Effect of Multiple Doses of Modafinil on the Pharmacokinetics of Single Dose Lorlatinib in Healthy Participants
Condition: Adult; Drug Interactions; Healthy Volunteers; Humans
Study type: Interventional
Phase: Phase 1

Summary: 
      The primary purpose of the study is to characterize the safety profile of lorlatinib in the
      presence of a moderate CYP3A4/5 inducer, modafinil. In another drug-drug interaction study
      for lorlatinib coadministered with a strong CYP3A4/5 inducer, rifampin, all participants
      experienced increases in liver enzymes after receiving the combination of a single dose
      lorlatinib (100 mg) with rifampin (600 mg daily (QD)) after multiple doses of rifampin. The
      AST and ALT continued to increase over the next 24-48 hours, but recovered below the upper
      limit of normal for all participants upon discontinuation of rifampin.

      We hypothesize the combination of lorlatinib with the moderate CYP3A inducer modafinil will
      not have a safety findings related to liver enzyme elevation similar to what occurred in the
      study with rifampin and lorlatinib.
    

Detailed description: 
      This will be a Phase 1 study in approximately 16 healthy participants employing
      administration of a single dose of lorlatinib in the fasted state alone, and with multiple
      doses of modafinil 400 mg once daily. This study will consist of up to 3 lorlatinib treatment
      groups: 50, 75, or 100 mg single doses of lorlatinib given alone and in combination with
      multiple doses of modafinil.

      Each enrolled participant will receive lorlatinib 50, 75, or 100 mg alone in Period 1 and
      then lorlatinib 50, 75, or 100 mg in combination with multiple dose modafinil in Period 2
      after a washout period of at least 19 days between lorlatinib doses in Periods 1 and 2. A
      single PK sample is taken prior to lorlatinib dosing in each period. Following administration
      of lorlatinib in each period, participants will undergo serial PK sampling.

      There will be 4 cohorts. Cohorts 1 to 3 will include 2 participants each, while Cohort 4 will
      include 10 participants. Participants in Cohorts 1 to 4 will be sequentially enrolled such
      that participants in a new cohort can receive their lorlatinib Period 2 dose only after
      participants from the prior cohort are 72 hours past their lorlatinib Period 2 combination
      dose (with modafinil) with no safety concerns. In addition, Cohorts 1 to 3 will employ
      sentinel dosing such that the second participant in each cohort can receive their lorlatinib
      Period 2 dose only after the first participant from the same cohort is 72 hours past their
      lorlatinib and modafinil Period 2 combination dose with no safety concerns. Participants in
      Cohort 4 may be dosed in parallel, as sentinel dosing of lorlatinib 100 mg will have been
      completed in Cohort 3. The overall study design will be identical in all 4 cohorts, with the
      only difference being the dose of lorlatinib administered.

      The decision to dose subsequent cohorts during Period 2 with lorlatinib will be made after
      reviewing the totality of the participants' clinical picture for safety by the investigator.
      Furthermore, participants in subsequent cohorts will not be dosed if the following liver
      function abnormalities are observed during the 72 hour time frame for safety evaluation after
      lorlatinib dosing in Period 2.

      For enrollment of each successive cohort, the period of safety evaluation will be at least 72
      hours after the Period 2 lorlatinib dosing in the previous cohort. During Period 2, safety
      laboratory assessments including urinalysis, hematology and chemistry will be performed once
      daily from Day 14 through Day 20. Only after the review of safety labs for at least 72 hours
      after lorlatinib+ modafinil dosing during Period 2 of the previous cohort, will participants
      in a new cohort receive lorlatinib in combination with modafinil in their Period 2.
      Additional safety laboratory assessments may be performed at any additional times at the
      discretion of the investigator. If safety events of concern are observed in Cohorts 1, 2, or
      3 during Period 2, this study will be terminated.
    

Intervention name(s): Lorlatinib 50 mg; Lorlatinib 75 mg; Lorlatinib 100 mg
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Participants will receive a single dose of lorlatinib 50 mg in Period 1. Participants will receive modafinil 400 mg daily for 19 days, and a single dose of lorlatinib 50 mg on Day 15 of Period 2.; Participants will receive a single dose of lorlatinib 75 mg in Period 1. Participants will receive modafinil 400 mg daily for 19 days, and a single dose of lorlatinib 75 mg on Day 15 of Period 2.; Participants will receive a single dose of lorlatinib 100 mg in Period 1. Participants will receive modafinil 400 mg daily for 19 days, and a single dose of lorlatinib 100 mg on Day 15 of Period 2.
Allocation: Non-Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Cytochrome P-450 CYP3A Inhibitors/metabolism; Cytochrome P-450 CYP3A Inhibitors/adverse effects; Cytochrome P-450 CYP3A Inhibitors/pharmacokinetics; Cytochrome P-450 CYP3A Inhibitors/pharmacology; Modafinil/adverse effects; Modafinil/pharmacokinetics; Modafinil/pharmacology