Effect of Multiple Doses of Modafinil on the Pharmacokinetics of Single Dose Lorlatinib in Healthy Participants

NCT03961997 | Completed Phase 1 FDA Drug

• 2 other identifiers: B74610262019-001455-40
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Adult; Drug Interactions; Healthy Volunteers; Humans

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

Outcome Measures

Primary Outcomes (3)

• Number of Participants With Treatment Emergent Treatment-Related Adverse Events (AEs)

  Treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to Y days after last dose that were absent before treatment or that worsened relative to pretreatment state. Relatedness to Drug X was assessed by the investigator (Yes/No). Participants with multiple occurrences of an AE within a category were counted once within the category.

  Baseline up to 28 days after last dose of modafinil or lorlatinib.

• Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities

  Laboratory parameters included: hematology (hemoglobin, hematocrit, red blood cell, platelet and white blood cell count, neutrophils, eosinophils, monocytes, basophils and lymphocytes), chemistry (blood urea nitrogen, creatinine, sodium, potassium, aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase, albumin, total protein and serum pregnancy test \[for all female participants\]) and urine (urine pregnancy test \[for all female participants\]). Clinical significance of laboratory parameters was determined at the investigator's discretion.

  Baseline up to 28 days after last dose of modafinil or lorlatinib.

• Number of Participants With Clinically Significant Change From Baseline in Vital Signs

  Vital signs (temperature, respiratory rate, pulse, systolic and diastolic blood pressure) were obtained with participant in the seated position, after having sat calmly for at least 5 minutes. Clinical significance of vital signs was determined at the investigator's discretion.

  Baseline up to 28 days after last dose of modafinil or lorlatinib.

Secondary Outcomes (7)

• Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) of lorlatinib

  0 (pre-dose), 0.5, 1, 1.5, 2, 4, 6, 12, 24, 36, 48, 60, 72, 96, and 120 hours post-dose in both Period 1 and Period 2.

• Maximum Observed Plasma Concentration (Cmax) of lorlatinib

  0 (pre-dose), 0.5, 1, 1.5, 2, 4, 6, 12, 24, 36, 48, 60, 72, 96, and 120 hours post-dose in both Period 1 and Period 2.

• Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of lorlatinib

  0 (pre-dose), 0.5, 1, 1.5, 2, 4, 6, 12, 24, 36, 48, 60, 72, 96, and 120 hours post-dose in both Period 1 and Period 2.

• Apparent Oral Clearance (CL/F) of lorlatinib

  0 (pre-dose), 0.5, 1, 1.5, 2, 4, 6, 12, 24, 36, 48, 60, 72, 96, and 120 hours post-dose in both Period 1 and Period 2.

• Plasma Decay Half-Life (t1/2) of lorlatinib

  0 (pre-dose), 0.5, 1, 1.5, 2, 4, 6, 12, 24, 36, 48, 60, 72, 96, and 120 hours post-dose in both Period 1 and Period 2.

Study Arms (3)

Lorlatinib 50 mg

OTHER

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.

Drug: Lorlatinib 50 mg

Lorlatinib 75 mg

OTHER

Participants will receive a single dose of lorlatinib 75mg 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.

Drug: Lorlatinib 75 mg

Lorlatinib 100 mg

OTHER

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.

Drug: Lorlatinib 100 mg

Interventions

Lorlatinib 50 mg DRUG

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.

Lorlatinib 50 mg

Lorlatinib 75 mg DRUG

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.

Lorlatinib 75 mg

Lorlatinib 100 mg DRUG

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.

Lorlatinib 100 mg

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Male and female participants who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and ECG.
• Adequate Renal Function, including:
• Estimated creatinine clearance ≥90 mL/min as calculated using chronic kidney disease epidemiology collaboration equation (CKD EPI). In equivocal cases, a 24 hour urine collection test can be used to estimate the creatinine clearance more accurately.
• \- Adequate Liver Function, including: Total serum bilirubin within normal limits (WNL). Aspartate and Alanine aminotransferase (AST and ALT) WNL. Alkaline phosphatase WNL.
• Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures.
• Male participants of childbearing potential must agree to use a highly effective method of contraception from the first screen throughout the study and for 97 days after the last dose of assigned treatment if male participant. A participant is of childbearing potential if, in the opinion of the investigator, he/she is biologically capable of having children and is sexually active.
• Body mass index (BMI) of 17.5 to 30.5 kg/m2; and a total body weight \>50 kg (110 lb).
• Capable of giving signed informed consent as described in Appendix 1, which includes compliance with the requirements and restrictions listed in the informed consent document (ICD) and in this

