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O3‐07‐07: A study to evaluate the effects of single oral doses of BMS‐708163 in the cerebrospinal fluid of healthy young men
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2010
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Neurochemical BiomarkersPharmacotherapySingle Oral DosesHealthy Young MenNeurobiology Of DiseaseAlzheimer's DiseaseCerebrospinal FluidIntracranial PressureBrain InjuryNeurologyNeuropathologyNeuroimmunologyCsf AβHealth SciencesCsf SamplesNeuropharmacologyNeuroprotectionCerebral Blood FlowMg. Csf ExposurePharmacologyNeurological AssessmentNeurodegenerative DiseasesTreatment EvaluationNeuroscienceMedicine
BMS-708163, in Phase II development for Alzheimer's Disease, selectively inhibits Aβ synthesis relative to Notch, and is a potent and orally active γ-secretase inhibitor. The primary objective of this double-blind, placebo-controlled, randomized, single-dose study was to assess the effects of single oral BMS-708163 doses on CSF Aβ. Healthy non-Japanese (n = 8) and Japanese (n = 3) males aged 20-45y were assigned to each of 3 sequential panels (50 mg, 200 mg, 400 mg) to receive BMS-708163 or placebo as a single oral dose. CSF samples were obtained prior to dosing and hourly until 39h post-dose. Plasma samples were collected until 144h post-dose. Thirty-four subjects were randomized; 33 completed the study. One subject in the placebo group discontinued from the study on Day 7 due to difficulties with the spinal fluid collection procedure. Median CSF Aβ1-40 concentrations 12h post-dose were 111%, 88%, 63%, and 60% of baseline values after placebo, 50-mg, 200-mg, and 400-mg doses of BMS-708163, respectively. Corresponding values for CSF Aβ1-38 were 111%, 90%, 60%, and 58%, respectively; and for CSF Aβ1-42 were 112%, 97%, 68%, and 66%, respectively. BMS-708163 was quickly absorbed (Tmax, 1-2h); Cmax and AUC at 200 mg and 400 mg were similar. Plasma profiles were biphasic, with a terminal half-life of ˜40h. Exposure for BMS-708163 in CSF was much lower (<1%) than in plasma. AEs occurred with similar frequency between drug and placebo; the most common AEs were headache (n = 12), post-lumbar puncture syndrome (n = 8), and back pain (n = 7). CSF Aβ reduction responses were similar in Japanese and non-Japanese; Japanese had higher mean plasma AUC0-t and AUCinf (17% and 39%, respectively) and higher mean CSF AUC0-t and AUCinf (5% and 69%, respectively) versus non-Japanese subjects, but the actual values were within the range of values for non-Japanese subjects. Single 200-mg or 400-mg BMS-708163 doses resulted in marked decreases in CSF Aβ; single 50-mg doses resulted in smaller and less-sustained decreases. Evidence of saturation in exposure was present at doses >200 mg. CSF exposure correlated with plasma exposure but was of lower magnitude. BMS-708163 was safe and well tolerated. CSF Aβ reduction responses were similar in Japanese and non-Japanese.