Pharmacokinetics of venlafaxine enantiomers and their metabolites in psoriasis patients

Abstract

Psoriasis is a chronic inflammatory disease associated with several comorbidities, including depression. Previous studies have shown that inflammatory diseases downregulate the expression and suppress activity of CYP isoforms. Venlafaxine (VLX) is an antidepressant metabolized mainly by CYP2D6 to O-desmethylvenlafaxine (ODV), CYP3A to N-desmethylvenlafaxine (NDV), and CYP2D6 and CYP3A to N,O-didesmethylvenlafaxine (DDV). This study evaluated the influence of psoriasis on the enantioselective pharmacokinetics of VLX. Psoriasis patients (n = 13) and healthy volunteers (n = 11) phenotyped as CYP2D6 extensive (EM) or poor metabolizers (n = 1) received a single oral dose of 150 mg racemic VLX. Plasma concentrations of TNF-α, IFN-γ, IL-6, IL-8, and IL-17 cytokines were higher in EM psoriasis patients when compared with healthy volunteers. IL-6 plasma concentrations varied from 0.4 to 12.9 pg/mL (mean, 2.1 pg/mL) in healthy volunteers and from 0.4 to 29.3 pg/mL (mean, 4.2 pg/mL) in psoriatic patients. VLX pharmacokinetics are enantioselective in healthy volunteers and psoriasis patients phenotyped as EM. Higher AUC values for the (S)-VLX, (S)-NDV, and (S)-DDV enantiomers were observed in healthy volunteers, whereas higher AUC values for (S)-VLX and (R)-ODV were found in psoriasis patients phenotyped as EM. Psoriasis does not alter the pharmacokinetics of the VLX enantiomers probably because of the low levels of IL-6 plasma concentrations.

<p>In Vitro and In Vivo Rat Model Assessments of the Effects of Vonoprazan on the Pharmacokinetics of Venlafaxine</p>

“…In the present study, the significant alteration in MR ODV in the presence of 5 and 20 mg/kg vonoprazan suggested that vonoprazan is capable of altering the formation of ODV, which is mainly metabolized by CYP2D6. 15,20 As shown in Figure 5, while the slope of the concentration-time curve was similar in all the rats after oral administration, the coadministration of vonoprazan increased the AUC (0-t) , C max and MR ODV of VEN with a decrease in the total plasma clearance. These results indicate that vonoprazan can reduce the metabolism in the GI tract during the intestinal absorption.…”

“…16 It has been previously established that metabolism of VEN is dominated by CYP2D6 and it is transformed into the active metabolite ODV in the liver, [17][18][19] In addition, CYP3A4/5 also participate partially in the metabolism of VEN. 20 Therefore, VEN is susceptible to CYP450mediated DDI, especially through the CYP2D6 metabolic pathway. 21 In this study, the plasma concentrations of VEN and ODV were significantly elevated, suggesting that vonoprazan causes clinically relevant inhibition of VEN metabolism via CYP3A4 or 2D6.…”

Disease–Drug Interactions in Inflammatory States via Effects on CYP‐Mediated Drug Clearance

“…No meaningful difference in the PK of venlafaxine was observed, presumably because of the low concentrations of IL-6 (and other cytokines) circulating in patients with psoriasis. 25 The magnitude of the change in CYP activity in this article is the same scale as used by the Food and Drug Administration (FDA) for drug index inhibitors. 26 A weak change by an inflammatory disease state is defined as a less than 2-fold shift in the AUC exposure of a sensitive CYP index substrate, and the metabolism of the sensitive substrate is predominantly mediated by a single CYP isoform (eg, midazolam by CYP3A).…”

“…A study of venlafaxine, which is metabolized by CYP2D6 and CYP3A, had its systemic exposure recently compared in psoriasis patients (n = 12) with healthy controls (n = 11). No meaningful difference in the PK of venlafaxine was observed, presumably because of the low concentrations of IL‐6 (and other cytokines) circulating in patients with psoriasis …”

The therapeutic landscape of non‐alcoholic steatohepatitis

“…Venlafaxine‐103 (VLX‐103) is an oral form of pentamidine that exhibits hepatoprotective activity by reducing serum concentration of proinflammatory cytokines, such as tumour necrosis factor (TNF) . VLX‐103 has markedly decreased hepatic steatosis, hepatocyte injury and cell death, and inflammation in experimental models for alcoholic liver disease .…”