Pharmacokinetics of Lorlatinib After Single and Multiple Dosing in Patients with Anaplastic Lymphoma Kinase (ALK)-Positive Non-Small Cell Lung Cancer: Results from a Global Phase I/II Study

Abstract

Background: Lorlatinib demonstrated efficacy (including intracranial activity) in patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) in a phase I/II study (NCT01970865).

Background and objective: This analysis describes the pharmacokinetics (PK) of lorlatinib following single and multiple dosing.

Methods: This ongoing, multicenter, open-label, single-arm, phase I/II trial enrolled patients with ALK-positive or c-ros oncogene 1 (ROS1)-positive advanced NSCLC. In phase I, patients received escalating doses of lorlatinib (10-200 mg orally once daily) and twice-daily doses of 35, 75, and 100 mg in continuous 21-day cycles. In phase II, lorlatinib was administered at a starting dose of 100 mg once daily in continuous 21-day cycles. Parameters investigated included the potential for lorlatinib to inhibit/induce cytochrome P450 (CYP) 3A; the absorption/metabolism of lorlatinib and its major metabolite PF-06895751; and differences in these parameters between Asian and non-Asian patients.

Results: Data were available for 54 patients from phase I and 275 patients from phase II. Lorlatinib plasma exposure increased dose proportionally after single doses of 10-200 mg, and slightly less than dose proportionally after multiple doses. Lorlatinib clearance increased following multiple dosing compared with single dosing, indicating autoinduction. The area under the concentration-time curve from time zero to time τ (the dosing interval; AUCτ) of PF-06895751 was approximately 80% higher than that of lorlatinib after multiple dosing. Lorlatinib exhibited brain penetration. Furthermore, no overt differences in single- and multiple-dose PK parameters between the Asian and non-Asian patients were observed.

Conclusions: Lorlatinib is highly brain penetrant and exhibits autoinduction after multiple dosing. There appears to be no inherent differences in lorlatinib PK between healthy subjects and cancer patients, or between Asian and non-Asian patients. ClinicalTrials.gov NCT01970865.

Conflict of interest statement

Joseph Chen, Yazdi K. Pithavala, and Melissa T. O’Gorman are employees of Pfizer Inc. and may own stock or stock options in Pfizer. Lee P. James, Karen J. Klamerus, and Ganesh Mugundu are former employees of Pfizer Inc. and may own stock or stock options in Pfizer.

© 2021. The Author(s).

Figures

Fig. 1

Median plasma lorlatinib concentration-time profiles following a single oral doses (Day −7) linear scale; b single oral doses (Day −7) semi-logarithmic scale; c multiple oral doses (Cycle 1 Day 15) linear scale; and d multiple oral doses (Cycle 1 Day 15) semi-logarithmic scale. BID twice daily, QD once daily

Fig. 2

Linear plot of lorlatinib dose-normalized PK parameters versus dose following multiple oral doses: a AUCτ with QD dosing; bCmax with QD dosing; c AUCτ with BID dosing; and dCmax with BID dosing. Circles represent individual values and stars represent the geometric mean. AUCτ area under the concentration-time profile from time zero to time τ, the dosing interval, where τ = 24 h, BID twice daily, Cmax maximum observed plasma concentration, PK pharmacokinetic, QD once daily

Fig. 3

Median plasma midazolam concentration-time profiles following a single 2 mg dose alone and in the presence of a 25 mg QD lorlatinib and b 150 mg QD lorlatinib. MDZ midazolam, QD once daily

Fig. 4

Median plasma lorlatinib concentration-time profiles following a single oral doses at lead-in Day −7, and b multiple oral doses of lorlatinib at Cycle 1 Day 15 in Asian versus non-Asian patients