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A review of the use of microdoses and isotopic microtracers for clinical intravenous pharmacokinetic (i.v. PK) data provision is presented. The extent of application of the varied approaches available and the relative merits of each are highlighted with the aim of assisting practitioners in making informed decisions on the most scientifically appropriate design to adopt for any given new drug in development. It is envisaged that significant efficiencies will be realized as i.v. PK data in humans becomes more routinely available for suitable assets in early development, than has been the case prior to the last decade. [ABSTRACT FROM AUTHOR]

The human absorption, distribution, metabolism, and excretion (hADME) study is the cornerstone of the clinical pharmacology package for small molecule drugs, providing comprehensive information on the rates and routes of disposition and elimination of drug‐related material in humans through the use of 14C‐labeled drug. Significant changes have already been made in the design of the hADME study for many companies, but opportunity exists to continue to re‐think both the design and timing of the hADME study in light of the potential offered by newer technologies, that enable flexibility in particular to reducing the magnitude of the radioactive dose used. This paper provides considerations on the variety of current strategies that exist across a number of pharmaceutical companies and on some of the ongoing debates around a potential move to the so called "human first/human only" approach, already adopted by at least one company. The paper also provides a framework for continuing the discussion in the application of further shifts in the paradigm. [ABSTRACT FROM AUTHOR]

The disposition and metabolism of prexasertib, a CHK-1 inhibitor was characterised over a 120 h period following a single 170-mg intravenous dose of [14C]prexasertib (50 µCi) to 6 patients with advanced/metastatic solid tumours. The prexasertib safety profile was consistent with prior studies. Plasma, urine, and faeces were analysed for radioactivity, prexasertib, and metabolites. Geometric mean t1/2 in plasma was 34.2 h for prexasertib and 73.8 h for total radioactivity. Unchanged prexasertib accounted for approximately 9% of plasma total radioactivity, indicating extensive metabolism by the presence of circulating metabolites. Both renal and faecal excretion were identified as important routes of elimination since 41.8% (±12.9%) of the total administered radioactivity was recovered in the renal excretions and 32.2% (±7.28%) in the faecal excretions. Mean renal clearance was approximately 15% of the total systemic clearance, while biliary clearance was also low. Prexasertib was cleared predominantly by metabolism with only 23% of the dose recovered in excreta as intact drug. Radioactivity was eliminated predominantly within 72 h in urine, but faecal elimination was protracted. The metabolism of prexasertib was complex while primary metabolic clearance pathways involved were oxidative deamination, O-dealkylation, mono-oxidation, and possibly direct glucuronide conjugation. Although prexasertib was the major component in plasma, up to 11 metabolites were observed. The most abundant metabolites identified in plasma were glucuronides and none of these are expected to contribute to the pharmacological activity or pose a safety concern. [ABSTRACT FROM AUTHOR]

1. This study assessed the value of a static in vitro human hepatocyte-murine stromal cell coculture model to qualitatively and quantitatively predict human in vivo metabolic clearance pathways using 14C-labeled test compounds and compared these results to an in vitro suspended human hepatocyte model and the in vivo human 14C ADME studies. 2. Test compounds represented a diverse set of clearance pathways (Phase I and Phase II). Compounds were incubated for 4 h in suspended human hepatocytes and for 24 and 168 h in the human co-culture model. Multivariate analysis revealed that long-term (168 h) incubation of test compounds in the co-culture had reasonable quantitative prediction of the in vivo human clearance pathways as compared to the 4 h suspended hepatocytes or the 24 h co-culture incubation. 3. In vivo and in vitro disconnects were observed in cases where extra-hepatic metabolism or urinary excretion was observed in vivo. Differences in the relative percentages of Phase I and Phase II metabolites observed were likely due to microbial _-glucuronidase hydrolysis of conjugates and microflora mediated metabolism in the gut not present in the in vitro systems. [ABSTRACT FROM AUTHOR]

