Long acting injectables (LAI) products are a popular intervention for treating a number of chronic conditions, with their long drug release reducing the administration frequency and thus improving patient adherence. The extended release, however, can provide a major challenge to bioequivalence (BE) testing since the long absorption half-life results in a long washout period, meaning that a traditional BE study can be many months or years in length. The unique PK profile for LAI products also means that it is critical to have appropriate metrics to summarise the plasma concentration profile. In this work, we use paliperidone as a case study to demonstrate how Population PK modelling can be utilised to explore sensitivity of summary metrics to different products. We also determine a range of products that are bioequivalent after both multiple dosing and single dosing. Finally, we show how the modelling can be used in a (virtual) PK study as an alternative approach to determining bioequivalence. This work demonstrates the potential for Population PK modelling in bioequivalence assessment, opening doors to more streamlined product development.

Background/Objectives: This paper describes the use of physiologically based biopharmaceutics modelling (PBBM) to predict the effect of food on diclofenac and ibuprofen absorption from ultra-rapid-release Surge Dose^® tablets. Methods: Fasted-state diclofenac pharmacokinetics (PK) were used with published IV data and biorelevant dissolution data for the diclofenac tablets to develop a mechanistic PBBM model which could be used to predict absorption. Results: The resultant model that best fitted the PK data showed that, in vivo, the ultra-rapid-release tablets behaved like a solution with a median time to peak plasma concentration (T_max) of 20 min. Incorporating a well-established model for gastric emptying in the fed state, the fed T_max for these tablets was predicted to be 21 min, similar to that seen in fasted subjects. Use of a PBBM model to predict absorption of ibuprofen in the fasted and fed states again showed that ultra-rapid-release tablets produced fast and consistent absorption independent of the presence of food. Predicted mean T_max values were 31.8 and 35.4 min in the fasted and fed states, respectively. Conclusions: Therefore, even if Surge Dose^® formulations are taken after food, as frequently recommended for NSAIDs, the speed of absorption and subsequent onset of action should not be impacted.

Demonstratingbioequivalence (BE) is important for the development of lower cost genericproducts, and also for approving post-submission manufacturing changes.However, for many complex parenteral products, BE demonstration can be verychallenging. For example, long-acting injectable products are engineered tohave an extended release over several weeks or months, but this also means thata traditional BE study can take many months or years to perform. Here, we summarisehow population PK modelling, which captures differences in PK profiles due topopulation variation, could be used explore hundreds of virtual formulations,and thus determine a range of products that are bioequivalent after bothmultiple and single dosing. This provides a guide for formulation developmentbut also opens alternative, more streamlined routes to BE assessment.

Forming amorphous solid dispersions (ASDs) is one method for improving the solubility and subsequent absorption of poorly-water soluble drugs. An ASD is a matrix of a poorly water-soluble compound with a hydrophilic polymer carrier, which stabilises the drug in its amorphous form. The choice of polymer is often made based on previous success and precedence in other ASD products, and not on the suitability for the drug in development. A bespoke in-silico polymer selection tool (PST) has been developed which selects polymers based on their structural complementarity with the drug. Here, we demonstrate how use of the PST in early development of the Tacrolimus ASD would have identified a more optimal polymer with better API miscibility.