Population Pharmacokinetic Analysis of R- and S-Fluoxetine and Norfluoxetine in Children and Adolescents
Presenter Status
Post-Doctorial Research
Abstract Type
Translational Research
Primary Mentor or Principal Investigator
Laura B Ramsey
Presentation Type
Poster
Start Date
19-5-2026 12:00 PM
End Date
19-5-2026 1:00 PM
Abstract Text
Background: Fluoxetine is a commonly prescribed selective serotonin reuptake inhibitor in children and adolescents. It is administered as a racemate where the R- and S-enantiomers differ in pharmacological activity and metabolism. Additionally, fluoxetine and its primary metabolite, norfluoxetine, contribute to overall therapeutic effects. S-fluoxetine is primarily metabolized by CYP2D6 to form S-norfluoxetine, while R-fluoxetine is metabolized by CYP2D6, CYP2C9, and CYP2C19 to form R-norfluoxetine. These enzymes are highly polymorphic, and the combination of alleles an individual carries corresponds to a metabolizer phenotype, such as CYP2D6 poor (PM), intermediate (IM), normal (NM), and ultrarapid metabolizers (UM). Further, fluoxetine and norfluoxetine are strong CYP2D6 inhibitors that cause auto-inhibition and phenoconversion, a process where functional enzymatic activity is assumedly reduced to PM levels regardless of genotype. Previous population pharmacokinetic (PK) models have described total fluoxetine and norfluoxetine exposure but have not considered PK differences for each enantiomer. This gap may obscure important differences in exposure-response relationships and highlights the need for enantioselective PK models to better characterize fluoxetine disposition in pediatric patients.
Objectives/Goal: To develop a population parent-metabolite PK model of R- and S-fluoxetine and norfluoxetine in children and adolescents.
Methods/Design: Data were obtained from an open-label prospective study of participants (6-18 years old) prescribed fluoxetine. After two weeks of adherence monitoring, participants completed a 24-hour PK study visit where ≤18 blood samples were collected across the dosing interval. Fluoxetine and norfluoxetine plasma concentrations for each enantiomer were measured using liquid chromatography with tandem mass spectrometry. Participant demographics, clinical, and pharmacogenetic results for CYP2D6, CYP2C19, and CYP2C9 were collected. Population PK analysis was performed using NONMEM. Covariate analysis was performed using a stepwise approach and considered age, sex, weight, and CYP2D6, CYP2C19, and CYP2C9 phenotype.
Results: A total of 814 samples (n=204 for each fluoxetine enantiomer, n=203 for each norfluoxetine enantiomer) from 13 individuals (median age: 17.1 (8.8-18.7), 62% female) were included. This included 2 CYP2D6 PMs, 5 IMs, 4 NMs, and 2 UMs. A one-compartment model with first-order absorption, lag time, first-pass effect, and first-order formation of the metabolite best described both enantiomers. R-fluoxetine exhibited 5-fold faster clearance (16.4 vs 3.51 L/h/70kg) and 3-fold larger volume of distribution (935 vs 282 L/70kg) compared to S-fluoxetine. Similarly, R-norfluoxetine clearance was 3-fold faster than S-norfluoxetine (18.9 vs 6.12 L/h/70kg). CYP2D6 phenotype significantly influenced S-norfluoxetine formation, with PMs having an 80% reduction, IMs a 45% reduction, and UMs a 63% increase relative to NMs. CYP2D6, CYP2C9, or CYP2C19 phenotypes did not influence R-norfluoxetine formation.
Conclusions: This is the first population PK model describing R- and S-fluoxetine and norfluoxetine. Enantioselective differences in the PK of fluoxetine and norfluoxetine were observed. S-fluoxetine to S-norfluoxetine biotransformation differed by CYP2D6 phenotype, which aligns with stereoselective CYP2D6 metabolism of S-fluoxetine and suggests incomplete phenoconversion. CYP2D6, CYP2C19, or CYP2C9 phenotypes did not affect R-fluoxetine metabolism, which could be due to the involvement of multiple enzymatic pathways. By characterizing enantioselective PK and metabolism, this model will enable more accurate predictions to support precision dosing strategies for fluoxetine in children and adolescents.
