Abstract
Congenital erythropoietic porphyria (CEP), also known as Günther’s disease, results from a deficient activity in the fourth enzyme, uroporphyrinogen III synthase (UROIIIS), of the heme pathway. Ciclopirox (CPX) is an off-label drug, topically prescribed as an antifungal. It has been recently shown that it also acts as a pharmacological chaperone in CEP, presenting a specific activity in deleterious mutations in UROIIIS. Despite CPX is active at subtoxic concentrations, acute gastrointestinal (GI) toxicity was found due to the precipitation in the stomach of the active compound and subsequent accumulation in the intestine. To increase its systemic availability, we carried out pharmacokinetic (PK) and pharmacodynamic (PD) studies using alternative formulations for CPX. Such strategy effectively suppressed GI toxicity in WT mice and in a mouse model of the CEP disease (UROIIISP248Q/P248Q). In terms of activity, phosphorylation of CPX yielded good results in CEP cellular models but showed limited activity when administered to the CEP mouse model. These results highlight the need of a proper formulation for pharmacological chaperones used in the treatment of rare diseases.
Highlights
IntroductionShortcomings in the pharmacological properties constitute one of the main sources in the failure of clinical trials for drugs that have proven active in preclinical studies [1]
Shortcomings in the pharmacological properties constitute one of the main sources in the failure of clinical trials for drugs that have proven active in preclinical studies [1].To be safe, a drug must be completely eliminated from the body, ideally not long after the activity’s window timeframe [2]
We have explored all these strategies over ciclopirox, a topical antifungal that has been repositioned as a potential drug for the treatment of congenital erythropoietic porphyria (CEP), acting as a pharmacological chaperone [3]
Summary
Shortcomings in the pharmacological properties constitute one of the main sources in the failure of clinical trials for drugs that have proven active in preclinical studies [1]. A drug must be completely eliminated from the body, ideally not long after the activity’s window timeframe [2]. Has to be fine-tuned with the biochemical and physiological effect of the drug (pharmacodynamics, PD). A complex formulation may help PK optimization without jeopardizing the active principle’s efficacy, but this strategy may be of limited applicability. We have explored all these strategies over ciclopirox, a topical antifungal that has been repositioned as a potential drug for the treatment of congenital erythropoietic porphyria (CEP), acting as a pharmacological chaperone [3]
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