Authors: Swan Lin, Jason Gong, George C. Canas, Peter Winkle, Kathleen Pelletier, Robert R. LaBadie, Katherine Ginman & Yazdi K. Pithavala
Abstract
Background and Objectives
Lorlatinib is approved (100 mg once daily [QD]) for the treatment of patients with anaplastic lymphoma kinase- (ALK) positive metastatic non-small cell lung cancer. This study evaluated the impact of varying degrees of renal impairment on the safety and pharmacokinetics of lorlatinib.
Methods
Participants were assigned to mild, moderate, and severe renal impairment groups and to a matching normal renal function group based on absolute estimated glomerular filtration rate (eGFR, based on the Modification of Diet in Renal Disease equation and adjusted for body surface area [BSA]) and were evaluated for pharmacokinetics and safety.
Results
A total of 29 participants (5 with severe renal impairment; 8 each with moderate and mild impairment and normal renal function) were enrolled and received a single dose of lorlatinib 100 mg. One of the participants with severe renal impairment had end-stage renal disease with a baseline absolute eGFR of 10.3 mL/min. No serious adverse events (AEs) were reported. Eighteen AEs, all mild or moderate in severity, were reported by 12 participants (5, 2, 4, and 1 in the normal, mild, moderate, and severe groups, respectively). Area under the plasma concentration–time profile from time zero extrapolated to infinity (AUCinf) for lorlatinib was increased by 4%, 19%, and 41% in the mild, moderate, and severe renal impairment groups, respectively, compared with the normal renal function cohort.
Conclusion
Lorlatinib 100 mg was well tolerated. As participants with mild and moderate renal impairment did not experience clinically meaningful increases in lorlatinib exposure, no lorlatinib dose adjustment is recommended in these populations. Patients with severe renal impairment are recommended to reduce the starting dose of lorlatinib from 100 mg QD to 75 mg QD.
Clinicaltrials.gov identifier
NCT03542305 (available May 31, 2018 on clinicaltrials.gov)
Key Points |
Study participants with mild and moderate kidney dysfunction did not have very different results compared to those with normal kidney function, and no lorlatinib dose adjustments are recommended in these populations. |
Those with severe kidney dysfunction had 41% higher lorlatinib concentrations, and instead of the 100 mg QD lorlatinib starting dose, a lower starting dose of 75 mg QD is recommended in this population. |