Principal Scientist Certara, Simcyp Sheffield, England, United Kingdom
Background: Venlafaxine is an antidepressant prescribed for major depression disorder. Both venlafaxine and its metabolite, O-desmethylvenlafaxine (ODV), which demonstrate similar antidepressant efficacy, are excreted into breast milk with mean milk-to-plasma ratios of 2.69 and 2.82, respectively. The FDA and EMA recommend that when prescribing venlafaxine to lactating mothers, the potential risks to the infant, the need for treatment, and the benefits of breastfeeding should be considered. Methods: This study utilised established physiologically-based pharmacokinetic (PBPK) models for venlafaxine and ODV to assess the exposure of both moieties in lactating mothers and their breastfed infants, factoring in relevant genetic polymorphisms and ontogenies. Results: Venlafaxine is primarily metabolised to ODV via CYP2D6, with minor contributions from CYP2C9 and CYP2C19. ODV undergoes CYP3A4-mediated metabolism and renal excretion. Clinically observed venlafaxine and ODV levels from therapeutic drug monitoring samples in children aged 12 to 17 years were accurately captured by the models. Predicted exposures of venlafaxine and ODV in lactating mothers and breastfeeding infants aligned with observed data. Established ontogeny functions of CYP2D6, CYP2C9, CYP2C19, CYP3A4, and renal maturation significantly influenced the age-related PK of ODV, but not venlafaxine. Typically, a relative infant dose (RID) of 5%–10% serves as a safety benchmark during breastfeeding. Based on the simulated Cmax of active compounds (venlafaxine plus ODV) in milk, the estimated RID was 1.7% for CYP2D6 extensive metabolisers (EMs), 6.6% for poor metabolisers (PMs), and 10.3% for CYP2D6/2C9/2C19 PMs. While the RID exceeded 10% for nursing mothers who are PMs of CYP2D6/2C9/2C19, it is essential to note that the estimated infant daily dose (IDD) remained substantially below the toxic threshold (10 mg/kg) identified in a retrospective review of the dose-toxicity correlation for venlafaxine in patients aged 7 months to 19 years. The estimated IDD values for total active compounds from nursing mothers identified as CYP2D6 PMs and CYP2D6/2C9/2C19 PMs were 0.24 and 0.35 mg/kg/day, respectively. Conclusion: The findings of this study could help in making informed clinical decisions regarding the safety and appropriateness of venlafaxine treatment in lactating mothers.
