Brigatinib

Brigatinib is a tyrosine kinase inhibitor that targets ALK, c-ros oncogene 1 (ROS1), and insulin-like growth factor 1 receptor (IGF-1R). Brigatinib inhibited autophosphorylation of ALK and ALK-mediated phosphorylation of the downstream signalling protein STAT3 in in vitro and in vivo assays.

Brigatinib inhibited the in vitro proliferation of cell lines expressing EML4-ALK and NPM-ALK fusion proteins and demonstrated dose-dependent inhibition of EML4-ALK-positive NSCLC xenograft growth in mice. Brigatinib inhibited the in vitro and in vivo viability of cells expressing mutant forms of EML4-ALK associated with resistance to ALK inhibitors, including G1202R and L1196M.

Cardiac electrophysiology

In Study 101, the QT interval prolongation potential of brigatinib was assessed in 123 patients with advanced malignancies following once daily brigatinib doses of 30 mg to 240 mg. The maximum mean QTcF (corrected QT by the Fridericia method) change from baseline was less than 10 msec. An exposure-QT analysis suggested no concentration-dependent QTc interval prolongation.

Absorption

In Study 101, following administration of a single oral dose of brigatinib (30-240 mg) in patients, the median time to peak concentration (T_max) was 1-4 hours postdose. After a single dose and at steady state, systemic exposure was dose proportional over the dose range of 60-240 mg once daily. Modest accumulation was observed upon repeated dosing (geometric mean accumulation ratio: 1.9 to 2.4). The geometric mean steady state C_max of brigatinib at doses of 90 mg and 180 mg once daily was 552 and 1,452 ng/mL, respectively, and the corresponding AUC_0-τ was 8,165 and 20,276 h∙ng/mL, respectively. Brigatinib is a substrate of the transporter proteins P-gp and BCRP.

In healthy subjects, compared to overnight fasting, a high fat meal reduced brigatinib C_max by 13% with no effect on AUC. Brigatinib can be administered with or without food.

Distribution

Brigatinib was moderately bound (91%) to human plasma proteins and binding was not concentration-dependent. The blood-to-plasma concentration ratio is 0.69. In patients given brigatinib 180 mg once daily, the geometric mean apparent volume of distribution (V_z/F) of brigatinib at steady state was 307 L, indicating moderate distribution into tissues.

Biotransformation

In vitro studies demonstrated that brigatinib is primarily metabolised by CYP2C8 and CYP3A4, and to a much lesser extent by CYP3A5.

Following oral administration of a single 180 mg dose of [¹⁴C]brigatinib to healthy subjects, N-demethylation and cysteine conjugation were the two major metabolic clearance pathways. In urine and faeces combined, 48%, 27%, and 9.1% of the radioactive dose was excreted as unchanged brigatinib, N-desmethyl brigatinib (AP26123), and brigatinib cysteine conjugate, respectively. Unchanged brigatinib was the major circulating radioactive component (92%) along with AP26123 (3.5%), the primary metabolite also observed in vitro. In patients, at steady state, the plasma AUC of AP26123 was <10% of brigatinib exposure. In in vitro kinase and cellular assays, the metabolite, AP26123, inhibited ALK with approximately 3-fold lower potency than brigatinib.

Elimination

In patients given brigatinib 180 mg once daily, the geometric mean apparent oral clearance (CL/F) of brigatinib at steady state was 8.9 L/h and the median plasma elimination half-life was 24 h.

The primary route of excretion of brigatinib is in faeces. In six healthy male subjects given a single 180 mg oral dose of [¹⁴C]brigatinib, 65% of the administered dose was recovered in faeces and 25% of the administered dose was recovered in urine. Unchanged brigatinib represented 41% and 86% of the total radioactivity in faeces and urine, respectively, the remainder being metabolites.

Specific populations

Hepatic impairment

The pharmacokinetics of brigatinib was characterised in healthy subjects with normal hepatic function (N=9), and patients with mild hepatic impairment (Child-Pugh class A, N=6), moderate hepatic impairment (Child-Pugh class B, N=6), or severe hepatic impairment (Child-Pugh class C, N=6). The pharmacokinetics of brigatinib was similar between healthy subjects with normal hepatic function and patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment. Unbound AUC_0-INF was 37% higher in patients with severe hepatic impairment (Child-Pugh class C) as compared to healthy subjects with normal hepatic function.

Renal impairment

The pharmacokinetics of brigatinib is similar in patients with normal renal function and in patients with mild or moderate renal impairment (eGFR ≥30 mL/min) based on the results of population pharmacokinetic analyses. In a pharmacokinetic study, unbound AUC_0-INF was 94% higher in patients with severe renal impairment (eGFR <30 mL/min, N=6) as compared to patients with normal renal function (eGFR ≥90 mL/min, N=8).

Race and gender

Population pharmacokinetic analyses showed that race and gender had no impact on the pharmacokinetics of brigatinib.

Age, body weight, and albumin concentrations

The population pharmacokinetic analyses showed that body weight, age, and albumin concentration had no clinically relevant impact on the pharmacokinetics of brigatinib.

Safety pharmacology studies with brigatinib identified potential for pulmonary effects (altered respiration rate; 1-2 times the human C_max), cardiovascular effects (altered heart rate and blood pressure; at 0.5 times the human C_max), and renal effects (reduced renal function; at 1-2.5 times the human C_max), but did not indicate any potential for QT prolongation or neurofunctional effects.

Adverse reactions seen in animals at exposure levels similar to clinical exposure levels with possible relevance to clinical use were as follows: gastrointestinal system, bone marrow, eyes, testes, liver, kidney, bone, and heart. These effects were generally reversible during the non-dosing recovery period; however, effects in the eyes and testes were notable exceptions due to lack of recovery. In repeated dose toxicity studies, lung changes (foamy alveolar macrophages) were noted in monkeys at ≥0.2 times the human AUC; however, these were minimal and similar to those reported as background findings in naive monkeys, and there was no clinical evidence of respiratory distress in these monkeys.

Carcinogenicity studies have not been performed with brigatinib.

Brigatinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) or the mammalian cell chromosomal aberration assays, but slightly increased the number of micronuclei in a rat bone marrow micronucleus test. The mechanism of micronucleus induction was abnormal chromosome segregation (aneugenicity) and not a clastogenic effect on chromosomes. This effect was observed at approximately five fold the human exposure at the 180 mg once daily dose.

Brigatinib may impair male fertility. Testicular toxicity was observed in repeat-dose animal studies. In rats, findings included lower weight of testes, seminal vesicles and prostate gland, and testicular tubular degeneration; these effects were not reversible during the recovery period. In monkeys, findings included reduced size of testes along with microscopic evidence of hypospermatogenesis; these effects were reversible during the recovery period. Overall, these effects on the male reproductive organs in rats and monkeys occurred at exposures ≥0.2-times the AUC observed in patients at the 180 mg once daily dose. No apparent adverse effects on female reproductive organs were observed in general toxicology studies in rats and monkeys.

In an embryo-foetal development study in which pregnant rats were administered daily doses of brigatinib during organogenesis; dose-related skeletal anomalies were observed at doses as low as approximately 0.7-times the human exposure by AUC at the 180 mg once daily dose. Findings included embryo-lethality, reduced foetal growth, and skeletal variations.