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

• ClinicalTrials.gov Identifier: NCT02838264
• Recruitment Status: Completed
• First Posted: July 20, 2016
• Last Update Posted: May 15, 2017
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Healthy	Drug: PF-06463922; Drug: Itraconazole	Phase 1

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 16 participants
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: 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
• Actual Study Start Date: August 16, 2016
• Actual Primary Completion Date: March 31, 2017
• Actual Study Completion Date: May 3, 2017

Arms and Interventions

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 Name: Lorlatinib; Drug: Itraconazole; 200 mg oral dose of itraconazole on Days 1 to 11 during Period 2; Other Name: 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 75 mg on Day 1 of Period 1 and Day 5 of Period 2; Other Name: Lorlatinib; Drug: Itraconazole; 200 mg oral dose of itraconazole on Days 1 to 11 during Period 2; Other Name: 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 100 mg on Day 1 of Period 1 and Day 5 of Period 2; Other Name: Lorlatinib; Drug: Itraconazole; 200 mg oral dose of itraconazole on Days 1 to 11 during Period 2; Other Name: 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; 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 Name: Lorlatinib; Drug: Itraconazole; 200 mg oral dose of itraconazole on Days 1 to 11 during Period 2; Other Name: Sporanox

Outcome Measures

Primary Outcome Measures :

1. AUCinf for PF-06463922 [ Time Frame: 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. ]
   Area under the plasma concentration-time profile from time zero extrapolated to infinite time
2. Cmax for PF-06463922 [ Time Frame: 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. ]
   Maximum plasma concentration

Secondary Outcome Measures :

1. AUClast for PF-06463922 [ Time Frame: 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. ]
   Area under the plasma concentration-time profile from time zero to the time of the last quantifiable concentration (Clast)
2. Tmax for PF-06463922 [ Time Frame: 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. ]
   Time to Cmax
3. t1/2 for PF-06463922 [ Time Frame: 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. ]
   Terminal plasma elimination half-life
4. CL/F for PF-06463922 [ Time Frame: 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. ]
   Apparent clearance
5. Vz/F for PF-06463922 [ Time Frame: 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. ]
   Apparent volume of distribution
6. AUCinf for any potential PF-06463922 metabolite if necessary [ Time Frame: 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. ]
   Area under the plasma concentration-time profile from time zero extrapolated to infinite time
7. AUClast for any potential PF-06463922 metabolite if necessary [ Time Frame: 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. ]
   Area under the plasma concentration-time profile from time zero to the time of the last quantifiable concentration (Clast)
8. Cmax for any potential PF-06463922 metabolite if appropriate [ Time Frame: 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. ]
   Maximum plasma concentration
9. Tmax for any potential PF-06463922 metabolite if appropriate [ Time Frame: 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. ]
   Time to Cmax
10. t1/2 for any potential metabolite of PF-06463922 if appropriate [ Time Frame: 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. ]
    Terminal plasma elimination half-life
11. MRCmax for any potential PF-06463922 metabolite if appropriate [ Time Frame: 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. ]
    metabolite to parent ratio for Cmax
12. MRAUClast for any potential PF-06463922 metabolite if appropriate [ Time Frame: 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. ]
    metabolite to parent ratio for AUClast
13. MRAUCinf for any potential PF-06463922 metabolite if appropriate [ Time Frame: 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. ]
    metabolite to parent ratio for AUCinf
14. PR interval after PF-06463922 alone and after increased exposure of PF 06463922 (due to concomitant itraconzole administration). [ Time Frame: Within 24 hours after single dose administration of PF-06463922 alone and in combination with itraconazole. ]
    Change in PR interval from baseline after administration of PF-06463922 single dose as assessed by ECG.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 55 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

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.

Contacts and Locations

Locations

Belgium

Pfizer Clinical Research Unit

Brussels, Belgium, B-1070

Sponsors and Collaborators

Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

More Information

Additional Information:

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

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT02838264
• Other Study ID Numbers: B7461012; 2016-002386-57 ( EudraCT Number ); ITRACONAZOLE DDI STUDY ( Other Identifier: Alias Study Number )
• First Posted: July 20, 2016
• Last Update Posted: May 15, 2017
• Last Verified: May 2017

Additional relevant MeSH terms:

Itraconazole; Antifungal Agents; Anti-Infective Agents; 14-alpha Demethylase Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Steroid Synthesis Inhibitors; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Cytochrome P-450 CYP3A Inhibitors