You may not qualify if:

• Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing).
• Any condition possibly affecting drug absorption (eg, gastrectomy, cholecystectomy).
• History of human immunodeficiency virus (HIV) infection, hepatitis B, or hepatitis C; positive testing for HIV, hepatitis B surface antigen (HepBsAg), or hepatitis C antibody (HCVAb). A positive hepatitis B surface antibody (HepBsAb) serology indicating Hepatitis B vaccination is allowed.
• Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the participant inappropriate for entry into this study. Psychiatric adverse experiences have been reported in patients treated with modafinil with many, but not all, with prior psychiatric history. Participants with a history of psychosis, depression, or mania are excluded from this study.
• Use of prescription or nonprescription drugs and dietary and herbal supplements within 7 days or 5 half lives (whichever is longer) prior to the first dose of investigational product. As an exception, acetaminophen/paracetamol may be used at doses of ≤1 g/day. Limited use of nonprescription medications that are not believed to affect participant safety or the overall results of the study may be permitted on a case by case basis following approval by the sponsor.
• Previous administration with lorlatinib within 30 days (or as determined by the local requirement) or 5 half lives preceding the first dose of lorlatinib used in this study (whichever is longer).
• Previous treatment with lorlatinib
• A positive urine drug test, as confirmed by a single repeat.
• Screening supine blood pressure (BP) ≥130 mm Hg (systolic) or ≥80 mm Hg (diastolic), following at least 5 minutes of supine rest. If BP is ≥130 mm Hg (systolic) or ≥80 mm Hg (diastolic), the BP should be repeated 2 more times and the average of the 3 BP values should be used to determine the participant's eligibility.
• History of pancreatitis (elevated amylase or lipase) or hyperlipidemia.
• Screening supine 12 lead ECG demonstrating PR interval \>200 msec, corrected QT (QTc) \>450 msec or a QRS interval \>120 msec.
• History of cardiac arrhythmia (excluding asymptomatic sinus arrhythmia with heart rate \>50, and occasional asymptomatic premature atrial contraction and premature ventricular contractions), history of atrioventricular (AV) block, history of symptomatic bradycardia, history of QTc prolongation.
• Participants with ANY of the following abnormalities in clinical laboratory tests at screening: Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level \> upper limit of normal (ULN); Total bilirubin level \> ULN; participants 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.
• History of alcohol abuse or binge drinking and/or any other illicit drug use or dependence within 6 months of Screening. Binge drinking is defined as a pattern of 5 (male) and 4 (female) or more alcoholic drinks in about 2 hours. As a general rule, alcohol intake should not exceed 14 units per week for males or 7 units per week for females (1 unit = 8 ounces (240 mL) beer, 1 ounce (30 mL) of 40% spirit or 3 ounces (90 mL) of wine).
• As modafinil is a controlled substance, participants with a history drug abuse will be excluded.

Sponsors & Collaborators

• Pfizer: lead

Study Sites (1)

Brussels Clinical Research Unit

Brussels, Be-bru, B-1070, Belgium

Location

Related Publications (2)

• Rodrigues AD, Wood LS, Vourvahis M, Rowland A. Leveraging Human Plasma-Derived Small Extracellular Vesicles as Liquid Biopsy to Study the Induction of Cytochrome P450 3A4 by Modafinil. Clin Pharmacol Ther. 2022 Feb;111(2):425-434. doi: 10.1002/cpt.2440. Epub 2021 Nov 2.

  PMID: 34623637 DERIVED

• Li J, Pithavala YK, Gong J, LaBadie RR, Mfopou JK, Chen J. The Effect of Modafinil on the Safety and Pharmacokinetics of Lorlatinib: A Phase I Study in Healthy Participants. Clin Pharmacokinet. 2021 Oct;60(10):1303-1312. doi: 10.1007/s40262-021-01026-w. Epub 2021 May 3.

  PMID: 33937953 DERIVED

Related Links

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

MeSH Terms

Interventions

lorlatinib

Study Officials

• Pfizer CT.gov Call Center

  Pfizer

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 22, 2019
• First Posted: May 23, 2019
• Study Start: August 22, 2019
• Primary Completion: December 9, 2019
• Study Completion: December 9, 2019
• Last Updated: January 18, 2020

Record last verified: 2020-01

Data Sharing

• IPD Sharing: Will not share

Locations

BE (1)