Neratinib

Neratinib is an irreversible pan–erythroblastic leukaemia viral oncogene homolog (ERBB) tyrosine kinase inhibitor (TKI) that blocks mitogenic growth factor signal transduction through covalent, high affinity binding to the ATP binding site of 3 epidermal growth factor receptors (EGFRs): EGFR (encoded by ERBB1), HER2 (encoded by ERBB2), and HER4 (encoded by ERBB4) or their active heterodimers with HER3 (encoded by ERBB3). This results in sustained inhibition of these growth promoting pathways with HER2-amplified or over-expressed, or HER2-mutant breast cancers. Neratinib binds to the HER2 receptor, reduces EGFR and HER2 autophosphorylation, downstream MAPK and AKT signaling pathways, and potently inhibits tumour cell proliferation in vitro. Neratinib inhibited EGFR and/or HER2-expressing carcinoma cell lines with a cellular IC₅₀ <100 nM.

The mass balance after administration of a single oral dose of 200 mg of neratinib was studied in six healthy subjects.

Absorption

Following oral administration of 240 mg neratinib, absorption was slow and peak plasma concentrations of neratinib occurred around 7 hours after administration. A single dose of 240 mg neratinib taken with food increased C_max and AUC by approximately 17% and 13%, respectively, compared with administration in the fasting state. A single oral dose of 240 mg neratinib taken with a meal high in fat increased both C_max and AUC by approximately 100%. In a mass balance study, the total recovery (urinary and fecal excretion) of intact neratinib and metabolites demonstrates that the fraction absorbed for neratinib is at least 10% and likely more than 20%. Moreover, model-based predictions suggested an overall absorbed fraction from the gut (fa) of 26%.

In vitro neratinib solubility is pH-dependent. Treatments that increase gastrointestinal pH may lower the absorption of neratinib, thus decreasing systemic exposure.

Distribution

Binding of neratinib to human plasma proteins, including covalent binding to human serum albumin (HSA), was greater than 98% and independent of the tested neratinib concentration. Neratinib bound predominantly to HSA and human alpha-1 acid glycoprotein (AAG). Binding of M6 main metabolite (M6) to human plasma proteins was greater than 99% and independent of the tested M6 concentrations.

In vitro studies demonstrated that neratinib is a substrate for P-glycoprotein (P-gp) and BCRP. In vitro studies demonstrated that neratinib and its main metabolite M6 are not substrates of hepatic uptake transporters OATP1B1*1a and OATP1B3 at relevant clinical concentration.

Biotransformation

Neratinib is metabolised primarily in liver microsomes by CYP3A4 and to a lesser extent by flavincontaining monooxygenase (FMO).

Preliminary metabolite profiling in human plasma indicates that after oral administration, neratinib undergoes oxidative metabolism through CYP3A4. Circulating metabolites include neratinib pyridine N-oxide (M3), N-desmethyl neratinib (M6), neratinib dimethylamine N-oxide (M7) and traces of hydroxyl neratinib N-oxide and neratinib bis-N-oxide (M11). Neratinib represents the most prominent component in plasma and amongst circulating metabolites (M2, M3, M6, M7 and M11) none is above 8% of neratinib plus metabolite total exposure after oral administration of neratinib. The neratinib metabolites M3, M6, M7 and M11 were shown to have similar potencies to neratinib in either in vitro enzyme (binding assays) or cell based assays against cells expressing ERBB1, ERBB2 (HER2) and ERBB4.

Based on steady state exposures, neratinib provides the majority of pharmacological activity (73%), with 20% provided by exposure to M6, 6% provided by M3, and negligible contribution (<1%) from M7 and M11 AUC.

Elimination

Following single doses of neratinib, the mean apparent plasma half-life of neratinib was 17 hours in patients.

Excretion of neratinib is primarily via the faeces

Following the administration of a single radiolabelled dose of 240 mg neratinib oral solution, 95.5% and 0.96% of the administered dose was recovered in the faeces and urine, respectively.

The excretion was rapid and complete, with most of the dose recovered in faeces within 48 hours and 96.5% of total radioactivity recovered in excreta after 8 days. Unchanged neratinib was the most abundant species in excreta accounting for 62.1% of total dose recovered in excreta. The most abundant metabolites in faeces were M6 (19.7% of administered dose), followed by M2, M3 and M7, all below 10% of administered dose.

