A Study To Evaluate The Effect Of Itraconazole On Pharmacokinetics Of PF-06463922 In Healthy Volunteers

Phase 1, Open-label, Fixed Sequence, 2-period Study To Investigate The Effect Of Multiple Doses Of Itraconazole On The Pharmacokinetics Of Single Dose Pf-06463922 In Healthy Volunteers In The Fasted Condition

The purpose of this study is to estimate the effect of itraconazole on the single dose pharmacokinetics of PF-06463922 in healthy volunteers in the fasted state.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: PF-06463922; Drug: PF-06463922; Drug: PF-06463922; Drug: PF-06463922; Drug: Itraconazole

Detailed Description

This will be a Phase 1, open-label, 2-period, fixed-sequence, crossover study to investigate the effect of the strong CYP3A inhibitor itraconazole on PF-06463922 PK in approximately 16 healthy volunteers. The study will consist of potentially up to 6 treatments: single dose of PF-06463922 50, 75 or 100 mg and PF-06463922 50, 75 or 100 mg in combination with multiple dose itraconazole.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium, B-1070
    • Pfizer Clinical Research Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 51 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy female subjects of non childbearing potential and/or male subjects, who at the time of screening, are between the ages of 18 and 55 years, inclusive.
• Body Mass Index (BMI) of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lbs).

Exclusion Criteria:

• Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing).
• Any condition possibly affecting drug absorption.
• A positive urine drug test.
• History of HIV, Hep B or Hep C.
• History of regular alcohol consumption.
• Screening supine 12 lead ECG demonstrating PR interval >180 msec, QTc >450 msec or a QRS interval >120 msec.
• Subjects with ANY of the following abnormalities in clinical laboratory tests at screening, as assessed by the study-specific laboratory and confirmed by a single repeat, if deemed necessary: Use this criterion to describe any laboratory parameters that are not acceptable for the study. Examples included below:
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level >1.0 × upper limit of normal (ULN);
• Total bilirubin level >1.0 × ULN; subjects with a history of Gilbert's syndrome may have direct bilirubin measured and would be eligible for this study provided the direct bilirubin level is <= ULN.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1; All subjects in this cohort will receive the same dose of PF-06463922 in both periods. Subjects will receive PF-06463922 Alone in Period 1 followed by PF-06463922 with Itraconazole in Period 2.	Drug: PF-06463922; Single oral dose of PF-06463922 50 mg on Day 1 of Period 1 and Day 5 of Period 2; Other Names: Lorlatinib; Drug: PF-06463922; Single oral dose of PF-06463922 75 mg on Day 1 of Period 1 and Day 5 of Period 2; Other Names: Lorlatinib; Drug: PF-06463922; Single oral dose of PF-06463922 100 mg on Day 1 of Period 1 and Day 5 of Period 2; Other Names: Lorlatinib; Drug: PF-06463922; Highest safe single oral dose (mg) of PF-06463922 identified in the previous cohorts will be administered on Day 1 of Period 1 and Day 5 of Period 2; Other Names: Lorlatinib; Drug: Itraconazole; 200 mg oral dose of itraconazole on Days 1 to 11 during Period 2; Other Names: Sporanox
Experimental: Cohort 2; All subjects in this cohort will receive the same dose of PF-06463922 in both periods. Subjects will receive PF-06463922 Alone in Period 1 followed by PF-06463922 with Itraconazole in Period 2.	Drug: PF-06463922; Single oral dose of PF-06463922 50 mg on Day 1 of Period 1 and Day 5 of Period 2; Other Names: Lorlatinib; Drug: PF-06463922; Single oral dose of PF-06463922 75 mg on Day 1 of Period 1 and Day 5 of Period 2; Other Names: Lorlatinib; Drug: PF-06463922; Single oral dose of PF-06463922 100 mg on Day 1 of Period 1 and Day 5 of Period 2; Other Names: Lorlatinib; Drug: PF-06463922; Highest safe single oral dose (mg) of PF-06463922 identified in the previous cohorts will be administered on Day 1 of Period 1 and Day 5 of Period 2; Other Names: Lorlatinib; Drug: Itraconazole; 200 mg oral dose of itraconazole on Days 1 to 11 during Period 2; Other Names: Sporanox
Experimental: Cohort 3; All subjects in this cohort will receive the same dose of PF-06463922 in both periods. Subjects will receive PF-06463922 Alone in Period 1 followed by PF-06463922 with Itraconazole in Period 2.	Drug: PF-06463922; Single oral dose of PF-06463922 50 mg on Day 1 of Period 1 and Day 5 of Period 2; Other Names: Lorlatinib; Drug: PF-06463922; Single oral dose of PF-06463922 75 mg on Day 1 of Period 1 and Day 5 of Period 2; Other Names: Lorlatinib; Drug: PF-06463922; Single oral dose of PF-06463922 100 mg on Day 1 of Period 1 and Day 5 of Period 2; Other Names: Lorlatinib; Drug: PF-06463922; Highest safe single oral dose (mg) of PF-06463922 identified in the previous cohorts will be administered on Day 1 of Period 1 and Day 5 of Period 2; Other Names: Lorlatinib; Drug: Itraconazole; 200 mg oral dose of itraconazole on Days 1 to 11 during Period 2; Other Names: Sporanox
Experimental: Cohort 4; All subjects in this cohort will receive the same dose of PF-06463922 in both periods. Subjects will receive the highest safe dose (mg) of PF-06463922 as a single-dose Alone in Period 1 followed by PF-06463922 with Itraconazole in Period 2.	Drug: PF-06463922; Single oral dose of PF-06463922 50 mg on Day 1 of Period 1 and Day 5 of Period 2; Other Names: Lorlatinib; Drug: PF-06463922; Single oral dose of PF-06463922 75 mg on Day 1 of Period 1 and Day 5 of Period 2; Other Names: Lorlatinib; Drug: PF-06463922; Single oral dose of PF-06463922 100 mg on Day 1 of Period 1 and Day 5 of Period 2; Other Names: Lorlatinib; Drug: PF-06463922; Highest safe single oral dose (mg) of PF-06463922 identified in the previous cohorts will be administered on Day 1 of Period 1 and Day 5 of Period 2; Other Names: Lorlatinib; Drug: Itraconazole; 200 mg oral dose of itraconazole on Days 1 to 11 during Period 2; Other Names: Sporanox

