What is the Objective of the Mass Balance Study? A Retrospective Analysis of Data in Animal and Human Excretion Studies Employing Radiolabeled Drugs

Abstract

Mass balance excretion studies in laboratory animals and humans using radiolabeled compounds represent a standard part of the development process for new drugs. From these studies, the total fate of drug-related material is obtained: mass balance, routes of excretion, and, with additional analyses, metabolic pathways. However, rarely does the mass balance in radiolabeled excretion studies truly achieve 100% recovery. Many definitions of cutoff criteria for mass balance that identify acceptable versus unacceptable recovery have been presented as ad hoc statements without a strong rationale. To address this, a retrospective analysis was undertaken to explore the overall performance of mass balance studies in both laboratory animal species and humans using data for 27 proprietary compounds within Pfizer and extensive review of published studies. The review has examined variation in recovery and the question of whether low recovery was a cause for concern in terms of drug safety. Overall, mean recovery was greater in rats and dogs than in humans. When the circulating half-life of total radioactivity is greater than 50 h, the recovery tends to be lower. Excretion data from the literature were queried as to whether drugs linked with toxicities associated with sequestration in tissues or covalent binding exhibit low mass balance. This was not the case, unless the sequestration led to a long elimination half-life of drug-related material. In the vast majority of cases, sequestration or concentration of drug-related material in an organ or tissue was without deleterious effect and, in some cases, was related to the pharmacological mechanism of action. Overall, from these data, recovery of radiolabel would normally be equal to or greater than 90%, 85%, and 80% in rat, dog, and human, respectively. Since several technical limitations can underlie a lack of mass balance and since mass balance data are not sensitive indicators of the potential for toxicity arising via tissue sequestration, absolute recovery in humans should not be used as a major decision criteria as to whether a radiolabeled study has met its objectives. Instead, the study should be seen as an integral part of drug development answering four principal questions: 1) Is the proposed clearance mechanism sufficiently supported by the identities of the drug-related materials in excreta, so as to provide a complete understanding of clearance and potential contributors to interpatient variability and drug-drug interactions? 2) What are the drug-related entities present in circulation that are the active principals contributing to primary and secondary pharmacology? 3) Are there findings (low extraction recovery of radiolabel from plasma, metabolite structures indicative of chemically reactive intermediates) that suggest potential safety issues requiring further risk assessment? 4) Do questions 2 and 3 have appropriate preclinical support in terms of pharmacology, safety pharmacology, and toxicology? Only if one or more of these four questions remain unanswered shou...

Apixaban Metabolism and Pharmacokinetics after Oral Administration to Humans

“…Studies in rat and dog models have indicated good mass balance and no tissue accumulation of radioactivity (data not shown). The problems sometimes associated with attaining complete mass balance in human absorption, distribution, metabolism, and elimination studies have been documented in a recent review of the subject (Roffey et al, 2007).…”

Addressing the Challenges of Low Clearance in Drug Research

“…Quantitative radiometric profiling of metabolites in biological fluids from these studies can be difficult because the drug-related material becomes too dilute. Also, it has been shown that recovery of radioactivity in an excretion study is lower when the half-life of the compound is long (1).…”

Sugammadex is cleared rapidly and primarily unchanged via renal excretion

“…There may be many causes of incomplete recovery of the radiolabel in mass balance trials (such as technical limitations and tissue retention), and it is actually rare for the mass balance in radiolabeled excretion studies to truly achieve 100% recovery [16]. 16 The minimal role of metabolism in the clearance of sugammadex is fully in line with the excretion profile of other cyclodextrins, which has been noted to be almost entirely renal [14,15,17,18], particularly in man. Subsequent profiling for metabolites in urine and plasma samples demonstrated that the major part of total radioactivity could be attributed to the parent compound, sugammadex (data on file).…”

“…There may be many causes of incomplete recovery of the radiolabel in mass balance trials (such as technical limitations and tissue retention), and it is actually rare for the mass balance in radiolabeled excretion studies to truly achieve 100% recovery [16]. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 Studies in volunteers and surgical patients receiving sugammadex to reverse rocuronium-or vecuronium-induced blockade have also demonstrated that the predominant route of elimination for the complex is via the renal route, and in the presence of sugammadex, the major route of elimination of rocuronium changes from the hepatic to the renal route [10][11][12].…”