Hannah Britz (1), Nina Hanke (1) and Thorsten Lehr (1)
(1) Clinical Pharmacy, Saarland University, Saarbruecken, Germany
Objectives: Fluvoxamine is described as a potent CYP1A2 and CYP2C19 inhibitor. The US Food and Drug Administration (FDA) recommends fluvoxamine as a perpetrator drug to evaluate the impact of CYP1A2/CYP2C19 inhibition on CYP1A2/CYP2C19 substrates (victim drugs) during co-administration [1]. The objectives of this study were to establish a whole-body PBPK model of fluvoxamine, to describe and predict the pharmacokinetics of fluvoxamine, and to apply this model for the investigation of fluvoxamine drug-gene interactions (DGIs) and drug-drug interactions (DDIs).
Methods: The whole-body fluvoxamine PBPK model was built with PK-Sim® and MoBi® (7.2.1). Drug-dependent parameters (e.g. logP, solubility), plasma concentration-time profiles (30 mg as intravenous and 10-200 mg as oral administration) and study population demographics (e.g. age, weight) of clinical studies with fluvoxamine were obtained from literature. To characterize the impact of different CYP2D6 genotypes on fluvoxamine pharmacokinetics, plasma concentration-time profiles of CYP2D6 extensive metabolizers (EMs) and CYP2D6 poor metabolizers (PMs) were included into the dataset. Model parameters that could not be obtained from literature were optimized utilizing observed plasma concentration-time profiles of fluvoxamine after intravenous and oral administration (training dataset, 10 different studies). Model evaluation was performed by prediction of plasma concentration-time profiles of studies that have not been used for parameter optimization (test dataset, 17 different studies), followed by the comparison of predicted versus observed plasma concentration-time profiles, AUC (area under the curve) values and Cmax (peak plasma concentration) values.
Results: The developed fluvoxamine model incorporates metabolism via CYP2D6 and CYP1A2 as well as glomerular filtration. The metabolic pathways were implemented with saturable Michaelis-Menten kinetics to describe the non-linear pharmacokinetics of fluvoxamine [2]. Fractions metabolized by CYP2D6 and CYP1A2 are depicted accurately. Plasma concentration-time profiles of CYP2D6 extensive metabolizers can be precisely predicted with AUC and Cmax ratios (predicted/observed) of 0.87 and 1.0, respectively. Plasma concentration-time profiles of CYP2D6 poor metabolizers can be successfully predicted with AUC and Cmax ratios (predicted/observed) of 1.28 and 1.13. The competitive inhibition of CYP1A2 by fluvoxamine was implemented and evaluated with clinical DDI data of fluvoxamine co-administration with the CYP1A2 victim drug caffeine (PK-Sim template model). During concomitant treatment with fluvoxamine, the observed AUC and Cmax of caffeine increase 13.71- and 1.40-fold [3]. The DDI model predicts a 19.48-fold increase in caffeine AUC and a 1.08-fold increase in Cmax during co-treatment with fluvoxamine.
Conclusions: The newly developed whole-body fluvoxamine PBPK model precisely describes and predicts plasma concentration-time profiles of fluvoxamine over the full range of administered doses and administration protocols. It is a valuable tool to predict the impact of CYP2D6 polymorphism on the pharmacokinetics of fluvoxamine (DGI) and to predict the impact of CYP1A2 inhibition on the pharmacokinetics of the CYP1A2 victim drug caffeine (DDI).
References:
[1] U.S. Department of Health and Human Services, Food and Drug Administration Center for Drug Evaluation and Research (CDER): Drug interaction studies – Study design, data analysis, implications for dosing, and labeling recommendations (2017).
[2] Spigset O, Granberg K, Hägg S, Söderström E, Dahlqvist R. Non-linear fluvoxamine disposition. Br J Clin Pharmacol (1998) 45(3): 257-63.
[3] Culm-Merdek KE, von Moltke LL, Harmatz JS, Greenblatt DJ. Fluvoxamine impairs single-dose caffeine clearance without altering caffeine pharmacodynamics. Br J Clin Pharmacol (2005) 60(5): 486-93.
Reference: PAGE 27 (2018) Abstr 8496 [www.page-meeting.org/?abstract=8496]
Poster: Drug/Disease Modelling - Absorption & PBPK