AimsThe objective of the study was to evaluate the pharmacokinetics (and how they are affected by food), CNS pharmacodynamics and the adverse event profile of brivaracetam after single increasing doses. MethodsHealthy males (n = 27, divided into three alternating panels of nine subjects) received two different single oral doses of brivaracetam (10-1400 mg) and one dose of placebo during three periods of a randomized, double-blind, placebo-controlled study. The effect of food on its pharmacokinetics was assessed using a standard two-way crossover design in a further eight subjects who received two single oral doses of brivaracetam (150 mg) in the fasting state and after a high fat meal. ResultsAdverse events, none of which were serious, were mostly CNS-related and included somnolence, dizziness, and decreased attention, alertness, and motor control. Their incidence, severity and duration were dose-related. The maximum tolerated dose was established to be 1000 mg. Severe somnolence lasting 1 day occurred in one subject following 1400 mg. Brivaracetam was rapidly absorbed under fasting conditions, with a median tmax of approximately 1 h. Cmax was dose-proportional from 10 to1400 mg, whereas AUC deviated from dose linearity above 600 mg. A high-fat meal had no effect on AUC (point estimate 0.99, 90%CI: 0.92-1.07) but delayed tmax (3 h) and decreased Cmax (point estimate 0.72, 90%CI: 0.66-0.79). ConclusionsBrivaracetam was well tolerated after increasing single doses that represent up to several times the expected therapeutic dose. Brivaracetam was found to have desirable pharmacokinetic properties. The most common adverse events were somnolence and dizziness.

SUMMARYObjective: Rapid distribution to the brain is a prerequisite for antiepileptic drugs used for treatment of acute seizures. The preclinical studies described here investigated the high-affinity synaptic vesicle glycoprotein 2A (SV2A) antiepileptic drug brivaracetam (BRV) for its rate of brain penetration and its onset of action. BRV was compared with levetiracetam (LEV). Methods: In vitro permeation studies were performed using Caco-2 cells. Plasma and brain levels were measured over time after single oral dosing to audiogenic mice and were correlated with anticonvulsant activity. Tissue distribution was investigated after single dosing to rat (BRV and LEV) and dog (LEV only). Positron emission tomography (PET) displacement studies were performed in rhesus monkeys using the SV2A PET tracer [11 C]UCB-J. The time course of PET tracer displacement was measured following single intravenous (IV) dosing with LEV or BRV. Rodent distribution data and physiologically based pharmacokinetic (PBPK) modeling were used to compute blood-brain barrier permeability (permeability surface area product, PS) values and then predict brain kinetics in man. Results: In rodents, BRV consistently showed a faster entry into the brain than LEV; this correlated with a faster onset of action against seizures in audiogenic susceptible mice. The higher permeability of BRV was also demonstrated in human cells in vitro. PBPK modeling predicted that, following IV dosing to human subjects, BRV might distribute to the brain within a few minutes compared with approximately 1 h for LEV (PS of 0.315 and 0.015 ml/min/g for BRV and LEV, respectively). These data were supported by a nonhuman primate PET study showing faster SV2A occupancy by BRV compared with LEV. Significance: These preclinical data demonstrate that BRV has rapid brain entry and fast brain SV2A occupancy, consistent with the fast onset of action in the audiogenic seizure mice assay. The potential benefit of BRV for treatment of acute seizures remains to be confirmed in clinical studies.

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Allometric scaling is widely used to predict human pharmacokinetic parameters from preclinical species, and many different approaches have been proposed over the years to improve its predictive performance. Nevertheless, prediction errors are commonly observed in the practical application of simple allometry, for example, in cases where the hepatic metabolic clearance is mainly determined by enzyme activities, which do not scale allometrically across species. Therefore, if good correlation was noted for some drugs, poor correlation was observed for others, highlighting the need for other conceptual approaches. Physiologically based pharmacokinetic (PBPK) models are now a well-established approach to conduct extrapolations across species and to generate simulations of pharmacokinetic profiles under various physiological conditions. While conventional pharmacokinetic models are defined by drug-related data themselves, PBPK models have richer information content and integrate information from various sources, including drug-dependent, physiological, and biological parameters as they vary in between species, subjects, or with age and disease state. Therefore, the biological and mechanistic bases of PBPK models allow the extrapolation of the kinetic behavior of drugs with regard to dose, route, and species. In addition, by providing a link between tissue concentrations and toxicological or pharmacological effects, PBPK modeling represents a framework for mechanistic pharmacokinetic-pharmacodynamic models.

Motor symptoms in Parkinson disease (PD) are caused by a loss of dopamine input from the substantia nigra to the striatum. Blockade of adenosine 2A (A 2A ) receptors facilitates dopamine D 2 receptor function. In phase 2 clinical trials, A 2A antagonists (istradefylline, preladenant, and tozadenant) improved motor function in PD. We developed a new A 2A PET radiotracer, 18 F-MNI-444, and used it to investigate the relationship between plasma levels and A 2A occupancy by preladenant and tozadenant in nonhuman primates (NHP). Methods: A series of 20 PET experiments was conducted in 5 adult rhesus macaques. PET data were analyzed with both plasma-input (Logan graphical analysis) and reference-region-based (simplified reference tissue model and noninvasive Logan graphical analysis) methods. Whole-body PET images were acquired for radiation dosimetry estimates. Human pharmacokinetic parameters for tozadenant and preladenant were used to predict A 2A occupancy in humans, based on median effective concentration (EC 50 ) values estimated from the NHP PET measurements. Results: 18 F-MNI-444 regional uptake was consistent with A 2A receptor distribution in the brain. Selectivity was demonstrated by dose-dependent blocking by tozadenant and preladenant. The specific-to-nonspecific ratio was superior to that of other A 2A PET radiotracers. Pharmacokinetic modeling predicted that tozadenant and preladenant may have different profiles of A 2A receptor occupancy in humans. Conclusion: 18 F-MNI-444 appears to be a better PET radiotracer for A 2A imaging than currently available radiotracers. Assuming that EC 50 in humans is similar to that in NHP, it appears that tozadenant will provide a more sustained A 2A receptor occupancy than preladenant in humans at clinically tested doses. Par kinson disease (PD) has a prevalence of 1.6% in individuals over the age of 65 y (1) and a lifetime risk of 6.7% from age 45 to 100 y (2). Motor symptoms, which include tremor, bradykinesia, and rigidity, emerge when there is a loss of more than 50% of dopamine neurons in the substantia nigra (SN) (3,4). Loss of these neurons reduces dopamine input to the striatum, where dopamine binds to both D 1 and D 2 receptors. Most striatal D 1 receptors are localized in the so-called direct pathway, whereas most striatal D 2 receptors are localized in medium spiny neurons that project to the globus pallidus pars externa (indirect pathway). Adenosine signals via 4 different G-protein-coupled receptors: A 1 , A 2A , A 2B , and A 3 (5). A 2A receptors are predominantly expressed in striatum, with lower levels present in cortex and thalamus and even lower in cerebellum (5-9). A 2A receptors may play a role in inflammation (10) and could therefore be important in a variety of neurologic diseases, including multiple sclerosis, in which A 2A receptor density is increased (11). In PD, A 2A receptors may be important because they form heterodimers with D 2 receptors in the striatum (5,12), and agonists of A 2A (e.g., adenosine) reduce the affinity of D 2 for dopamin...