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUCinf for PF-06463922	Area under the plasma concentration-time profile from time zero extrapolated to infinite time	PF-06463922 pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and up to 168 hours post-dose.
Cmax for PF-06463922	Maximum plasma concentration	PF-06463922 pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and up to 168 hours post-dose.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUClast for PF-06463922	Area under the plasma concentration-time profile from time zero to the time of the last quantifiable concentration (Clast)	PF-06463922 pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and up to 168 hours post-dose.
Tmax for PF-06463922	Time to Cmax	PF-06463922 pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and upto 168 hours post-dose.
t1/2 for PF-06463922	Terminal plasma elimination half-life	PF-06463922 pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and up to 168 hours post-dose.
CL/F for PF-06463922	Apparent clearance	PF-06463922 pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and up to 168 hours post-dose.
Vz/F for PF-06463922	Apparent volume of distribution	PF-06463922 pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and up to 168 hours post-dose.
AUCinf for any potential PF-06463922 metabolite if necessary	Area under the plasma concentration-time profile from time zero extrapolated to infinite time	PF-06463922 pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and up to 168 hours post-dose.
AUClast for any potential PF-06463922 metabolite if necessary	Area under the plasma concentration-time profile from time zero to the time of the last quantifiable concentration (Clast)	PF-06463922 pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and up to 168 hours post-dose.
Cmax for any potential PF-06463922 metabolite if appropriate	Maximum plasma concentration	PF-06463922 pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and up to 168 hours post-dose.
Tmax for any potential PF-06463922 metabolite if appropriate	Time to Cmax	PF-06463922 pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and up to 168 hours post-dose.
t1/2 for any potential metabolite of PF-06463922 if appropriate	Terminal plasma elimination half-life	PF-06463922 pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and up to 168 hours post-dose.
MRCmax for any potential PF-06463922 metabolite if appropriate	metabolite to parent ratio for Cmax	PF-06463922 pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and up to 168 hours post-dose.
MRAUClast for any potential PF-06463922 metabolite if appropriate	metabolite to parent ratio for AUClast	PF-06463922 pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and up to 168 hours post-dose.
MRAUCinf for any potential PF-06463922 metabolite if appropriate	metabolite to parent ratio for AUCinf	PF-06463922 pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and up to 168 hours post-dose.
PR interval after PF-06463922 alone and after increased exposure of PF 06463922 (due to concomitant itraconzole administration).	Change in PR interval from baseline after administration of PF-06463922 single dose as assessed by ECG.	Within 24 hours after single dose administration of PF-06463922 alone and in combination with itraconazole.

Collaborators and Investigators

• Sponsor: Pfizer

Publications and helpful links

General Publications

• Patel M, Chen J, McGrory S, O'Gorman M, Nepal S, Ginman K, Pithavala YK. The effect of itraconazole on the pharmacokinetics of lorlatinib: results of a phase I, open-label, crossover study in healthy participants. Invest New Drugs. 2020 Feb;38(1):131-139. doi: 10.1007/s10637-019-00872-7. Epub 2019 Nov 14.

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start (Actual): August 16, 2016
• Primary Completion (Actual): March 31, 2017
• Study Completion (Actual): May 3, 2017

Study Registration Dates

• First Submitted: July 17, 2016
• First Submitted That Met QC Criteria: July 17, 2016
• First Posted (Estimate): July 20, 2016

Study Record Updates

• Last Update Posted (Actual): May 15, 2017
• Last Update Submitted That Met QC Criteria: May 12, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Itraconazole
• Other Study ID Numbers: B7461012; 2016-002386-57 (EudraCT Number); ITRACONAZOLE DDI STUDY (Other Identifier: Alias Study Number)