Two-Part Phase 1 Study to Evaluate the Taste Profile of Novel Belumosudil Oral Suspensions and Assess the Relative Bioavailability and Food Effect of the Selected Belumosudil Oral Suspension Compared With Oral Tablet Reference in Healthy Male Participants.

Belumosudil is a selective rho-associated coiled-coil-containing protein kinase 2 inhibitor in clinical use for the treatment of chronic graft-versus-host disease. The current tablet formulation may be inappropriate for children or adults with dysphagia and/or upper gastrointestinal manifestations of chronic graft-versus-host disease. This study (NCT04735822) assessed the taste and palatability of oral suspensions of belumosudil, evaluated the relative bioavailability of an oral suspension versus the tablet formulation, and characterized the effect of food on the pharmacokinetics of an oral suspension. Addition of sweetener and/or flavor vehicle improved the taste. Relative bioavailability of 200-mg doses of the oral suspension and tablet in the fed state was similar for belumosudil and its metabolites (KD025m1 and KD025m2), but absorption was faster with the oral suspension (median time to maximum concentration: 2 vs 3 hours). Administration of the oral suspension with food increased exposure compared with fasted administration, with maximum observed concentration being increased by 16% and area under the concentration-time curve from time 0 to the last measurable concentration (AUC0-last) by 19%. Safety and tolerability were consistent with the known safety profile of belumosudil. These results may support administration of a 200-mg belumosudil oral suspension with or without food.

Absolute Bioavailability, Mass Balance, and Metabolic Profiling Assessment of [14 C]-Belumosudil in Healthy Men: A Phase 1, Open-Label, 2-Part Study.

Belumosudil is a selective Rho-associated coiled-coil containing protein kinase 2 (ROCK2) inhibitor. ROCK2 has been shown to drive proinflammatory response and fibrosis that occurs with chronic graft-versus-host disease; therefore, inhibition of ROCK2 has emerged as a therapeutic target for chronic graft-versus-host disease. In this phase 1 two-part study, the pharmacokinetics, mass balance, and metabolic profile of belumosudil were evaluated after single doses of unlabeled belumosudil oral tablets (200 mg), radiolabeled belumosudil intravenous (IV) microtracer infusions (100 µg), and radiolabeled oral capsules (200 mg). Absolute bioavailability based on area under the plasma concentration-time curve from time 0 to infinity for the oral dose/area under the plasma concentration-time curve from time 0 to infinity for the IV dose was calculated as 63.7%. Radiolabeled IV microtracer dosing demonstrated a low extraction ratio and distribution of belumosudil into tissues. The majority of total radioactivity was recovered in feces, with minimal amounts recovered in urine, suggesting minimal renal elimination of belumosudil. In addition to parent and main metabolite KD025m2, metabolites identified in plasma included the phase 2 metabolites O-dealkylated belumosudil sulfate and belumosudil glucuronide. These metabolites (with the exception of the glucuronide) in addition to monohydroxy-belumosudil, and belumosudil diol were identified in feces. No metabolites in urine accounted for >10% of the radioactive dose.

Rational Design of a Multipurpose Bioadhesive Vaginal Film for Co-Delivery of Dapivirine and Levonorgestrel.

Human immunodeficiency virus (HIV) infection and unintended pregnancy, which can lead to life-threatening complications, are two major burdens for female reproductive health. To address these pressing health issues, multipurpose prevention technologies (MPTs) are proposed to deliver two or more drugs simultaneously. MPTs could offer several benefits for users such as improved convenience, increased effectiveness, reduced cost, and decreased environmental burden. Here, we report the development, and in vitro and in vivo assessment of a bioadhesive vaginal film as a coitally-independent MPT dosage form for delivering dapivirine (DPV) and levonorgestrel (LNG) to prevent HIV infection and unintended pregnancy, respectively. After confirming the feasibility of bioadhesive film use for weekly drug delivery in vivo through colpophotography and MRI evaluation, the pharmacokinetics (PK) of DPV/LNG single entity and combination bioadhesive films was investigated in pigtailed macaques (n = 5). Both drugs from single entity or combination films were able to provide sustained drug release in vivo. The combination film showed lower local tissue clearance for DPV and exhibited significantly increased plasma concentration for LNG as compared to the single entity film. This proof-of-concept study demonstrates the ability of this novel bioadhesive film platform to deliver LNG and DPV simultaneously as an MPT product for the prevention of HIV infection and unintended pregnancy.

Delineating the effects of hot-melt extrusion on the performance of a polymeric film using artificial neural networks and an evolutionary algorithm.

The aim of this study was to utilize an artificial neural network (ANN) in conjunction with an evolutionary algorithm to investigate the relationship between hot melt extrusion (HME) process parameters and vaginal film performance. Investigated HME process parameters were: barrel temperature, screw speed, and feed rate. Investigated film performance attributes were: percent dissolution at 30 min, puncture strength, and drug content. An ANN model was successfully developed and validated with a root mean squared error of 0.043 and 0.098 for training and validation, respectively. Of all three assessed process parameters, the model revealed that barrel temperature has a significant impact on film performance. An increase in barrel temperature resulted in increased dissolution and punctures strength and decreased drug content. Additionally, a successful implementation of an evolutionary algorithm was carried out in order to demonstrate the potential applicability of the developed ANN model in film formulation optimization. In this analysis, the values predicted of film performance attributes were within 1% error of the experimental data. The findings of this study provide a quantitative framework to understand the relationship between HME parameters and film performance. This quantitative framework has the potential to be used for film formulation development and optimization.

Novel Application of Hot Melt Extrusion for the Manufacturing of Vaginal Films Containing Microbicide Candidate Dapivirine.

Polymeric films are safe and effective and can be used for vaginal administration of microbicide drug candidates. Dapivirine (DPV), an investigational and clinically advanced antiretroviral drug, was selected as a model compound for this study. We have previously developed and clinically tested a quick-dissolving DPV film using solvent cast (SC) manufacturing technique. As an alternative to current pharmaceutical film manufacturing techniques, we investigated hot melt extrusion (HME) process in this study because it has several benefits, including its capacity as a continuous manufacturing process, lack of solvents, smaller footprint, and ease of scalability. The goal of this work was to evaluate the feasibility of using HME for DPV vaginal film manufacturing and to develop a robust manufacturing process using HME by evaluating the effect of process parameters on film quality and performance. DPV was successfully incorporated into a vaginal film using HME and maintained acceptable characteristics. Three process parameters (zone temperature, screw speed, and feed rate) had an impact on film quality and performance. Of these, the zone temperature was found to most significantly affect weight, thickness, puncture strength, and dissolution of films. Additionally, film manufacturing using HME was highly reproducible. Finally, the DPV HME film was comparable to films manufactured using SC in terms of physicochemical, biological, and safety characteristics including in vitro drug release, mechanical strength, tissue permeability, compatibility with commensal vaginal Lactobacilli, and in vitro bioactivity. These results demonstrate that HME is an effective, robust, and viable manufacturing method to produce vaginal films.