pf-06463922 and Renal-Insufficiency

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.. 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.. 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 (AUC. 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.. NCT03542305 (available May 31, 2018 on clinicaltrials.gov).

Topics: Adult; Aminopyridines; Area Under Curve; Carcinoma, Non-Small-Cell Lung; Humans; Lactams; Lung Neoplasms; Pyrazoles; Renal Insufficiency

Lorlatinib, a selective inhibitor of anaplastic lymphoma kinase (ALK) and c-ROS oncogene 1 (ROS1) tyrosine kinase, is indicated for the treatment of ALK-positive metastatic non-small cell lung cancer (NSCLC) following progression on crizotinib and at least one other ALK inhibitor, or alectinib/ceritinib as the first ALK inhibitor therapy for metastatic disease. The population pharmacokinetics (PopPK) of lorlatinib was conducted by nonlinear mixed effects modeling of data from 330 patients with ALK-positive or ROS1-positive NSCLC and 95 healthy participants from six phase I studies in healthy volunteers; demographic, metabolizer phenotype, and patient prognostic factors were evaluated as covariates. Lorlatinib plasma PK was well-characterized by a two-compartment model with sequential zero-order and first-order absorption and a time-varying induction of clearance. Single dose clearance was estimated to be 9.04 L/h. Assuming that the metabolic auto-induction of lorlatinib reaches saturation in ~ 5 half-lives, clearance was estimated to approach a maximum of 14.5 L/h at steady-state after a period of ~ 7.25 days. The volume of distribution of the central compartment was estimated to be 121 L and the first-order absorption rate constant was estimated to be 3.1 h

Topics: Adult; Aminopyridines; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Female; Healthy Volunteers; Hepatic Insufficiency; Humans; Lactams; Lung Neoplasms; Male; Middle Aged; Prognosis; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Proton Pump Inhibitors; Pyrazoles; Renal Insufficiency; Serum Albumin