Defining a therapeutic window for the novel TGF-ß inhibitor LY2157299 monohydrate based on a pharmacokinetic/pharmacodynamic model.

AIMS: To identify prospectively a safe therapeutic window for administration of a novel oral transforming growth factor ß (TGF-ß) inhibitor, LY2157299 monohydrate, based on a pharmacokinetic/pharmacodynamic (PK/PD) model. Simulations of population plasma exposures and biomarker responses in tumour were performed for future trials of LY2157299 in glioblastoma and other cancer populations. METHODS: The model was updated after completion of each cohort during the first-in-human dose (FHD) study. The flexible design allowed continuous assessment of PK variability by recruiting the required number of patients in each cohort. Based on 30% inhibition of TGF-ß RI kinase phosphorylates (pSMAD), biologically effective exposures were anticipated to be reached from 160 mg onwards. The therapeutic window was predicted, based on animal data, to be between 160 and 360 mg. RESULTS: No medically significant safety issues were observed and no dose limiting toxicities were established in this study. Observed plasma exposures (medians 2.43 to 3.7 mg l⁻¹ h, respectively) with doses of 160 mg to 300 mg were within the predicted therapeutic window. Responses, based on the MacDonald criteria, were observed in these patients. CONCLUSIONS: A therapeutic window for the clinical investigation of LY2157299 in cancer patients was defined using a targeted PK/PD approach, which integrated translational biomarkers and preclinical toxicity. The study supports using a therapeutic window based on a PK/PD model in early oncology development.

TC-2559 excites dopaminergic neurones in the ventral tegmental area by stimulating alpha4beta2-like nicotinic acetylcholine receptors in anaesthetised rats.

1. The in vivo effects of a selective partial agonist for neuronal nicotinic acetylcholine receptor (nAChRs) alpha4beta2 subtype, TC-2559, characterised recently in in vitro preparations, have been profiled. The brain bioavailability of TC-2559 and its effects on the spontaneous firing and bursting properties of the dopaminergic (DAergic) neurones recorded extracellularly in the ventral tegmental area (VTA) were studied following systemic administration in anaesthetised rats. 2. Cumulative doses of TC-2559 (0.021-1.36 mg kg(-1), i.v.) increased both the firing and bursting activities of VTA DA neurones. The effect of bolus doses of TC-2559 of 0.66 or 1.32 mg kg(-1), i.v., was approximately equivalent to that of 0.0665 mg kg(-1), i.v. nicotine. 3. The excitation evoked by both nicotine and TC-2559 was fully reversed by DHbetaE (0.39-0.77 mg kg(-1), i.v.), an alpha4beta2-subtype-preferring nicotinic antagonist, and application of nicotine after DHbetaE failed to evoke any excitation. MLA (0.23 mg kg(-1), i.v.), an alpha7 selective antagonist, failed to alter TC-2559-evoked excitation and bursting activities, and a novel alpha7 agonist (PSAB-OFP; 0.23 mg kg(-1), i.v.) was also without effect. 4. The present results indicated that TC-2559 fully mimics nicotine by increasing both the excitability and bursting behaviour of VTA DA neurones, effects that are predominantly due to activation of alpha4beta2-like nAChRs. 5. TC-2559 has been demonstrated to be a useful in vivo pharmacological tool for studying the alpha4beta2 subtype of nicotinic receptor.