Population pharmacokinetics for total active moiety of fluoxetine in patients with depression
Objective To establish a population pharmacokinetic(PPK)model for total active moiety(TAM)of fluoxetine(FLX)in patients with depression and to study its influencing factors,providing a reference for individualized medication.Methods The clinical data of inpatients treated with FLX in Shenzhen Kangning Hospital from January 2020 to December 2023 were collected retrospectively,including medication,plasma concentrations of FLX and norfluoxetine(NFLX),liver and kidney function levels,blood lipid levels,and cytochrome enzyme P450 2D6(CYP2D6)genotypes.The sum of FLX and NFLX concentrations was calculated as plasma TAM concentrations.The PPK model was established by using the nonlinear mixed-effect modeling(NONMEM).The stability and prediction performance of the model were evaluated by using goodness-of-fit map(GOF),normalized prediction distribution error method(NPDE),and Bootstrap method(Bootstrap).Based on the significant covariates of the final model,the changes of concentrations across different populations and different doses were simulated,and the steady-state time was fitted and the dose was recommended.Results A one-compartment model with first-order absorption and elimination was established by FLX and NFLX.Body weight(WT)was a significant covariable affecting apparent clearance(CL/F).The population typical values of CL/F,apparent volume of distribution(V/F),and absorption rate constant(Ka)were 2.91 L/h,734 L and 0.3 h-1,respectively,in the final model.The expression of the model was as follows:CL/F(L·h-1)=2.91×(WT/55)0.531,V/F(L)=734,Ka(h-1)=0.3(Fixed).The Monte Carlo simulation results showed that the time for TAM concentration to reach a steady state was 6 to 11 weeks.With the same dosage,the lighter the body weight,the longer it took to reach a steady state.For patients weighing less than 70 kg,the optimal dosing regimen was 10 to 30 mg,and for those over 70 kg,it was 20 to 40 mg.Conclusion The PPK model of concentration in depressive patients treated with FLX was successfully established.The final model is stable and and reliable.Patients with low body weight should choose a lower dose to avoid adverse drug reactions caused by FLX accumulation.
fluoxetinetotal active moietypopulation pharmacokineticsplasma concentrationgene polymorphism
万方数据
维普
