Influence of the cytochrome P450 2D6 *10/*10 genotype on the pharmacokinetics of paroxetine in Japanese patients with major depressive disorder

Abstract

Unexpectedly, elimination was accelerated in individuals with the CYP2D6*10/*10 genotype. Our results show that the presence of one CYP2D6*5 allele or that of any CYP2D6*10 allele may have no major effect on paroxetine PKs in the steady state.

Pharmacokinetics of immediate and sustained-release formulations of paroxetine: Population pharmacokinetic approach to guide paroxetine personalized therapy in chinese psychotic patients

“…Even if there were errors in the serum sampling time, the trough concentrations’ changes were not significant ( Xiao et al, 2021 ). The absorption rate constant (Ka) was set to previously published values of 0.908/h due to the absence of serum samples throughout the absorption phase ( Venkatakrishnan and Obach, 2005 ; Nishimura et al, 2016 ). Similarly, absorption lag time could not be assessed.…”

“…One of the most potent selective serotonin reuptake inhibitors (SSRIs), paroxetine is frequently prescribed to treat depression, anxiety, panic disorder, and obsessive-compulsive disorder ( Venkatakrishnan and Obach, 2005 ; Nishimura et al, 2016 ). The recommended daily dose of paroxetine is generally 20 mg, which is gradually increased by 10 mg/day (once daily) every week until a maximally tolerated dose is reached ( Nishimura et al, 2016 ). The guidelines from the Arbeitsgemeinschaft für Neuropsychopharmakologie and Pharmakopsychiatri (AGNP) list the therapeutic range as 20–65 ng/ml ( Hiemke et al, 2018 ).…”

“…Paroxetine easily accumulates in vivo after repeated administration, and the pharmacokinetic (PK) characteristics alter with dosage, leading to nonlinear PKs and increased exposure with time ( Bourin et al, 2001 ). For healthy subjects, the overall average half-life of elimination is approximately 21 h ( Nishimura et al, 2016 ). For different formulations, immediate-release paroxetine is rapidly absorbed compared with sustained-release tablets (T max 5.2 versus 8 h) ( Foster and Goa, 1997 ; DeVane, 2003 ; U.S. Food and Drug Administration, 2014 ; U.S. Food and Drug Administration, 2015 ).…”

“…Some studies have suggested that serotonin (5-HT) transporter (SERT) candidate genes (such as SLC6A4 ) and serotonin receptor genes (such as HTRLPR ) may influence paroxetine treatment response ( Wilkie et al, 2009 ; Ishiguro et al, 2011 ; Marazziti et al, 2020 ). The CYP2D6 genetic polymorphism is widely documented as a primary predictor of paroxetine PK variability; thus, most PK studies of paroxetine have focused on the prediction of the paroxetine concentrations and CYP2D6 genotype ( Feng et al, 2006 ; Findling et al, 2006 ; Mikami et al, 2013 ; Nishimura et al, 2016 ). In clinical practice, the purpose of genotyping is to correlate genotypes to individual therapy responses and to alter treatment dosages accordingly.…”

“…Another study of older people evaluated the influence of parameters such as race, sex, age, weight, and CYP2D6 genotypes on paroxetine PKs and discovered that weight and CYP2D6 polymorphisms had an impact on maximum velocity (Vm), whereas sex had an impact on the volume of distribution ( Feng et al, 2006 ). Furthermore, age, weight, sex, CYP2D6 genotypes, and daily dosage were included as variables in a population PK (PPK) analysis of Japanese patients, and sex and genotypes were found to be significant ( Nishimura et al, 2016 ).…”