Quantitative approaches of time-varying weight gain effects of antipsychotic drugs for Schizophrenia by model based meta-analysis.
Jihyun Jeon(1), Jiyeon Jeon(1) Jung-woo Chae(1),(2)#, Hwi-yeol Yun(1),(2),#
(1)College of Pharmacy, Chungnam National University, Daejeon 34134, Korea , (2)Department of Bio-AI Convergence, Chungnam National University, Daejeon 34134, Korea
Objectives:
Despite weight gain is one of the most important adverse drug effect(ADR) of antipsychotics[1], the quantitative approach was restricted because of lack of methodology. In recent, model-based meta-analysis (MBMA) is an approach that quantifies the integrated data along with internal studied data which is capable of performing a quantified benefit-risk assessment of the drug[2]. Here, we predicted the effect of time-varying weight gain effect of several atypical antipsychotics (aripiprazole, olanzapine, clozapine, quetiapine and risperidone) on adult patients with schizophrenia and compared weight gains using model-based meta-analysis
Methods:
Data were collected using systematic reviewing of references released in PubMed. Time dependent exponential model was tested to predict time varying weight changes in aripiprazole, olanzapine, clozapine, quetiapine and risperidone. Placebo effect was included as fixed weight change. Each population during simulation included 500 patients with various baseline weight, and simulations were performed for 1000 populations. Simulation compared the % weight change of each antipsychotics. Modeling and simulation were performed using a nonlinear mixed effects modeling methodology in the NONMEM (ver 7.5) assisted by PsN (ver 5.2.6) and R (ver 4.2.1).
Results:
After reviewing 930 references, 40 references were selected to perform MBMA. References that do have time-varying weight change data, same indication and meet purpose of our study were included. Baseline weight, changed weight in different time points, dose, number of subjects were collected from references to make data set and perform modeling. During modeling, weight change due to placebo was fixed to 0.2463 (kg). The onset of drug, Kd(/week), and drug effects were estimated by fitting data into time-dependent exponential model. The Kd of aripiprazole, olanzapine, clozapine, quetiapine and risperidone were estimated by 0.001356, 0.0959, 0.00978, 0.103 and 0.0718, respectively. Estimated drug effects (kg) in collected dose range of aripiprazole, olanzapine, clozapine, quetiapine were 13.2, 4.62, 12.2, 2.88 respectively. Risperidone’s drug effect was estimated using Emax (kg) model which describes change in drug effects by different dose, and estimated parameter Emax was 16.5 and ED50 (mg) was 9.52. To compare the weight change for each drug, simulation studies was conducted during 1 year simulation period and baseline weight of each population was assumed by distribution from N ~ (74.8, 6.982) which was derived from collected baseline from 40 references. Result showed the average percent weight change from baseline for each drug to be: Risperidone (9.6%), clozapine (7.7%), olanzapine (7.04%), quetiapine (5.29%) and aripiprazole (4%)
Conclusions:
Although atypical antipsychotic’s weight gain risk is well known adverse effect, it was restricted to conduct direct comparison between all available treatment options during clinical trial. In consequence, MBMA should be suggested as an alternative method to compare the treatment directly atypical antipsychotics. In the further study, we are planning to use model based meta-analysis to compare co-administration of drugs that can potentially inhibit weight gain due to antipsychotic use in patients with schizophrenia. Also, we want to see if weight-inhibition is correlated to reducing risk for metabolic syndrome.
References:
[1] Wu, H., et al., Antipsychotic-Induced Weight Gain: Dose-Response Meta-Analysis of Randomized Controlled Trials. Schizophr Bull, 2022. 48(3): p. 643-654
[2] Chan, P., Peskov, K. & Song, X. Applications of Model-Based Meta-Analysis in Drug Development. Pharm Res 39, 1761–1777 (2022).
[3] Gross JL, Rogers J, Polhamus D, et al. A novel model-based meta-analysis to indirectly estimate the comparative efficacy of two medications: an example using DPP-4 inhibitors, sitagliptin and linagliptin, in treatment of type 2 diabetes mellitus. BMJ Open. 2013;3(3):e001844. Published 2013 Mar 5. doi:10.1136/bmjopen-2012-001844
[4] Vázquez-Bourgon J, Ibáñez Alario M, Mayoral-van Son J, et al. A 3-year prospective study on the metabolic effect of aripiprazole, quetiapine and ziprasidone: A pragmatic clinical trial in first episode psychosis patients. Eur Neuropsychopharmacol. 2020;39:46-55. doi:10.1016/j.euroneuro.2020.08.009
[5] Bak M, Fransen A, Janssen J, van Os J, Drukker M. Almost all antipsychotics result in weight gain: a meta-analysis. PLoS One. 2014;9(4):e94112. Published 2014 Apr 24. doi:10.1371/journal.pone.0094112
