Population Pharmacokinetic-Based Strategies for Switching Patients with Schizophrenia Between Long-Acting Injectable...

Area of Science:

• Pharmacokinetics and Pharmacodynamics
• Drug Development and Formulation
• Clinical Pharmacology

Background:

• Characterizing dosing conversions and switching strategies for long-acting injectable (LAI) antipsychotics is crucial for patient care.
• Previous risperidone LAI formulations include R064766 (intramuscular, every 2 weeks) and RBP-7000 (subcutaneous, monthly).
• TV-46000 is a novel subcutaneous risperidone LAI formulation available in monthly (q1m) and every-2-month (q2m) dosing.

Purpose of the Study:

• To utilize pharmacokinetic (PK) modeling to assess dosing conversions and switching strategies from R064766 and RBP-7000 to TV-46000.
• To predict total active moiety (TAM) exposures following transitions to TV-46000 (q1m and q2m) from existing risperidone LAI formulations.
• To evaluate the PK comparability of switching from R064766 and RBP-7000 to TV-46000 based on simulated concentration-time profiles.

Main Methods:

• Population PK models were used to simulate TAM concentration-time profiles for virtual patient populations (n=5000).
• Simulations predicted TAM exposures when switching to TV-46000 (q1m/q2m) 2-6 weeks after the last R064766 dose.
• Simulations also predicted TAM exposures when switching to TV-46000 (q1m) 4 weeks after the last RBP-7000 dose.

Main Results:

• Switching to TV-46000 4-6 weeks after R064766 resulted in comparable maximal (Cmax) and minimal (Cmin) plasma concentration ratios.
• Switching to TV-46000 q1m 4 weeks after RBP-7000 showed slightly higher but generally comparable average plasma concentrations, Cmax, and Cmin.
• Comparable Cmin levels were observed between TV-46000 q2m and RBP-7000; similar concentration trends were seen regardless of administration site (arm vs. abdomen).

Conclusions:

• Simulations indicate that switching to TV-46000 at 4-6 weeks post-R064766 or 4 weeks post-RBP-7000 provides generally comparable PK exposures.
• The study supports the feasibility of transitioning patients to TV-46000 from existing risperidone LAI formulations with predictable PK profiles.
• Clinical decisions on the optimal switching strategy should consider patient preference, scheduling, and tolerability alongside PK data.