Levodopa-carbidopa intestinal gel high concentration formulation is clinically bioequivalent to commercial formulation.

A new levodopa-carbidopa intestinal gel (LCIG) system featuring a higher levodopa/carbidopa (LD/CD) concentration and viscosity, LCIG-HV, is being developed to reduce the intrajejunal volume of LD/CD that is administered as compared to the current commercial formulation, LCIG-LV. This study characterizes the LCIG-HV formulation and compares it to the LCIG-LV formulation via dissolution testing and a clinical pharmacokinetic bioequivalence study. In vitro release profiles of LD/CD were determined using a USP Dissolution Apparatus 2 with 500 mL of phosphate buffer (pH 4.5) operating at 25 RPM. A single dose, open-label study was conducted according to a two-period, randomized, crossover design in 28 healthy subjects. The point estimate (PE) of the levodopa Cmax geometric mean for the LCIG-HV formulation was 4% higher than that of the LCIG-LV formulation. PEs of levodopa AUCt and AUCinf geometric means were comparable for both formulations. PEs of carbidopa Cmax , AUCt and AUCinf geometric means for the LCIG-HV formulation were 3%-5% higher than those of the LCIG-LV formulation. For both formulations, the median Tmax for levodopa was 1.0 and 3.0 hours for carbidopa. The levodopa half-life harmonic mean was 1.6 hour for both formulations. The carbidopa half-life harmonic mean was 1.9 and 2.0 hour, respectively, for the LCIG-HV and LCIG-LV formulations. Cmax , AUCt and AUCinf of LD/CD carbidopa were comparable for both formulations. The current study demonstrates that the LCIG-LV and LCIG-HV formulations are clinically bioequivalent for LD/CD according to FDA guidance. However, the dissolution method was over discriminatory of formulation differences.

Development of In Vitro-In Vivo Correlation for Upadacitinib Extended-Release Tablet Formulation.

Upadacitinib is a selective Janus Kinase 1 inhibitor which is being developed for the treatment of several inflammatory diseases including rheumatoid arthritis. Upadacitinib was evaluated in Phase 3 studies as an oral extended-release (ER) formulation administered once daily. The purpose of this study was to develop a level A in vitro-in vivo correlation (IVIVC) for upadacitinib ER formulation. The pharmacokinetics of four upadacitinib extended-release formulations with different in vitro release characteristics and an immediate-release capsule formulation of upadacitinib were evaluated in 20 healthy subjects in a single-dose, randomized, crossover study. In vivo pharmacokinetic data and in vitro dissolution data (USP Dissolution Apparatus 1; pH 6.8; 100 rpm) were used to establish a level A IVIVC. Three formulations were used to establish the IVIVC, and the fourth formulation was used for external validation. A non-linear IVIVC best described the relationship between upadacitinib in vitro dissolution and in vivo absorption profiles. The absolute percent prediction errors (%PE) for upadacitinib Cmax and AUC were less than 10% for all three formulations used to establish the IVIVC, as well as for the %PE for the external validation formulation and the overall mean internal validation. Model was cross-validated using the leave-one-out approach; all evaluated cross-validation runs met the regulatory acceptance criteria. A level A IVIVC was successfully developed and validated for upadacitinib ER formulation, which meets the FDA and EMA regulatory validation criteria and can be used as surrogate for in vivo bioequivalence.