The oral bioavailability of a pleuromutilin antibiotic candidate is increased after co-administration with the CYP3A4 inhibitor ritonavir and the P-gp inhibitor zosuquidar formulated as amorphous solid dispersions

The aim of the present work was to investigate if CYP-mediated metabolism or P-gp recognition were the main limitations to developing oral formulations of the pleuromutilin drug candidate CVH-174, 16, and to subsequently increase the bioavailability through a formulation design based on amorphous solid dispersions (ASDs) containing either a CYP3A inhibitor or a P-gp inhibitor or both. ASDs were produced using HPMC-5 with ritonavir and zosuquidar as CYP3A4 and P-gp inhibitors, respectively, through freeze-drying. The ASDs were characterized using XRPD over time to assess the stability of the formulations. The oral bioavailability was investigated in Sprague-Dawley rats following either oral or intravenous (IV) dosing. The results showed that ritonavir could be supersaturated when formulated in an HPMC-5 ASD, whereas HPMC-5 could not increase the solubility of CVH-174 and zosuquidar. The ASD formulations remained stable for the period covering the experiments. In vivo IV dosing showed that CVH-174 was metabolized fast with a half-life of 0.15 h. The oral bioavailability of CVH-174 was low ∼ 1 % and could not be increased by co-dosing with a P-gp inhibitor alone, whereas the CYP3A4 inhibitor did increase the bioavailability. The combined co-administration of ritonavir- and zosuquidar-containing ASDs surprisingly increased CVH-174 bioavailability to around 18 %. In conclusion, the oral bioavailability of CVH-174 can be significantly increased through a formulation design encompassing an inhibitor of the CYP3A4 enzyme, and this holds great potential for the future development of an inherent metabolic labile pleuromutilin drug class.