Chemical formula: C₃₀H₃₄N₈O₃ Molecular mass: 554.275 g/mol PubChem compound: 121269225
Lazertinib is an irreversible EGFR tyrosine kinase inhibitor (TKI). It selectively inhibits both primary activating EGFR mutations (exon 19 deletions and exon 21 L858R substitution mutations) and the EGFR T790M resistance mutation, while having less activity against wild-type EGFR.
Based on the exposure-response analyses for safety, paraesthesia and stomatitis appeared to show a trend of increasing occurrence with increase in lazertinib exposure.
The QTc interval prolongation potential of lazertinib was evaluated by exposure-response (E-R) analysis conducted with clinical data from 243 NSCLC patients who received 20, 40, 80, 120, 160, 240 or 320 mg lazertinib once daily in a phase 1/II study. The E-R analysis revealed no clinically relevant relationship between lazertinib plasma concentration and change in QTc interval.
Following single and multiple once daily oral administration, lazertinib maximum plasma concentration (Cmax) and area under plasma concentration time curve (AUC) increased approximately dose proportionally across 20 to 320 mg dose range.
The steady state plasma exposure was achieved by day 15 of once daily administration and approximately 2-fold accumulation was observed at steady state with 240 mg once daily dose.
The lazertinib plasma exposure was comparable when lazertinib was administered either in combination with amivantamab or as a monotherapy.
The median time to reach single dose and steady state Cmax was comparable and ranged from 2 to 4 hours.
Following administration of 240 mg lazertinib with a high-fat meal (800~1000 kcal, fat content approximately 50%), the Cmax and AUC of lazertinib were comparable to that under fasting conditions suggesting lazertinib can be taken with or without food.
Lazertinib was extensively distributed, with mean (CV%) apparent volume of distribution of 4264 (43.2%) L at 240 mg dose. Lazertinib mean (CV%) plasma protein binding was approximately 99.2% (0.13%) in humans. Lazertinib demonstrated covalent binding to human blood and plasma proteins after oral dosing, and during in vitro incubations.
Lazertinib is primarily metabolised by glutathione conjugation, either enzymatic via glutathione-S-transferase (GST) or non-enzymatic, as well as by CYP3A4. The most abundant metabolites are glutathione catabolites and considered clinically inactive. The plasma exposure of lazertinib was affected by GSTM1 mediated metabolism, leading to lower exposure (less than 2-fold difference) in Non-null GSTM1 patients. No dose adjustment is required based on GSTM1 status.
The mean (CV%) apparent clearance and terminal half-life of lazertinib at 240 mg dose were 44.5 (29.5%) L/h and 64.7 (32.8%) hours, respectively.
Following a single oral dose of radiolabelled lazertinib, approximately 86% of the dose was recovered in faeces (<5% as unchanged) and 4% in urine (<0.5% as unchanged).
The co-administration of multiple doses of lazertinib did not increase metformin (OCT1 substrate) Cmax and AUC. Lazertinib does not inhibit OCT1.
Based on in vitro studies, lazertinib may inhibit UGT1A1. However, due to lack of effect on indirect bilirubin levels in clinical study, no clinically relevant interaction is expected with UGT1A1 substrates.
Based on population PK analysis, no clinically meaningful age-based differences in pharmacokinetics of lazertinib were observed.
Based on population PK analysis, no dose adjustment is required for patients with mild, moderate or severe renal impairment with estimated glomerular filtration rate (eGFR) of 15 to 89 mL/min. Data in patients with severe renal impairment (eGFR of 15 to 29 mL/min) are limited (n=3), but there is no evidence to suggest that dose adjustment is required in these patients. No data are available in patients with end stage renal disease (eGFR <15 mL/min).
Based on findings from clinical pharmacology study, moderate hepatic impairment (Child-Pugh Class B) had no clinically meaningful effect on lazertinib single dose PK. Based on population PK analysis, no dose adjustment is required for patients with mild (total bilirubin ≤ ULN and AST > ULN or ULN < total bilirubin ≤ 1.5×ULN and any AST) or moderate (1.5×ULN < total bilirubin ≤ 3×ULN and any AST) hepatic impairment. No data are available in patients with severe hepatic impairment (total bilirubin > 3×ULN and any AST).
The pharmacokinetics of lazertinib in paediatric patients have not been investigated.
No clinically meaningful differences in lazertinib PK were observed based on sex, body weight, race, ethnicity, baseline laboratory assessments (creatinine clearance, albumin, alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase), ECOG performance status, EGFR mutation type, initial diagnosis cancer stage, prior therapies, brain metastasis, and history of smoking.
The main findings observed in repeat-dose toxicity studies with lazertinib in rats and dogs comprised mild epithelial atrophy to degenerative erosions, inflammation, and necrosis affecting the eye (corneal atrophy) skin (thin and rough hair coat, hair follicle degeneration, alopecia, ulcer), liver (increased liver enzymes, Kupffer cell hypertrophy and hepatocellular necrosis), lungs (alveolar macrophage infiltrate, lung inflammation and hyperplasia of alveolar type II cells), kidney (tubular dilatation, papillary necrosis, higher urea nitrogen, creatinine (females only), inorganic phosphorus, and potassium), GI (oesophageal epithelial atrophy, villus blunting/fusion in duodenum, and jejunum, liquid faeces), reproductive system (testis tubular degeneration, hypospermia, decreased oestrous cycles and corpora lutea, atrophy in uterus and vagina) These findings were observed in animals in exposures ranges of 0.9-3.4x than estimated exposures of patients administered with the recommended dose (240 mg) and were fully or partially resolved during the recovery phases. The heart was considered a target organ in dog alone and occurred at exposure levels 7x to that of exposure levels expected at the human recommended dose.
No evidence of genotoxicity for lazertinib was observed in in vitro bacterial mutagenicity, in vitro chromosomal aberration, and in vivo micronucleus tests in rats. Long-term animal studies have not been conducted to evaluate the carcinogenic potential of lazertinib.
Based on studies in animals, male and female fertility may be impaired by treatment with lazertinib. Degenerative changes were present in the testes of rats and dogs resulting in reduced luminal sperm in dogs following exposure to lazertinib for 1 month at clinically relevant exposure levels. Decreased numbers of corpora lutea were noted in the ovaries of rats exposed to lazertinib for ≥1 month at clinically relevant exposure levels. In a fertility and early embryonic development study in male and female rats, lazertinib induced a decrease in the number of oestrus cycles, an increase in post-implantation loss and decreased live litter size at or below the dose level that approximated the human clinical exposure at the recommended dose of 240 mg.
Developmental toxicity was observed in embryo-foetal development studies in rats and rabbits. In rats, decreases in foetal body weights in association with maternal toxicity were observed at a maternal exposure approximately 4 times higher than the human clinical exposure at 240 mg. In rabbits, an increased incidence of a foetal skull bone fusion (zygomatic arch fused to the maxillary process) was observed at maternal exposures well below the human clinical exposure at 240 mg.
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