Medicinal product interactions

Effect of CYP3A4/P-gp inducer on neratinib

Following concomitant administration of 240 mg neratinib with repeated doses of 600 mg rifampicin, a strong CYP3A4/P-gp inducer, neratinib exposures were significantly decreased by 76% and 87% for C_max and AUC, respectively, compared with neratinib administration alone.

Effect of CYP3A4/P-gp inhibitor on neratinib

Co-administration of a single oral dose of 240 mg of neratinib in the presence of ketoconazole (400 mg once daily for 5 days), a strong CYP3A4/P-gp inhibitor, increased neratinib systemic exposure by 3.2- and 4.8-fold for C_max and AUC, respectively, compared with neratinib administered alone.

Model-based predictions suggested that co-administration of a single oral dose of 240 mg of neratinib in the presence of fluconazole (200 mg once daily for 8 days), a moderate CYP3A4 inhibitor, increased neratinib systemic exposure by 1.3- and 1.7-fold for C_max and AUC, compared with neratinib administered alone.

Model-based predictions suggested that co-administration of a single oral dose of 240 mg of neratinib in the presence of verapamil (120 mg twice daily for 8 days), a moderate CYP3A4/strong P-gp inhibitor, increased neratinib systemic exposure by 3.0- and 4.0-fold for C_max and AUC, compared with neratinib administered alone.

Effect of gastric pH modifiers on neratinib

Co-administration of lansoprazole or ranitidine (1x300 mg) with a 240 mg single dose of neratinib in healthy volunteers resulted in a decreased neratinib exposure by around 70% or 50%, respectively. The magnitude of ranitidine interaction on neratinib AUC was reduced by around 25%, by staggering the administration of ranitidine (2x150 mg) 2 hours after neratinib administration.

Effect of other treatment on neratinib

There were no apparent clinically relevant drug-drug interactions observed for neratinib when administered concomitantly with capecitabine, paclitaxel, trastuzumab, vinorelbine, or antidiarrhoeals (loperamide). Effect of neratinib on CYP substrates Neratinib and metabolite M6 were not potent direct inhibitors of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2D6, or 3A4 and no time-dependent inhibition is expected. Neratinib did not induce CYP1A2, 2B6, 2C9, or 3A4.

Effect of neratinib on transporters

There was no clinically relevant inhibition of human BSEP efflux transporter activity in vitro, with a reported IC₅₀ value of >10 µM. Neratinib at 10 µM appeared to inhibit the BCRP efflux transporter which could be clinically relevant at intestinal level.

In in vitro studies, neratinib was an inhibitor of P-glycoprotein (P-gp) efflux transporters, which was further confirmed in a clinical study. Multiple oral doses of neratinib 240 mg increased digoxin exposures (54 and 32% increase in C_max and AUC, respectively) with no impact on its renal clearance level.

Neratinib produced no inhibitory activity towards the uptake transporters, OATP1B1*1a, OATP1B3, OAT1, OAT3 and OCT2, with reported IC₅₀ values were >10µM. Neratinib produced inhibitory activity in OCT1 uptake transporter, with an IC₅₀ of 2.9 µM.

Special populations

Renal impairment

Pharmacokinetic studies in patients with renal impairment or undergoing dialysis have not been carried out. Population pharmacokinetic modelling revealed that creatinine clearance did not explain the variability between patients, hence, no dose modifications are recommended for patients with mild to moderate renal impairment.

Hepatic impairment

Neratinib is extensively metabolised in the liver. In subjects with severe pre-existing hepatic impairment (Child-Pugh Class C) without cancer, the clearance of neratinib was decreased by 36% and exposure to neratinib increased by about 3-fold as compared to healthy volunteers.

Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows:

Carcinogenesis, mutagenesis

Neratinib was neither clastogenic nor mutagenic in the standard battery of genotoxicity studies.

Neratinib metabolites M3, M6, M7 and M11 are negative in the standard battery of in vitro genotoxicity studies.

A 6-month carcinogenicity study in Tg.rasH2 transgenic mice and the rat 2-year data showed no signs of carcinogenic potential.

Reproductive toxicity

In rabbits, there were no effects on mating or the ability of animals to become pregnant, but embryofoetal lethality and foetal morphologic anomalies (e.g. domed head, dilation of brain ventricles and misshapen anterior fontanelles and enlarged anterior and/or posterior fontanelles) were observed at doses that may be considered to be clinically relevant.

Environmental risk assessment (ERA)

Environmental risk assessment studies have shown that neratinib has an evident potential to be persistent, bioaccumulative, and toxic to the environment.