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Yazdi Pithavala
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P2.14 - Targeted Therapy (ID 183)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.14-39 - Effects of Renal Function on Lorlatinib Safety and Pharmacokinetics (ID 19)
10:15 - 18:15 | Author(s): Yazdi Pithavala
- Abstract
Background
Lorlatinib (Lorbrena®) is a small-molecule inhibitor of the anaplastic lymphoma kinase (ALK) and c-ROS oncogene 1 kinase recently approved at the recommended starting dose of 100 mg once daily in the United States, Japan, and Canada for the treatment of patients with ALK-positive metastatic non-small cell lung cancer (NSCLC). In humans, unchanged lorlatinib accounted for less than 1% of dose in urine, indicating minimal urinary excretion of parent drug. Therefore, renal impairment would not be expected to have a major effect on lorlatinib pharmacokinetics (PK) or safety. However, results from a population PK analysis demonstrated that baseline creatinine clearance was a statistically significant predictor of variability in lorlatinib plasma clearance; the median estimated single-dose lorlatinib clearance was 18% and 26% lower in NSCLC patients with mild and moderate renal impairment, respectively. Therefore, it is important to evaluate the potential impact of varying degrees of renal impairment on the safety and PK of lorlatinib via a prospective study. Preliminary results from the ongoing study, B7461010 (NCT03542305), of single-dose lorlatinib in subjects with mild, moderate and severe renal impairment are reported here.
Method
B7461010 is an ongoing multi-center, open-label, single-dose study comparing the safety and PK of lorlatinib in otherwise healthy subjects with varying degrees of renal impairment. This study was planned to enroll 28–32 subjects (8 each in normal, mild and moderate impairment groups and 4–8 in severe impairment group) who complete PK assessments. Group assignment was based on estimated glomerular filtration rate calculated using the Modification of Diet in Renal Disease equation and as defined in the Kidney Disease Outcomes Quality Initiative guidelines. Subjects with increasing severity of renal impairment have been enrolled sequentially to allow for safety evaluations. Subjects with normal renal function will be enrolled and matched based on age, sex and weight following completion of dosing of the renal impairment groups.
Result
As of March 14, 2019, 8 subjects with mild renal impairment, 7 with moderate renal impairment and 3 with severe renal impairment not requiring dialysis have been enrolled. All 18 subjects to date received the clinical dose of lorlatinib 100 mg and completed the study. Among them, 6 subjects experienced adverse events (AEs), which were all transient and of mild or moderate intensity. Only 3 AEs (elevation of blood pressure, myalgia and diarrhea) were deemed related to study treatment. Preliminary analysis of plasma PK in 8 mild renal impairment subjects demonstrated similar exposures (geometric mean [%CV] Cmax of 549.7 [51.7%] and AUCinf of 8609.2 [29.2%]) compared to previous data from patients with normal renal function.
Conclusion
Data showed that a single dose of lorlatinib 100 mg administered in subjects with mild, moderate or severe renal impairment was well tolerated. No dose adjustment was indicated for mild renal impairment. Updated results will be reported.
