Poster
67
(#67) Pharmacokinetic Profile of Xanomeline and Trospium Chloride With Adjunctive Antipsychotic Treatment
Psych Congress 2025
Abstract: Background: ARISE (NCT05145413) evaluated adjunctive xanomeline and trospium chloride (X/T) in adults with schizophrenia on stable background antipsychotic (bAPD) therapy. The primary endpoint was not met: adjunctive X/T showed numerical but not statistically significant improvements in schizophrenia symptoms. Subgroup analysis indicated no greater numerical improvement with X/T+risperidone vs placebo+risperidone. Additional analyses assessed potential pharmacokinetic contributions to differences observed between bAPD treatment groups.
Methods: ARISE was a phase 3, randomized, double-blind, placebo-controlled trial in adults with inadequately controlled schizophrenia symptoms on a stable dose of antipsychotic monotherapy. Subjects (PANSS total score ≥70; CGI-S ≥4) were randomized 1:1 to adjunctive X/T or placebo for 6 weeks. Sparse samples for pharmacokinetic analysis were collected at baseline and 4 timepoints throughout the treatment period. Population pharmacokinetic modeling incorporated data from ARISE, three 5-week EMERGENT trials, and five phase 1 trials. Pharmacokinetic parameters for xanomeline and trospium were compared across subgroups defined by bAPD.
Results: Clearance estimates and plasma Cavg of xanomeline and trospium were generally consistent ( 20% difference in the mean) across bAPD subgroups (aripiprazole, n=58; risperidone, n=52; paliperidone, n=23; other, n=53). Xanomeline plasma Cavg was not correlated with treatment response (≥30% improvement in PANSS score at week 6). Overall, xanomeline and trospium exposures in ARISE aligned with those in the EMERGENT trials. In addition, risperidone concentrations (combined risperidone and 9-hydroxy-risperidone) were similar in placebo and X/T arms throughout the trial.
Conclusions: No evidence of bAPD drug-drug interactions affecting X/T pharmacokinetics or X/T pharmacokinetic effects on responder status was observed.
Short Description: Pharmacokinetic parameters from ARISE were assessed to determine if variability in xanomeline exposure could explain a difference in efficacy observed between risperidone and non-risperidone groups. Xanomeline exposures were consistent across subgroups, and no significant drug-drug interactions with risperidone or other background antipsychotics were observed. Pharmacokinetics in ARISE aligned with data modeled from the EMERGENT trials of X/T in adults with schizophrenia.
Name of Sponsoring Organization(s): Bristol Myers Squibb
Methods: ARISE was a phase 3, randomized, double-blind, placebo-controlled trial in adults with inadequately controlled schizophrenia symptoms on a stable dose of antipsychotic monotherapy. Subjects (PANSS total score ≥70; CGI-S ≥4) were randomized 1:1 to adjunctive X/T or placebo for 6 weeks. Sparse samples for pharmacokinetic analysis were collected at baseline and 4 timepoints throughout the treatment period. Population pharmacokinetic modeling incorporated data from ARISE, three 5-week EMERGENT trials, and five phase 1 trials. Pharmacokinetic parameters for xanomeline and trospium were compared across subgroups defined by bAPD.
Results: Clearance estimates and plasma Cavg of xanomeline and trospium were generally consistent ( 20% difference in the mean) across bAPD subgroups (aripiprazole, n=58; risperidone, n=52; paliperidone, n=23; other, n=53). Xanomeline plasma Cavg was not correlated with treatment response (≥30% improvement in PANSS score at week 6). Overall, xanomeline and trospium exposures in ARISE aligned with those in the EMERGENT trials. In addition, risperidone concentrations (combined risperidone and 9-hydroxy-risperidone) were similar in placebo and X/T arms throughout the trial.
Conclusions: No evidence of bAPD drug-drug interactions affecting X/T pharmacokinetics or X/T pharmacokinetic effects on responder status was observed.
Short Description: Pharmacokinetic parameters from ARISE were assessed to determine if variability in xanomeline exposure could explain a difference in efficacy observed between risperidone and non-risperidone groups. Xanomeline exposures were consistent across subgroups, and no significant drug-drug interactions with risperidone or other background antipsychotics were observed. Pharmacokinetics in ARISE aligned with data modeled from the EMERGENT trials of X/T in adults with schizophrenia.
Name of Sponsoring Organization(s): Bristol Myers Squibb
