title: An evaluation of human ADME and mass balance studies using regular or low doses of radiocarbon.
abstract: There has been increased interest in conducting human absorption, distribution, metabolism, and excretion (ADME) studies with low doses (up to 0.1 MBq) as opposed to regular doses (1.85-3.7 MBq) of radiocarbon (14C). This is due to the fact that low-dose human ADME studies may be conducted without dosimetry calculations and will lead to lower human radiation exposure. Here, we sought to compare the outcomes of low-dose versus regular-dose human ADME studies in healthy volunteers. Forty oral human ADME studies conducted at PRA were surveyed, among which 12 were low-dose studies. The fraction of drug material absorbed was 67% ± 7% in the regular-dose studies (data for 13 studies) versus 39% ± 16% in the low-dose studies (data for 5 studies). The average total recovery of14C in excreta was 93% ± 5% for regular-dose studies, and 21 of 28 such studies showed recoveries more than 90%. For low-dose studies, average total recovery was 89% ± 9%, and 6 of 12 studies showed recoveries more than 90%. Metabolite profiling was successful in all cases reported (13 regular-dose studies and 5 low-dose studies). There was no obvious relationship between the total recoveries of14C in excreta and the proportion of14C excreted in feces, or between the total recoveries and the plasma elimination half-lives for parent or total14C, neither in the low-dose nor the regular-dose studies. A significant correlation was found between the fraction absorbed and the recovery in feces in the low-dose but not in the regular-dose studies, and no correlation was found between the fractions absorbed and the total recoveries in both types of studies. Low-dose studies were more often conducted on drugs that had a plasma elimination half-life of parent drug more than 100 hours (5 of 12 studies) than regular-dose studies (1 of 26 studies). We conclude that both low-dose as well as regular-dose human ADME studies provide adequate data to support decision making for further drug development.
authors.affiliation: PRA Health Sciences, Groningen, The Netherlands.
authors.forename: A F
authors.initials: AF
authors.lastname: Roffel
authors.affiliation: PRA Health Sciences, Groningen, The Netherlands.
authors.forename: S P
authors.initials: SP
authors.lastname: van Marle
authors.affiliation: PRA Health Sciences, Groningen, The Netherlands.
authors.forename: J J
authors.initials: JJ
authors.lastname: van Lier
authors.affiliation: PRA Health Sciences, Groningen, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Hartstra
authors.affiliation: PRA Health Sciences, Groningen, The Netherlands.
authors.forename: E-J
authors.initials: EJ
authors.lastname: van Hoogdalem
mesh_terms: D065966:Absorption, Physicochemical; D000284:Administration, Oral; D002250:Carbon Radioisotopes / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D006801:Humans; D014018:Tissue Distribution
chemical_list: D002250:Carbon Radioisotopes
keywords: dosimetry; drug development; human ADME studies; mass balance; metabolite profiling; microtracer; radiocarbon