A Phase I, Single Centre, Double-blind, Randomised, Placebo-controlled, Parallel-group Study to Assess the Safety, Tolerability and Pharmacokinetics of Oral AZD6088 After Single Ascending Doses in Healthy Male and Non-Fertile Female Volunteers

The aims of the study are to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of AZD6088 following single ascending dose administration in healthy male and non-fertile females.

Start Date01 Jun 2009

Sponsor / Collaborator

AstraZeneca PLC

100 Clinical Results associated with AZD-6088

100 Translational Medicine associated with AZD-6088

100 Patents (Medical) associated with AZD-6088

Literatures (Medical) associated with AZD-6088

01 Aug 2019·Journal of Nuclear MedicineQ1 · MEDICINE

Evaluation of ¹¹C-LSN3172176 as a Novel PET Tracer for Imaging M₁ Muscarinic Acetylcholine Receptors in Nonhuman Primates

Q1 · MEDICINE

Article

Author: Bois, Frederic ; Barth, Vanessa ; Huang, Yiyun ; Jesudason, Cynthia ; Nabulsi, Nabeel B ; Kant, Nancy ; Najafzadeh, Soheila ; Shirali, Anupama ; Slieker, Lawrence ; Zheng, Ming-Qiang ; Holden, Daniel ; Carson, Richard E ; Gao, Hong ; Ropchan, Jim ; Labaree, David ; Lin, Shu-Fei ; Navarro, Antonio ; Lara-Jaime, Teresa

The M₁ muscarinic acetylcholine receptor (mAChR) plays an important role in learning and memory, and therefore is a target for development of drugs for treatment of cognitive impairments in Alzheimer disease and schizophrenia. The availability of M₁-selective radiotracers for PET will help in developing therapeutic agents by providing an imaging tool for assessment of drug dose-receptor occupancy relationship. Here we report the synthesis and evaluation of ¹¹C-LSN3172176 (ethyl 4-(6-(methyl-¹¹ C)-2-oxoindolin-1-yl)-[1,4'-bipiperidine]-1'-carboxylate) in nonhuman primates. Methods: ¹¹C-LSN3172176 was radiolabeled via the Suzuki-Miyaura cross-coupling method. PET scans in rhesus macaques were acquired for 2 h with arterial blood sampling and metabolite analysis to measure the input function. Blocking scans with scopolamine (50 μg/kg) and the M₁-selective agent AZD6088 (0.67 and 2 mg/kg) were obtained to assess tracer binding specificity and selectivity. Regional brain time-activity curves were analyzed with the 1-tissue-compartment model and the multilinear analysis method (MA1) to calculate regional distribution volume. Nondisplaceable binding potential values were calculated using the cerebellum as a reference region. Results: ¹¹C-LSN3172176 was synthesized with greater than 99% radiochemical purity and high molar activity. In rhesus monkeys, ¹¹C-LSN3172176 metabolized rapidly (29% ± 6% parent remaining at 15 min) and displayed fast kinetics and extremely high uptake in the brain. Imaging data were modeled well with the 1-tissue-compartment model and MA1 methods. MA1-derived distribution volume values were high (range, 10-81 mL/cm³) in all known M₁ mAChR-rich brain regions. Pretreatment with scopolamine and AZD6088 significantly reduced the brain uptake of ¹¹C-LSN3172176, thus demonstrating its binding specificity and selectivity in vivo. The cerebellum appeared to be a suitable reference region for derivation of nondisplaceable binding potential, which ranged from 2.42 in the globus pallidus to 8.48 in the nucleus accumbens. Conclusion: ¹¹C-LSN3172176 exhibits excellent in vivo binding and imaging characteristics in nonhuman primates and appears to be the first appropriate radiotracer for PET imaging of human M₁ AChR.

01 Dec 2012·The AAPS JournalQ3 · MEDICINE

Evaluation of an Innovative Population Pharmacokinetic-Based Design for Behavioral Pharmacodynamic Endpoints

Q3 · MEDICINE

Article

Author: Giovanni Martino ; Etienne Lessard ; Anders Viberg ; Jennifer M. A. Laird

Pre-clinical behavioral pharmacology studies supporting indications like analgesia typically consist of at least three different studies; dose-finding, duration of effect, and tolerance-development studies. Pharmacokinetic (PK) plasma samples are generally taken from a parallel group of animals to avoid disruption of the behavioral pharmacodynamic (PD) endpoint. Our objective was to investigate if pre-clinical behavioral pharmacology studies in rats could be performed effectively by combining three studies into a single experimental design and using sparse PK sampling in the same animals as for PD. A refined dosing strategy was applied for a muscarinic agonist, AZD6088, using the rat spinal nerve ligation heat hyperalgesia model. PD measurements were performed on day 1, 3, 5 and 8. Two PK samples per day were taken day 2 and 4. In a separate control group, PD measurements were performed on rats without PK sampling. Data was analyzed using a population approach in NONMEM. The animals produced a consistent and reproducible response irrespective of day of testing suggesting that blood sampling on alternate days did not interfere with the PD responses. A direct concentration-effect relationship with good precision was established and no tolerance development was observed. The new design combining three studies into one and eliminating a satellite PK group realized substantial savings compared to the old design; animal use was reduced by 58% and time required to generate results was reduced by 55%. The design described here delivers substantial savings in animal lives, time, and money whilst still delivering a good quality and precise description of the PKPD relationship.

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