An Integrated Pharmacokinetic–Pharmacodynamic–Pharmacoeconomic Modeling Method to Evaluate Treatments for Adults with Schizophrenia

Abstract

Introduction Schizophrenia is a chronic mental disorder that worsens with each relapse. Long-acting injectable (LAI) antipsychotics may prevent the exacerbation of symptoms and occurrence of relapses through improved continuity of care. Different dose regimens are available for the LAIs aripiprazole monohydrate (AM) and aripiprazole lauroxil (AL), but their cost effectiveness is unclear. Objectives The study aim was to compare costs and effects (relapses) of the different aripiprazole LAI dose regimens to inform clinical and US payer decisions. Methods A state-transition model calculated the outcomes of eight LAI dose regimens based on their relapse rates. As effectiveness data from randomized controlled trials were unavailable, relapse rates were modeled using pharmacokinetic and pharmacodynamic evidence. These described blood plasma levels of aripiprazole as a function of AM and AL dose regimens and described the probability of relapse as a function of aripiprazole blood plasma levels. The analysis had a time horizon of 1 year and took the US healthcare payer perspective. The incremental cost per relapse avoided and the probability of cost effectiveness were calculated in deterministic and probabilistic analyses. Scenario analyses explored the model's main assumptions, and results were validated against external data and other cost-effectiveness analyses. Results Monthly administration of AM 400 mg consistently yielded the lowest predicted number of relapses across deterministic, probabilistic, and scenario analyses. The costs of treatment and relapses were projected to be the lowest with a monthly administration of AL 441 mg. The incremental cost per relapse avoided with AM 400 mg ranged from AM 400 mg being dominant to $US83,300. From willingness-to-pay thresholds of $US30,000 per relapse avoided, the probability of cost effectiveness was highest for AM 400 mg. The validation showed alignment with external data. Conclusion The analysis highlighted the robustness of the novel framework based on pharmacokinetic and pharmacodynamic evidence and demonstrated an application in a postmarketing setting.

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“…At the time of an ROV analysis, future innovation has not yet been approved, but preliminary data on its efficacy are usually available from early-stage trials, interim analyses, etc. [ 18 ]. If the survival function and time in each health state on future innovation are known, the expected incremental QALYs of future innovation can be projected in a disease progression model such as a Markov state transition model.…”

Comment on “An Integrated Pharmacokinetic–Pharmacodynamic–Pharmacoeconomic Modeling Method to Evaluate Treatments for Adults with Schizophrenia”

“…A recent article by Piena et al [ 1 ] used integrated pharmacokinetic (PK)–pharmacodynamic (PD)–pharmacoeconomic modeling to compare costs and effects (relapses) of long-acting injectable (LAI) aripiprazole monohydrate (AM) and aripiprazole lauroxil (AL) dosing regimens in patients with schizophrenia. Because risk of relapse remains high in patients treated with antipsychotic drugs [ 2 , 3 ], this important area of research can inform treatment decisions.…”

“…Second, Piena et al described the 95 ng/mL threshold as “consistent with the lower boundary of the established therapeutic window for aripiprazole” [ 1 ] based on the median C min at steady state for the lowest effective dose of oral aripiprazole (10 mg/day) [ 11 , 12 ]. They then assumed that aripiprazole exposures with a C min below that median value fall outside of the therapeutic window and therefore are associated with an increased risk of relapse.…”

“…Finally, some additional points affect the interpretation of the PK–PD analysis. The authors state that “according to expert opinion, in clinical practice, AL 441 mg and AM 300 mg are generally used only when patients do not tolerate higher doses” [ 1 ]. However, the cited source discusses AM 300 mg only [ 20 ], and that assertion is not true for AL 441 mg. On the contrary, AL can be initiated using any of the approved dosing regimens, including 441 mg monthly [ 17 , 21 ].…”

Response to Comment on “An Integrated Pharmacokinetic-Pharmacodynamic-Pharmacoeconomic Modeling Method to Evaluate Treatments for Adults with Schizophrenia”

“…We appreciate the opportunity to respond to the comments submitted to you by Dr. Bhaskar Rege and colleagues [ 1 ] regarding our October 2021 article entitled, “An integrated pharmacokinetic–pharmacodynamic–pharmacoeconomic modeling method to evaluate treatments for adults with schizophrenia” [ 2 ]. As mentioned in the introduction section of our article, the purpose of this article was to present an application of a novel pharmacokinetic–pharmacodynamics–pharmacoeconomic (PK–PD–PE) framework that would enable pharmacoeconomic comparisons of the aripiprazole lauroxil (AL) and aripiprazole monohydrate (AM) long-acting injectable formulations based on publicly available, where possible peer-reviewed sources given that no comparative clinical evidence currently exists.…”