Population Pharmacokinetic Analysis of R- and S-Fluoxetine and Norfluoxetine in Children and Adolescents
Background: Fluoxetine is a commonly prescribed selective serotonin reuptake inhibitor in children and adolescents. It is administered as a racemate where the R- and S-enantiomers differ in pharmacological activity and metabolism. Additionally, fluoxetine and its primary metabolite, norfluoxetine, contribute to overall therapeutic effects. S-fluoxetine is primarily metabolized by CYP2D6 to form S-norfluoxetine, while R-fluoxetine is metabolized by CYP2D6, CYP2C9, and CYP2C19 to form R-norfluoxetine. These enzymes are highly polymorphic, and the combination of alleles an individual carries corresponds to a metabolizer phenotype, such as CYP2D6 poor (PM), intermediate (IM), normal (NM), and ultrarapid metabolizers (UM). Further, fluoxetine and norfluoxetine are strong CYP2D6 inhibitors that cause auto-inhibition and phenoconversion, a process where functional enzymatic activity is assumedly reduced to PM levels regardless of genotype. Previous population pharmacokinetic (PK) models have described total fluoxetine and norfluoxetine exposure but have not considered PK differences for each enantiomer. This gap may obscure important differences in exposure-response relationships and highlights the need for enantioselective PK models to better characterize fluoxetine disposition in pediatric patients.
Objectives/Goal: To develop a population parent-metabolite PK model of R- and S-fluoxetine and norfluoxetine in children and adolescents.
Methods/Design: Data were obtained from an open-label prospective study of participants (6-18 years old) prescribed fluoxetine. After two weeks of adherence monitoring, participants completed a 24-hour PK study visit where ≤18 blood samples were collected across the dosing interval. Fluoxetine and norfluoxetine plasma concentrations for each enantiomer were measured using liquid chromatography with tandem mass spectrometry. Participant demographics, clinical, and pharmacogenetic results for CYP2D6, CYP2C19, and CYP2C9 were collected. Population PK analysis was performed using NONMEM. Covariate analysis was performed using a stepwise approach and considered age, sex, weight, and CYP2D6, CYP2C19, and CYP2C9 phenotype.
Results: A total of 814 samples (n=204 for each fluoxetine enantiomer, n=203 for each norfluoxetine enantiomer) from 13 individuals (median age: 17.1 (8.8-18.7), 62% female) were included. This included 2 CYP2D6 PMs, 5 IMs, 4 NMs, and 2 UMs. A one-compartment model with first-order absorption, lag time, first-pass effect, and first-order formation of the metabolite best described both enantiomers. R-fluoxetine exhibited 5-fold faster clearance (16.4 vs 3.51 L/h/70kg) and 3-fold larger volume of distribution (935 vs 282 L/70kg) compared to S-fluoxetine. Similarly, R-norfluoxetine clearance was 3-fold faster than S-norfluoxetine (18.9 vs 6.12 L/h/70kg). CYP2D6 phenotype significantly influenced S-norfluoxetine formation, with PMs having an 80% reduction, IMs a 45% reduction, and UMs a 63% increase relative to NMs. CYP2D6, CYP2C9, or CYP2C19 phenotypes did not influence R-norfluoxetine formation.
Conclusions: This is the first population PK model describing R- and S-fluoxetine and norfluoxetine. Enantioselective differences in the PK of fluoxetine and norfluoxetine were observed. S-fluoxetine to S-norfluoxetine biotransformation differed by CYP2D6 phenotype, which aligns with stereoselective CYP2D6 metabolism of S-fluoxetine and suggests incomplete phenoconversion. CYP2D6, CYP2C19, or CYP2C9 phenotypes did not affect R-fluoxetine metabolism, which could be due to the involvement of multiple enzymatic pathways. By characterizing enantioselective PK and metabolism, this model will enable more accurate predictions to support precision dosing strategies for fluoxetine in children and adolescents.
Comments
Full text not provided by primary author
Poser Board Number: 28