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2014 (v.22 no.2)

Translational and Clinical Pharmacology

Korean Society for Clinical Pharmacology and Therapeutics
ISSN: 2289-0882

  • Serotonin transporter occupancy of SKL10406 in humans: comparison of pharmacokinetic-pharmacodynamic modeling methods for estimation of occupancy parameters

    Jung-Shin Park, Jongtae Lee, Jeffrey Meyer, Palanichamy Ilankumaran, Seunghoon Han, Dong-Seok Yim

    TCP | v.22, no.2, pp.83-91, Dec, 2014


    SKL10406, triple monoamine reuptake inhibitor, is a novel antidepressant candidate. A PET study
    was performed to investigate the occupancies of serotonin and dopamine transporters (SERT and
    DAT) in human brain, and the relationship between SKL10406 concentration and SERT occupancy
    was assessed using pharmacokinetic-pharmacodynamic (PK-PD) modeling methods. Fifteen
    healthy volunteers were given SKL10406 100 mg/day for 6 days or 150 mg/day for 6 days after 100
    mg/day for 4 days. Each subject underwent full PK sampling for SKL10406 and PET scans at predose,
    4 h and 16 h after dosing at a steady state to investigate the occupancies of SERT and DAT using
    11C-DASB and 11C-PE2I, respectively. Naive pooled method (NPM) and nonlinear mixed-effect
    methods (ME) including a direct ME (DME) and an effect compartmental ME (EME) were used
    (NONMEM Ver. 7.2). Six and five subjects completed the studies for SERT and DAT, respectively.
    The final estimates of Emax (53.4%) and EC50 (11.8 ng/mL) from DME were relatively lower than
    those from NPM (Emax, 74.1%; EC50, 36.8 ng/mL) and EME (Emax, 68.6%; EC50, 40.2 ng/mL). DAT
    occupancy results were not modeled because of lower occupancies. The results showed that the dosage
    regimens may be applied in patient studies. However, difference between estimation methods
    alerts that ME may not be a recommendable analysis tool for sparsely sampled PET scan data.


    serotonin transporter, NONMEM, PET, SKL10406