A pseudo-reference region method applied to measurement of GlyT1 occupancy in human brain using [11C]GSK931145 and PET

Searle, Graham; Salinas, Cristian; Bullich, Santiago; Raduà, Joaquim; Herance, José Raúl; López-Vilanova, N; Pardo, Ricardo; Farré, Magı́; Ouellet, Danièle; Rabiner, Eugenii A.; Catafau, Ana M.; Murthy, Venkatesh; Laruelle, Marc; Gunn, Roger N.

doi:10.1016/j.neuroimage.2010.04.129

Cited by 3 publications

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“…Based on the exposure–AE relationship, we predicted the therapeutic window for the compound for different target receptor occupancy rates. In a separate study conducted in healthy subjects, [ 11 C]GSK931145 was used as the GlyT–1 ligand to determine the concentration that would result in 50% receptor occupancy 22 , 23 . The mean (95% confidence interval) 50% receptor occupancy estimated in that study was 45.7 ng/ml (25.6–65.8), and therefore <1%, 8%, 40%, and >80% of the subjects would be predicted to experience dizziness at exposures resulting in 50, 80, 90, and 95% receptor occupancy, respectively.…”

Section: Discussionmentioning

confidence: 99%

First-Time-in-Human Study With GSK1018921, a Selective GlyT1 Inhibitor: Relationship Between Exposure and Dizziness

Ouellet

Sutherland

Wang

et al. 2011

Clin Pharmacol Ther

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The pharmacokinetics (PK), safety, and tolerability of GSK1018921, a glycine transporter 1 (GlyT-1) inhibitor, were assessed in this first-time-in-human (FTIH) study. Single oral doses ranging from 0.5 to 280 mg and placebo were administered to 25 healthy subjects in a five-period, two-cohort, crossover study. GSK1018921 showed dose-proportional PK with a terminal half-life of ~17 h. The subjects reported dizziness with a dose-dependent frequency of 22-88% at doses of 70-280 mg. The time course of the dizziness paralleled the PK of the drug, with peak response at 2 h after the dose, consistent with time to maximum plasma concentration (T(max)). The dizziness was resolved by 10-12 h in all subjects. A Markov-chain logistic regression model was implemented in NONMEM to determine the probability of developing dizziness as a function of the plasma concentration of the compound. Frequency, onset (<1 h), and offset (4 h) were well described by the model. Exposure resulting in 80% receptor occupancy is predicted to be well tolerated.

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Section: Discussionmentioning

confidence: 99%