Fig. 3.

CNS exposure of three BTK inhibitors in nonhuman primates. Three healthy male animals were used in a crossover study conducted by a third-party vendor (Biomere, Worcester, MA). On days 1–4, animals received a single daily oral dose of one of three test articles at 3 or 10 mg/kg that were supplied using a blinding code such that the identity of the substances was unknown to the vendor. The dose was delivered by oral gavage in a volume of 5 mL/kg. Following a 7-day washout period, the same three animals received a single daily oral dose of a second test article at 3 or 10 mg/kg. This sequence was repeated a third time for the final test article. Data presented for the 10 mg/kg dose. A The plasma (filled symbols) and CSF (open symbols) concentrations of test article (indicated in the legend) are plotted as a function of time post-administration. The dashed horizontal lines represent the IC₉₀ value for each test article as described above (see Table 2). Data represent the mean values from the three animals. B The maximal CSF exposure observed is plotted relative to the in vitro IC₉₀ for each test article to estimate the extent to which the test article achieved bioactive exposures. At the dose of 10 mg/kg, only tolebrutinib exceeded the estimated IC₉₀ value (1.57-fold) while evobrutinib (0.02-fold) and fenebrutinib (0.31-fold) failed to reach their respective IC₉₀ values