1. The disposition and metabolism of galunisertib (LY2157299 monohydrate, a TGF-βRI Kinase/ALK5 Inhibitor) was characterized following a single oral dose of 150 mg of [14C]-galunisertib (100 µCi) to six healthy human subjects. 2. The galunisertib plasma half-life was 8.6 h, while the14C half-life was 10.0 h. Galunisertib was abundant in circulation (40.3% of the14C AUC024 h), with 7 additional metabolites detected in plasma. Two metabolites LSN3199597 (M5, mono-oxidation), and M4 (glucuronide of M3) were the most abundant circulating metabolites (10.7 and 9.0% of the 14C AUC024 h respectively). The pharmacological activity of LSN3199597 was tested and found to be significantly less potent than galunisertib. 3. The dose was recovered in feces (64.5%) and in urine (36.8%). Galunisertib was cleared primarily by metabolism, based on low recovery of parent in excreta (13.0% of dose). Due to the slowin vitrometabolism of galunisertib in suspended hepatocytes, a long term hepatocyte system was used to model the human excretion profile. 4. Expressed cytochromes P450 and hepatocytes indicated clearance was primarily CYP3A4-mediated. Mechanistic static modeling that incorporated small non-CYP-mediated metabolic clearance and renal clearance components predicted an AUC ratio of 4.7 for the effect of itraconazole, a strong CYP3A4 inhibitor, on galunisertib. [ABSTRACT FROM PUBLISHER]

The disposition and metabolism of prexasertib, a CHK-1 inhibitor was characterised over a 120 h period following a single 170-mg intravenous dose of [ 14 C]prexasertib (50 µCi) to 6 patients with advanced/metastatic solid tumours.The prexasertib safety profile was consistent with prior studies. Plasma, urine, and faeces were analysed for radioactivity, prexasertib, and metabolites. Geometric mean t 1/2 in plasma was 34.2 h for prexasertib and 73.8 h for total radioactivity. Unchanged prexasertib accounted for approximately 9% of plasma total radioactivity, indicating extensive metabolism by the presence of circulating metabolites. Both renal and faecal excretion were identified as important routes of elimination since 41.8% (±12.9%) of the total administered radioactivity was recovered in the renal excretions and 32.2% (±7.28%) in the faecal excretions. Mean renal clearance was approximately 15% of the total systemic clearance, while biliary clearance was also low. Prexasertib was cleared predominantly by metabolism with only 23% of the dose recovered in excreta as intact drug. Radioactivity was eliminated predominantly within 72 h in urine, but faecal elimination was protracted.The metabolism of prexasertib was complex while primary metabolic clearance pathways involved were oxidative deamination, O-dealkylation, mono-oxidation, and possibly direct glucuronide conjugation. Although prexasertib was the major component in plasma, up to 11 metabolites were observed. The most abundant metabolites identified in plasma were glucuronides and none of these are expected to contribute to the pharmacological activity or pose a safety concern.

1. The disposition and metabolism of galunisertib (LY2157299 monohydrate, a TGF-βRI Kinase/ALK5 Inhibitor) was characterized following a single oral dose of 150 mg of [ 14 C]-galunisertib (100 µCi) to six healthy human subjects. 2. The galunisertib plasma half-life was 8.6 h, while the 14 C half-life was 10.0 h. Galunisertib was abundant in circulation (40.3% of the 14 C AUC024 h), with 7 additional metabolites detected in plasma. Two metabolites LSN3199597 (M5, mono-oxidation), and M4 (glucuronide of M3) were the most abundant circulating metabolites (10.7 and 9.0% of the 14C AUC024 h respectively). The pharmacological activity of LSN3199597 was tested and found to be significantly less potent than galunisertib. 3. The dose was recovered in feces (64.5%) and in urine (36.8%). Galunisertib was cleared primarily by metabolism, based on low recovery of parent in excreta (13.0% of dose). Due to the slow in vitro metabolism of galunisertib in suspended hepatocytes, a long term hepatocyte system was used to model the human excretion profile. 4. Expressed cytochromes P450 and hepatocytes indicated clearance was primarily CYP3A4-mediated. Mechanistic static modeling that incorporated small non-CYP-mediated metabolic clearance and renal clearance components predicted an AUC ratio of 4.7 for the effect of itraconazole, a strong CYP3A4 inhibitor, on galunisertib.