Mass Balance Studies in Animals and Humans

Abstract

Before first‐in‐human (FIH) studies with a new drug candidate, preclinical studies need to be conducted to fulfill regulatory requirements or to facilitate regulatory approval. In the United States, investigational new drug (IND) applications with the Food and Drug Administration (FDA) may include IND enabling studies, such as (i) in vitro and in vivo pharmacology studies for intended use, (ii) toxicology studies supporting the starting dose and duration of an FIH study (such as single‐ or multiple‐dose studies in one rodent and nonrodent species with toxicokinetics, genotoxicity battery, safety pharmacology battery), (iii) single‐dose pharmacokinetics (PKs) in one rodent and nonrodent species, (iv) in vitro plasma protein binding in relevant species, and (v) in vitro cross species metabolism study in relevant species. While not mandatory for IND submissions, comprehensive preclinical absorption, distribution, metabolism, and excretion (ADME) studies, including biotransformation or metabolite profiling, conventional mass balance, or tissue distribution by quantitative whole‐body autoradiography (QWBA) studies can make a submission package more compelling for progression toward phase I clinical studies. Typically, preclinical ADME together with mass balance studies are recommended before conducting human ADME and mass balance studies, which are generally initiated after the successful synthesis of the radiolabeled drug. For preclinical ADME species, the selection of doses is often based on pre‐existing toxicity information and targeted therapeutic doses. For human ADME studies, which include the evaluation of mass balance, a relevant dose in the anticipated therapeutic range is typically chosen. Conventional mass balance studies only allow the calculation of mass recovery and PK parameters of the radiolabeled drug by quantification of the radioactivity present in excreta such as urine, feces, or bile. Nowadays, these mass balance studies are often conducted as part of more comprehensive ADME studies, where additional information is obtained, including (i) PK properties of the drug and its metabolite(s) in blood or plasma; (ii) absorption estimates via plasma/blood data, urinary data, or fecal data; (iii) elimination pathways and drug metabolism; (iv) total drug exposure and its metabolites in different organs and tissues at different time intervals. In this chapter, fundamental scientific considerations for the successful design, conduct, and interpretation of conventional, basic mass balance and more comprehensive ADME studies are reviewed and discussed.

Midostaurin, a Novel Protein Kinase Inhibitor for the Treatment of Acute Myelogenous Leukemia: Insights from Human Absorption, Metabolism, and Excretion Studies of a BDDCS II Drug

“…In human, the absorption of midostaurin was rapid after oral administration in a diluted microemulsion, with the average peak plasma concentration of total radioactivity observed between 1 and 3 hours postdosing. The extent of oral absorption can be estimated when radiolabeled drug is administered (Lin, et al, 2012). Midostaurin oral absorption was estimated to be high, because only 3.43% of unchanged midostaurin was found in the feces (Table 4) and midostaurin was confirmed to be stable in the in vitro fecal incubation study (Novartis data on file).…”

“…Midostaurin oral absorption is high (.90%), because only 3.43% of intact drug was found in the feces (Table 4), which was likely unabsorbed drug because midostaurin is stable in the gastrointestinal milieu. Preclinical studies also showed high absorption in rats (.90%) (Supplemental Material), and the rat is a predictive and commonly used model of absorption in humans (Chiou and Barve, 1998;Lin, et al, 2012). Because midostaurin is a lipophilic drug (cLogP .…”

“…Based primarily on the Phase III RATIFY clinical study, the United States Food and Drug Administration granted Breakthrough Therapy designation to PKC412 (midostaurin) in February 2016 (Novartis Press Release, 2016). To facilitate drug approval, mass balance studies are typically conducted during late drug development stages (Lin et al, 2012, Penner et al, 2012. Here, insights from absorption, metabolism, and excretion studies conducted with midostaurin, a highly lipophilic drug, are described.…”