Single-dose Study of [14C]Lorlatinib (PF-06463922) Metabolism In Healthy Male Volunteers
Condition: Healthy Volunteers
Study type: Interventional
Phase: Phase 1

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.
    

Detailed description: 
      This open-label, radiolabeled, single 100-mg dose study in approximately 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, PF-06895751) resulting from
      cleavage of the amide and aromatic ether bonds of lorlatinib, accounting for 21.0% of the
      circulating radioactivity or ~ 47.3% plasma M8 to lorlatinib AUC percent ratio. 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 the M8 metabolite will not
      be radiolabeled, its concentrations in plasma will be determined using a validated liquid
      chromatography tandem mass spectrometric (LC/MS/MS) assay.

      The sample size of approximately 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
      early release criteria is met. The early release criteria are: 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, and will aid in the understanding of the possible causes for the unexpected
      findings from a DDI study where a single 100 mg dose of lorlatinib was co-administered with
      600 mg rifampin QD (study B7461011).

      Banked biospecimens will be collected for the purpose of conducting research; specific uses
      are described in the Banked Biospecimens section. Comparing the deoxyribonucleic acid (DNA),
      ribonucleic acid (RNA), protein, and metabolite variation patterns of subjects who respond
      well and those who respond poorly to treatment may help to better define the most appropriate
      group of subjects in which to target a given treatment. Collecting biospecimens for
      exploratory pharmacogenomic/genomic/biomarker analyses and retaining them in the Biospecimen
      Banking System (BBS) make 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.
    

Intervention name(s): [14C]lorlatinib
Intervention type(s): Drug
Intervention description(s): Extemporaneously compounded oral solution of [14C]lorlatinib (approximately 100 mg/100 µCi)
Other intervention name(s): [14C]PF-06463922
Intervention model: Single Group Assignment
Intervention model description: Open-label, radiolabeled, single-dose study of an oral solution of [14C]lorlatinib (100 mg/100 µCi) in 6 healthy male volunteers. Confinement from Day -1 through Day 14 (or until 1 of 2 early release criteria is met). No returns; one follow-up phone call (at 28 to 35 days post dose).
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: healthy volunteers, lorlatinib, PF-06463922, ADME, NSCLC, radiolabel, metabolism