Development of in vitro-in vivo correlation for establishing patient-centric quality standards of dissolution for...

In vitro-in vivo correlation (IVIVC) studies have been commonly used for assessing the impact of formulation and manufacturing changes on drug performance. The current study developed an IVIVC to establish patient-centric quality standards (PCQS) for dissolution using lamotrigine extended release (ER) 300 mg tablets as model formulation. Dissolution of Lamotrigine ER tablets was tested using various dissolution apparatus (USP II & III), dissolution media (biorelevant, non-bio relevant), media composition, pH, and hydrodynamics. The plasma lamotrigine concentration time profiles following oral administration were simulated using a physiologically based pharmacokinetic (PBPK) model. This PBPK model was developed and verified using plasma lamotrigine profiles following administration of lamotrigine intravenous (IV) solution and oral immediate-release (IR) tablets. Model verification results showed accurate prediction of Cmax and AUC following IV and IR lamotrigine administration with confidence level exceeding 95 %. Various IVIVC models were investigated using dissolution data of fast, medium, and slow ER lamotrigine 300 mg tablets manufactured in-house. Optimal IVIVC models were obtained using a second order polynomial and a two-compartment Loo-Riegelman deconvolution. The results of IVIVC goodness of fit showed that the dissolution condition in standard compendial media using USP apparatus II established a Level A IVIVC. This IVIVC model passed both internal and external validation criteria. Using these dissolution conditions, a PCQS of ≤10 % release at 2 h, ≤45 % at 6 h, and ≥80 % at 18 h was derived. In conclusion, this study demonstrates that a PCQS for lamotrigine ER tablets dissolution can be established using verified PBPK and validated IVIVC model and offers a reliable approach for assessment of product performance.