Transl Clin Pharmacol.  2014 Dec;22(2):83-91. 10.12793/tcp.2014.22.2.83.

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

• Park JS
• Lee J
• Meyer J
• Ilankumaran P
• Han S
• Yim DS

• KMID: 2050941
• DOI: http://doi.org/10.12793/tcp.2014.22.2.83

Abstract

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.

Keyword

serotonin transporter; NONMEM; PET; SKL10406

MeSH Terms

Brain
Dopamine
Healthy Volunteers
Humans
Positron-Emission Tomography
Serotonin
Serotonin Plasma Membrane Transport Proteins*
Dopamine
Serotonin
Serotonin Plasma Membrane Transport Proteins

Figure

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  Figure 1. Occupancy effect of SKL10406 upon [11C] DASB (top) and [11C] PE2I (bottom) brain uptake

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  Figure 2. Effect compartmental PK-PD model (EME) for SKL10406. C, drug concentration in the central compartment; Ce, drug concentration in the effect compartment; CL, clearance; ka, absorption rate constant; Ke0, equilibrium rate constant; Q, inter-compartmental clearance

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  Figure 3. Plasma concentration and striatal SERT (panel A) and DAT (panel B) occupancy at 4 hours and 16 hours after dosing. The X-axis represents the plasma concentration of SKL10406 in ng/mL and the Y-axis represents the percent occupancy of serotonin/dopamine transporters in the striatum. The regression curve in the left panel (A) was obtained from NPM results.

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  Figure 4. Visual predictive check plots of the final pharmacokinetic and pharmacodynamic models. 1,000 data sets were simulated using the parameter estimates of the final model. Prediction interval curves of the 12.5th, 50th, and 87.5th percentiles from 1,000 simulated datasets from the PK and PD models were overlaid with observed data. Vertical dashed lines indicate the Tmax of SKL10406 and are shown to demonstrate a delay in predicted occupancy changes by EME compared with DME.

Reference

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