Extended Data Fig. 10. Phosphonate-containing drugs show similar, species-specific pharmacokinetics.

The PK properties of phosphonate containing drugs have been well-studied in diverse model species as well as human patients and exhibit remarkable similarity, despite extensive chemical diversity. The very similar PK properties of these diverse drugs, derives from the fact their physiochemistry and pharmacokinetics are predominantly dictated by the negatively charged phosphonate group, conferring water solubility and limited protein binding. This water solubility means that drugs distribute with water and are cleared by a predominantly renal mechanism. Renal excretion is passive glomerular filtration and active tubular secretion, which can be modulated by drugs like Probenecid⁴⁰. Rodent species rapidly eliminate phosphonate drugs, with >95% of injected drug excreted unchanged within 1 hr. In non-human primates, half-lives are typically 10-times longer, and in human patients even more so. This copious body of PK data provides a guide towards predictions of how HEX might behave in human patients. The comparison with fosmidomycin is especially informative as it is nearly identical, except for 1 C-C bond, to fosmidomycin. The elimination half-life of HEX in rodents and NHP falls very much in line with other phosphonate drugs and allows reasonable confidence in PK prediction in other models (canines) and in human patients. N/A = data not found in the literature.