Safety Assessment of Prodrugs

The safety assessment for a prodrug is generally more complicated compared to a per se pharmacologically active drug molecule. Thus, sufficient exposure in experimental preclinical safety studies in animal models must be obtained and documented not only in terms of the prodrug itself but also for the parent drug and other relevant metabolites. This is required for the establishment of relevant predictions, safety ratios, and therapeutic indices in humans and may prove very difficult for a prodrug. For example, selection of appropriate preclinical species such as mice, rats, dogs, and monkeys for risk assessment is critical as it is not only important to select the proper species in terms of pharmacological and toxicological relevance compared to humans. It is of equal importance to ensure that the species used in preclinical safety assessment of a prodrug adequately biotransform the prodrug into the active species to a similar extent and at the right site in order to fully explore and evaluate the risk/benefit of the prodrug. In addition, a development program for prodrugs must also include safety assessment of the promoiety or promoieties that are released in the body when the prodrug undergoes biotransformation. Although, a promoiety is normally designed to be inactive, potential toxicological effects must be properly addressed and documented during development.

One example of a potential problematic promoiety is formaldehyde, which is released during the biotransformation of various prodrugs, most importantly those utilizing the double-prodrug concept (Figure 9.6). Formation of formaldehyde from a prodrug could be considered a problem, but the amount released in the body from prodrugs is low compared to the release of formaldehyde from normal metabolic processing of endogenous compounds. Thus, the release of formaldehyde from prodrugs is not considered to pose a safety risk.

Another potentially more critical promoiety that is also widely used in prodrug design is pivalate or pivalic acid (Figure 9.10). This has been associated with changes in carnitine homeostasis through reaction with cellular coenzyme A and subsequent formation of pivaloyl-CoA, which can lead to depletion of carnitine from the body. The potential negative effects has gained attention from regulatory bodies can be evaluated based upon the intended daily dose of the prodrug and the duration of treatment. In most cases, however, exposure to the pivalic acid is regarded to have no or little toxicological impact, which may be outweighed by the clinical advantages offered by the prodrug. However, extended treatment with high dose prodrugs such as pivampicilin (Figure 9.9) may in extreme situations lead to clinical important carnitine deficiency. Thus, careful consideration of factors such as daily dose and duration of treatment should be given prior to a decision of designing and developing a pivalate-based prodrug and included in the overall benefit/risk evaluation of the development program.

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