Introduction: Pharmacokinetic differences between long-acting injectable antipsychotic (LAI) formulations, combined with a lack of clinical switch studies, contribute to clinician uncertainty when transitioning between LAIs. This analysis employed a population pharmacokinetic (popPK) modeling approach to characterize dosing conversions and switching strategies from intramuscular paliperidone palmitate once monthly (PP1m) to TV-46000, a long-acting subcutaneous formulation of risperidone, once monthly (q1m), with a secondary analysis of PP1m to TV-46000 every 2 months (q2m).
Methods: For PP1m and TV-46000, concentration-time profiles for paliperidone and TV-46000 total active moiety (TAM; risperidone + paliperidone) were simulated on the basis of published popPK models with virtual populations of 5000 patients. TAM exposure following oral administration served as a comparison benchmark.
Results: When switching from PP1m 234 mg at steady state (comparable to 6 mg/day oral risperidone), the most comparable switch involved initiating TV-46000 125 mg q1m 4 weeks after the last PP1m dose. Ratios of TV-46000 to PP1m for maximum, minimum, and average plasma concentration (Cmax, Cmin, and Cavg, respectively) post switch ranged from 1.0 to 1.4 after the first dose and 1.0-1.3 at steady state. Switching from other PP1m doses to TV-46000 q1m (comparable to 2-4 mg daily oral risperidone) using a 4-week interval demonstrated comparable TAM exposures. When switching from PP1m 234 mg to TV-46000 250 mg q2m, Cmax was higher and Cmin lower than that of q1m, though Cavg remained comparable to 5/6 mg daily oral risperidone.
Conclusion: Switching to TV-46000 125 mg q1m 4 weeks after the last PP1m 234-mg injection yielded generally comparable pharmacokinetic parameters at steady state. The same was true for other TV-46000 q1m or q2m dosages and equivalent dosages of PP1m. Clinician discretion will ultimately determine how to switch on the basis of factors such as patient preference, convenience, and concerns about tolerability or symptom breakthrough.
Keywords: Long-acting injectable antipsychotic; Paliperidone; Population pharmacokinetic modeling; Risperidone; Schizophrenia; TV-46000.
Injected drugs that last in the body for weeks or months can be used to treat people with schizophrenia. There are differences in the amount of drug in the blood over time between different brands of drugs. This can make it difficult for clinicians to figure out how much of a new drug to use and how long to wait between injections when switching patients from one injectable drug to another. The aim of this study was to use computer-generated predictions to test different options when switching from one drug to another. The options studied included how much time to wait between the last dose of one drug and the first dose of another. The different dose amounts were also studied. In this work, the drug being switched from (PP1m) is given once per month. The drug that is being switched to (TV-46000) is given once per month or once every 2 months. The predictions showed that TV-46000 injected 4 weeks after the last dose of PP1m did not significantly affect the amount of active drug in the blood over time. The amount of TV-46000 to use to avoid large changes in levels of active drug in the blood was also described. This study gives clinicians more information about how they can switch their patients from one injectable drug to another. The decision to switch from one drug to another will be based on many factors, such as the patient’s preferences, convenience, and any concerns about safety or symptoms returning.
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