The effect of itraconazole on the pharmacokinetics of lorlatinib: results of a phase I, open-label, crossover study in healthy participants.
Background The third-generation tyrosine kinase inhibitor lorlatinib is approved for the treatment of ALK-positive metastatic NSCLC. CYP3A plays a major role in lorlatinib metabolism; therefore, a drug-drug interaction study was warranted to evaluate the impact of the strong CYP3A inhibitor, itraconazole, on lorlatinib plasma exposure. Methods This phase 1, open-label, 2-period, crossover study estimated the effects of itraconazole on the plasma pharmacokinetics and safety of lorlatinib in healthy participants (NCT02838264). Single-dose lorlatinib 50 mg (n = 2), 75 mg (n = 2) and 100 mg (n = 12) was administered in Period 1. In Period 2, itraconazole oral solution 200 mg/day was administered on Days 1-11, and single-dose lorlatinib on Day 5. Blood samples were collected up to 168 h after lorlatinib dosing. Results During daily dosing with itraconazole (Period 2), the ratios of the adjusted geometric means for area under the plasma concentration-time profile extrapolated to infinity (AUCinf) and maximum plasma concentration (Cmax) of single-dose lorlatinib 100 mg were 141.79% (90% confidence interval, 128.71%, 156.21%) and 124.39% (110.20%, 140.41%), respectively, compared with Period 1 (lorlatinib alone). Lorlatinib was well tolerated alone and with itraconazole. No serious adverse events or withdrawals were reported. Conclusions Co-administration of itraconazole and lorlatinib increased the plasma exposure of lorlatinib relative to lorlatinib alone in healthy participants. Therefore, concomitant use of lorlatinib with strong CYP3A inhibitors should be avoided. If this combination is unavoidable, the starting dose of lorlatinib should be reduced from 100 mg to 75 mg.
['Patel|Maulik|M|', 'Chen|Joseph|J|', 'McGrory|Stephanie|S|', "O'Gorman|Melissa|M|", 'Nepal|Sunil|S|', 'Ginman|Katherine|K|', 'Pithavala|Yazdi K|YK|']
D000328:Adult D000631:Aminopyridines D000935:Antifungal Agents D019540:Area Under Curve D018592:Cross-Over Studies D004347:Drug Interactions D005260:Female D064368:Healthy Volunteers D006801:Humans D017964:Itraconazole D007769:Lactams D047029:Lactams, Macrocyclic D008297:Male D011720:Pyrazoles D014018:Tissue Distribution
Itraconazole Pharmacokinetics Lorlatinib Healthy participants Drug-drug interaction Phase 1 trial