Poster
68
(#68) Population Pharmacokinetic Analysis of Xanomeline and Trospium in Healthy Subjects and Adults With Schizophrenia Supports Dose Recommendations in Mild Renal Impairment and Elderly Populations
Psych Congress 2025
Abstract: Background: Population pharmacokinetic (PopPK) modeling provided support for the dose rationale of xanomeline and trospium chloride (X/T) for the treatment of schizophrenia in adults.
Methods: The PopPK analysis included data from the 5-week EMERGENT-1 (NCT03697252), EMERGENT-2 (NCT04659161), and EMERGENT-3 (NCT04738123) trials of adults with schizophrenia and five phase 1 trials that included healthy volunteers, elderly subjects, and adults with renal or hepatic impairment. Dosing ranged from 50-300 mg total daily dose (TDD) of xanomeline and 20-80 mg TDD of trospium chloride. Safety data were collected in all trials.
Results: Plasma concentration-time data from 9236 xanomeline samples and 9107 trospium samples from 520 participants (mean age, 47.7 years; mild renal impairment [RI], n=159; mild or moderate hepatic impairment, n=20; aged ≥65 years, n=57) were best described by 3- and 2-compartment models, respectively. The xanomeline PK model identified significant impacts of hepatic impairment and CYP2D6 phenotype on bioavailability and of RI on apparent clearance. RI and age ≥65 years were significant covariates for apparent trospium clearance, resulting in 60% higher AUC in elderly. Comparisons of post hoc exposure estimates of xanomeline and trospium in the EMERGENT trials show no clinically relevant exposure difference between participants with mild RI and those with normal renal function. Additionally, safety and tolerability of X/T were similar between mild RI and normal renal function groups.
Conclusion: PopPK analyses provided support for X/T 125/30 mg BID in adults with mild RI and a maximum dose of 100/20 mg BID in those aged ≥65 years.
Short Description: Short description: This PopPK analysis used data from the 5-week EMERGENT-1 (NCT03697252), EMERGENT-2 (NCT04659161), and EMERGENT-3 (NCT04738123) trials of adults with schizophrenia and from five phase 1 trials that included healthy volunteers, elderly subjects, and adults with renal or hepatic impairment. Exposure was comparable for both xanomeline and trospium between participants with mild renal impairment and those with normal renal function. Age ≥65 years was a significant covariate for trospium's apparent clearance.
Name of Sponsoring Organization(s): Bristol Myers Squibb
Methods: The PopPK analysis included data from the 5-week EMERGENT-1 (NCT03697252), EMERGENT-2 (NCT04659161), and EMERGENT-3 (NCT04738123) trials of adults with schizophrenia and five phase 1 trials that included healthy volunteers, elderly subjects, and adults with renal or hepatic impairment. Dosing ranged from 50-300 mg total daily dose (TDD) of xanomeline and 20-80 mg TDD of trospium chloride. Safety data were collected in all trials.
Results: Plasma concentration-time data from 9236 xanomeline samples and 9107 trospium samples from 520 participants (mean age, 47.7 years; mild renal impairment [RI], n=159; mild or moderate hepatic impairment, n=20; aged ≥65 years, n=57) were best described by 3- and 2-compartment models, respectively. The xanomeline PK model identified significant impacts of hepatic impairment and CYP2D6 phenotype on bioavailability and of RI on apparent clearance. RI and age ≥65 years were significant covariates for apparent trospium clearance, resulting in 60% higher AUC in elderly. Comparisons of post hoc exposure estimates of xanomeline and trospium in the EMERGENT trials show no clinically relevant exposure difference between participants with mild RI and those with normal renal function. Additionally, safety and tolerability of X/T were similar between mild RI and normal renal function groups.
Conclusion: PopPK analyses provided support for X/T 125/30 mg BID in adults with mild RI and a maximum dose of 100/20 mg BID in those aged ≥65 years.
Short Description: Short description: This PopPK analysis used data from the 5-week EMERGENT-1 (NCT03697252), EMERGENT-2 (NCT04659161), and EMERGENT-3 (NCT04738123) trials of adults with schizophrenia and from five phase 1 trials that included healthy volunteers, elderly subjects, and adults with renal or hepatic impairment. Exposure was comparable for both xanomeline and trospium between participants with mild renal impairment and those with normal renal function. Age ≥65 years was a significant covariate for trospium's apparent clearance.
Name of Sponsoring Organization(s): Bristol Myers Squibb
