Formulation Development and Optimization via In Vivo Predictive In Vitro and In Silico Tools

Abstract

Corallopyronin A (CorA) is a natural anti-infective compound which is able to deplete Wolbachia, endosymbionts of the filarial nematodes. Challenging physicochemical properties of the neat drug (low aqueous solubility, instability due to isomerization, and waxy consistency) required development of suitable enabling formulations to be used in preclinical studies and future human clinical trials. The amorphous solid dispersion (ASD) formulation principle was identified to be the most promising approach for CorA. The spray drying process, using a mini-scale spray drier, was identified to provide a powder intermediate with a drug load of 20%. Stability enhancement was demonstrated for two different enteric capsule formulations comprising either CorA-ASD based on the matrix polymer povidone or on the matrix polymer copovidone. A second option with an alternative release profile was addressed via a sustained release tablet formulation as efficacy studies indicated that the time above the minimum inhibitory concentration is the driving force for Wolbachia depletion. <br /> Dissolution performances were assessed using an in vivo relevant biphasic dissolution approach. Species specific adjustments of this in vitro approach enabled a cross-species evaluation of the preclinical animals, mouse, rat and dog. A physiological based pharmacokinetic (PBPK) model and a physiologically based biopharmaceutic model (PBBM) were developed by integrating the in vitro measured and in silico predicted physicochemical and physiological characteristics of CorA. By using the biorelevant dissolution data for mice, it was able to predict plasma concentration profiles reaffirming dissolution as the decisive factor for oral bioavailability. Further preclinical in vivo PK data of the species mouse, rat and dog were used to build a cross-species in silico model predicting elimination and distribution of CorA in human. The data for the capsule and tablet formulations were validated using the results of the dog PK study. This approach enabled a rational first-in-human (FIH) prediction. <br /> Another part of the preclinical process included seven-days exploratory toxicological studies in rats and dogs. For the toxicological studies in rats, CorA dissolved in polyethylene glycol (PEG) 200 was found to be a suitable vehicle for offering high solubility properties and good vehicle tolerability. Mesoporous silica was identified as a suitable alternative for oral administration in dogs offering high loading capacities and good release properties. In both studies, vehicle tolerability was confirmed by administration of the neat vehicle for seven consecutive days. In conclusion, oral drug product candidates (capsule and tablet) which are essential for a FIH clinical trial were successfully developed. Innovative biorelevant dissolution assays for different species were established which in combination with PBPK modeling enabled an efficient development process guiding the selection of suitable CorA formulation candidates for clinical studies in human. The outlined activities represented a resource-saving approach to optimize the oral treatment during preclinical drug development and enabled a rational selection of promising formulation principles for a successful entry into the clinical phase of the promising anti-infective drug candidate against neglected tropical diseases.