Metabolism, Excretion, and Pharmacokinetics of Lorlatinib (PF‐06463922) and Evaluation of the Impact of Radiolabel Position and Other Factors on Comparability of Data Across 2 ADME Studies

Abstract

While an initial clinical absorption, distribution, metabolism, and excretion (ADME) study (Study 1; N = 6) with 100 mg/100 µCi [14C]lorlatinib, radiolabeled on the carbonyl carbon, confirmed that the primary metabolic pathways for lorlatinib are oxidation (N‐demethylation, N‐oxidation) and N‐glucuronidation, it also revealed an unanticipated, intramolecular cleavage metabolic pathway of lorlatinib, yielding a major circulating benzoic acid metabolite (M8), and an unlabeled pyrido‐pyrazole substructure. Concerns regarding the fate of unknown metabolites associated with this intramolecular cleavage pathway led to conduct of a second ADME study (Study 2; N = 6) of identical design but with the radiolabel positioned on the pyrazole ring. Results were similar with respect to the overall mass balance, lorlatinib plasma exposures, and metabolic profiles in excreta for the metabolites that retained the radiolabel in both studies. Differences were observed in plasma total radioactivity exposures (2‐fold area under the plasma concentration–time curve from time 0 to infinity difference) and relative ratios of the percentage of dose recovered in urine vs feces (48% vs 41% in Study 1; 28% vs 64% in Study 2). In addition, an approximately 3‐fold difference in the mean molar exposure ratio of M8 to lorlatinib was observed for values derived from metabolic profiling data relative to those derived from specific bioanalytical methods (0.5 vs 1.4 for Studies 1 and 2, respectively). These interstudy differences were attributed to a combination of factors, including alteration of radiolabel position, orthogonal analytical methodologies, and intersubject variability, and illustrate that results from clinical ADME studies are not unambiguous and should be interpreted within the context of the specific study design considerations.

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

“…In vitro studies indicated that lorlatinib is a time-dependent inhibitor, as well as an inducer, of CYP3A via PXR activation [ 6 ]; thus, it was unclear if the net effect on CYP3A would be induction or inhibition. In the phase I midazolam substudy, lorlatinib was demonstrated to be a net moderate inducer of CYP3A.…”

“…Two absorption, metabolism, and excretion studies conducted in healthy participants have shown that lorlatinib is primarily eliminated via metabolism, with little renal excretion (< 5% of administered dose recovered in urine) [ 6 ]. The most abundant circulating human metabolite of lorlatinib is PF-06895751, which is pharmacologically inactive and is generated by the oxidative cleavage of the lorlatinib amide and aromatic ether bonds [ 6 ]. Lorlatinib is metabolized primarily by cytochrome P450 (CYP) 3A and UGT1A4, and to a lesser extent by CYP2C8, CYP2C19, CYP3A5, and UGT1A3 [ 2 ].…”

A Phase I Study to Evaluate the Pharmacokinetics and Safety of Lorlatinib in Adults with Mild, Moderate, and Severe Renal Impairment

“…Plasma and urine samples were analyzed for lorlatinib concentrations using validated, sensitive, and specific highperformance liquid chromatography-tandem mass spectrometric methods (HPLC-MS/MS) as previously described [9][10][11]. Plasma samples were analyzed for PF-06895751 concentrations by a validated LC-MS/MS method.…”

“…On the basis of findings from nonclinical in vitro studies and in vivo metabolic profiling, it was determined that extensive metabolism of lorlatinib occurred via oxidation and conjugation [ 6 ]. In two human absorption, distribution, metabolism, and excretion (ADME) studies, also called mass balance studies, unchanged lorlatinib accounted for < 2% of the dose in urine, indicating minimal urinary excretion of the parent drug [ 6 ]. Therefore, renal impairment would not be expected to have a major effect on lorlatinib pharmacokinetics or safety.…”

The Effect of Modafinil on the Safety and Pharmacokinetics of Lorlatinib: A Phase I Study in Healthy Participants

“…This is also consistent with a similar reduction in M8 AUC inf noted in the prior drug interaction study with rifampin [ 6 ]. The absorption, distribution, metabolism, and excretion properties of lorlatinib have been characterized separately [ 10 ].…”