Virtual Bioequivalence Assessment of Tofacitinib Once Daily Modified Release Dosage Form in Pediatric Subjects.

Abstract

Tofacitinib is a potent, selective inhibitor of the Janus kinase (JAK) family of kinases with a high degree of selectivity within the human genome's set of protein kinases. Currently approved formulations for tofacitinib citrate are immediate release (IR) tablets, modified release (MR) tablets and IR solution. A once daily MR microsphere formulation was developed for pediatric patients. Previously, bioequivalence (BE) between the 10 mg once daily (QD) MR microsphere formulation and 5 mg twice daily (BID) IR solution has been established with PBPK virtual BE trials (VBE) in place of a clinical BE trial in healthy adult population. In this research, the PBPK model based VBE approach was extended to pediatric population. Pediatric PBPK model verification was conducted by first examining predicted vs observed demographic information such as body weight (BWT) and glomerular filtration rate (GFR). After confirming the alignment in demographic background between clinical study participants vs virtual pediatric subjects, multiple ontogeny profiles for CYP3A4 and CYP2C19 were examined. The established model predicted AUC and C_max within 1.5-fold of observed values for multiple trials, age groups and formulations. Lastly, VBE trials in pediatric subjects were conducted with PBPK model generated pharmacokinetic (PK) parameter values with clinically observed intra-subject coefficient of variation (ICV) in adults. Since ICV in pediatric population is unknown, the sensitivity around ICV was also evaluated to assess the BE risk between IR solution and MR microsphere formulation in pediatric population. The results demonstrated that the IR oral solution BID and MR microsphere formulation QD are BE in pediatric population.