Dosage Appropriacy Evaluation of Oral Venlafaxine Related to CYP2D6 Genotype Using Physiologically Based Pharmacokinetic (PBPK) Model
Authors: Cho Changkeun 
Published: April 2020

Venlafaxine is an antidepressant drug of serotonin‐norepinephrine reuptake inhibitor (SNRI) class, used major depressive disorder, anxiety, and panic disorder patients. Desvenlafaxine, a major metabolite of venlafaxine mediated by cytochrome P450 2D6 (CYP2D6), is also used to treat depressive, anxiety disorder because it has pharmacological effect which inhibits reuptake of serotonin and norepinephrine. Therefore, sum of venlafaxine and desvenlafaxine concentration is important for adequate prediction of the drug response of venlafaxine. Venlafaxine is administrated 75mg/day conventionally, 225mg/day maximum. Venlafaxine is minorly metabolized to N‐desmethyl venlafaxine, and desvenlafaxine is metabolized to N, O‐didesmethyl venlafaxine, both compounds are inactive forms pharmacologically. Because CYP2D6*10 decreases its enzyme activity, and CYP2D6*4, CYP2D6*5 abolish its enzyme activity, the pharmacokinetics of venlafaxine and desvenlafaxine are considerably affected by CYP2D6 polymorphism. For an accurate evaluation of drug response followed CYP2D6 genotypes in venlafaxine and its metabolite, physiologically based pharmacokinetic (PBPK) model was used for concentration simulation of both compounds. In our study, we did an extensive investigation of literature and gathered pharmacokinetic profile data of venlafaxine and its metabolite. Through Engauge Digitizer®, pharmacokinetic profiles were extracted and converted to numerical values. For model development and verification, PK‐Sim® 8 software was used to get simulated values of pharmacokinetic parameters. Physiological and chemical parameters were inputted, and Vmax, Km values were adjusted to reflect the CYP2D6 enzyme activity difference. Extracted data and simulated data were compared using two‐fold error criteria. The ratio of simulated data and observed data in CYP2D6*1/*1, CYP2D6*1/*10, CYP2D6*10/*10, CYP2D6*5/*5 groups for AUC were 0.88, 1.24, 1.15, 0.72, Cmax were 0.80, 1.24, 1.14, 1.33, Tmax were 0.93, 0.87, 0.87, 0.87. All simulated data for model development were within suitable criteria, and data conducted diverse ethnic and dose for verification also were within criteria. Thus, it was confirmed that the PBPK model of venlafaxine and its metabolite had been properly developed. Based on the above model, we simulated blood concentration at 75mg, 150mg, 225mg dose, evaluated therapeutic effects and toxicity. In CYP2D6*1/*1, CYP2D6*1/*10, CYP2D6*10/*10 groups, the concentrations of active moiety were similar, but CYP2D6 PM was significantly increased. Because toxicity level was reached after 150mg administration of venlafaxine in CYP2D6 PM, dose reduction is mandatory required. In the future, through PBPK modeling, the adequacy of conventional dose of other drugs should be assessed, and individual dose adjustment will be made for maximum therapeutic effects and minimal toxicities.

Development of PBPK model in venlafaxine and its metabolite according to CYP2D6 genotype. (A) CYP2D6*1/*1 (B) CYP2D6 PM (C) CYP2D6*1/*10 (D) CYP2D6*10/*10

Figure 1

venlafaxine 75mg dosage evaluation based on CYP2D6 genotype. dotted lines represent concentrations of optimal therapeutic response

Figure 2