Single-dose Study of [14C]Lorlatinib (PF-06463922) Metabolism In Healthy Male Volunteers
Status:
Completed
Trial end date:
2017-08-25
Target enrollment:
Participant gender:
Summary
This open-label, radiolabeled, single 100-mg dose study in 6 healthy male volunteers has been
designed to further the understanding of human metabolism of lorlatinib. A prior radiolabel
study using [14C]lorlatinib (study B7461004) identified an unexpected major metabolite in
plasma; a benzoic acid metabolite (M8) resulting from cleavage of the amide and aromatic
ether bonds of lorlatinib, accounting for 21.0% of the circulating radioactivity. However,
due to the position of the 14C radiolabel on the carbonyl carbon, the metabolic fate of the
larger fragment of lorlatinib resulting from this cleavage, the pyrido-pyrazole substructure,
could not be determined. In this current study, the radiolabel will be on the pyrazole ring
allowing for monitoring the metabolic fate of the pyrido-pyrazole part of the lorlatinib
molecule cleaved during the formation of the M8 metabolite. Since M8 will not be
radiolabeled, its concentrations in plasma will be determined using a validated assay.
The sample size of 6 was selected to ensure at least 4 fully evaluable subjects with
completed collections of plasma, urine, and fecal samples. This is a standard sample size
used for mass-balance/ADME studies which include assessment of metabolic profiling, and is
not based on empirical data or hypothesis testing criteria.
Metabolic profiling of radiolabeled components will be performed on pooled plasma samples as
well as on cumulative urine and feces excreted until Day 14 postdose or until one of the
following early release criteria is met: 1) recovery in excreta of at least 90% of
administered radioactivity, or 2) less than 1% of administered radioactivity being recovered
in excreta from two consecutive days (ie, total for urine + feces should be <1% on 2
consecutive days). Plasma concentrations of both lorlatinib and its unlabeled M8 metabolite
will be analyzed using validated assays. Information from this study will complement the
metabolic profiling results from study B7461004, will help guide in the assessment of
potential drug-drug interactions (DDIs) and the need for other DDI studies with lorlatinib.
Banked biospecimens will be collected for the purpose of conducting research. Collecting
biospecimens for exploratory analyses makes it possible to better understand the
investigational product's mechanism of action and to seek explanations for differences in,
for example, exposure, tolerability, safety, and/or efficacy not anticipated prior to the
beginning of the study.