2D6 metabolizers impacted PK model-estimated VEN clearance, VEN exposure, and active moiety (VEN + O-desmethylvenlafaxine) exposure. Specifically, compared with CYP2D6 normal metabolizers, (i) CYP2D6 ultra-rapid metabolizers had higher VEN clearance; (ii) CYP2D6 intermediate metabolizers had lower VEN clearance; (iii) CYP2D6 poor metabolizers had lower VEN clearance, higher VEN exposure, and higher active moiety exposure. Overall, our study showed that including a pharmacogenetic factor in a population PK model could increase model fit, and this improved model demonstrated how CYP2D6 metabolizer status affected VEN-related PK parameters, highlighting the importance of genetic factors in personalized medicine.
Topics: Aged; Humans; Cyclohexanols; Cytochrome P-450 CYP2D6; Depression; Desvenlafaxine Succinate; Genotype; Phenotype; Venlafaxine Hydrochloride
PubMed: 38284409
DOI: 10.1002/cpt.3162 -
Journal of Pharmacological and... 2024We developed a novel, stress-free blood sampling method for minipigs, allowing continuous cortisol monitoring over 24 h. Baseline cortisol levels exhibited both...
We developed a novel, stress-free blood sampling method for minipigs, allowing continuous cortisol monitoring over 24 h. Baseline cortisol levels exhibited both ultradian and diurnal rhythms. During nighttime, smaller ultradian rhythms overlaid a lower baseline cortisol, which increased in sleeping pigs before lights were turned on. Additionally, we developed an analytical tool based on the R package "pracma" to quantify ultradian peak and circadian components of the cortisol profiles. To validate our model, we investigated the effects of Verucerfont, a CRH receptor antagonist, and Venlafaxine, a serotonin-norepinephrine reuptake inhibitor. Verucerfont reduced cortisol levels during the first 9 h without affecting diurnal rhythm. Cortisol peak parameters decreased, with a 31% reduction in overall area under the curve (AUC) and a 38% reduction in ultradian average AUC. Ultradian peaks decreased from 7 to 4.5, with 34% lower amplitude. Venlafaxine maintained plasma concentrations within the targeted human effective range. This method enables us to enhance our understanding of cortisol regulation and provide valuable insights for the impact of investigation drugs on the diurnal and ultradian rhythms of cortisol.
Topics: Animals; Swine, Miniature; Swine; Hydrocortisone; Circadian Rhythm; Venlafaxine Hydrochloride; Ultradian Rhythm; Blood Specimen Collection; Area Under Curve; Male; Female
PubMed: 38678804
DOI: 10.1016/j.vascn.2024.107504 -
The Journal of Emergency Medicine May 2024
Topics: Humans; Venlafaxine Hydrochloride; Electrocardiography; Epilepsy; Long QT Syndrome; Antidepressive Agents, Second-Generation; Male; Female; Seizures; Adult
PubMed: 38763732
DOI: 10.1016/j.jemermed.2023.11.027 -
Die Anaesthesiologie Jun 2024
Topics: Humans; Venlafaxine Hydrochloride; Heart Arrest; Extracorporeal Membrane Oxygenation; Male; Female; Adult
PubMed: 38717642
DOI: 10.1007/s00101-024-01412-6