Osimertinib

Osimertinib is a Tyrosine Kinase Inhibitor (TKI). It is an irreversible inhibitor of EGFRs harboring sensitising-mutations (EGFRm) and TKI-resistance mutation T790M.

In vitro studies have demonstrated that osimertinib has high potency and inhibitory activity against EGFR across a range of all clinically relevant EGFR sensitising-mutant and T790M mutant NSCLC cell lines (apparent IC_50s from 6 nM to 54 nM against phospho-EGFR). This leads to inhibition of cell growth, while showing significantly less activity against EGFR in wild-type cell lines (apparent IC_50s from 480 nM to 1.8 μM against phospho-EGFR). In vivo oral administration of osimertinib lead to tumour shrinkage in both EGFRm and T790M NSCLC xenograft and transgenic mouse lung tumour models.

Cardiac electrophysiology

The QTc interval prolongation potential of osimertinib was assessed in 210 patients who received osimertinib 80 mg daily in AURA2. Serial ECGs were collected following a single dose and at steady-state to evaluate the effect of osimertinib on QTc intervals. A pharmacokinetic/pharmacodynamic analysis predicted a drug-related QTc interval prolongation at 80 mg of 14 msec with an upper bound of 16 msec (90% CI).

Osimertinib pharmacokinetic parameters have been characterised in healthy subjects and NSCLC patients. Based on population pharmacokinetic analysis, osimertinib apparent plasma clearance is 14.3 L/h, apparent volume of distribution is 918 L and terminal half-life of approximately 44 hours. The pharmacokinetics in patients treated with osimertinib in combination with pemetrexed and platinum-based chemotherapy are similar to those in patients treated with osimertinib monotherapy. The AUC and C_max increased dose proportionally over 20 to 240 mg dose range. Administration of osimertinib once daily results in approximately 3-fold accumulation with steady-state exposures achieved by 15 days of dosing. At steady-state, circulating plasma concentrations are typically maintained within a 1.6-fold range over the 24-hour dosing interval.

Absorption

Following oral administration of osimertinib, peak plasma concentrations of osimertinib were achieved with a median (min-max) t_max of 6 (3-24) hours, with several peaks observed over the first 24 hours in some patients. The absolute bioavailability of osimertinib is 70% (90% CI 67, 73). Based on a clinical pharmacokinetic study in patients at 80 mg, food does not alter osimertinib bioavailability to a clinically meaningful extent (AUC increase by 6% (90% CI -5, 19) and C_max decrease by 7% (90% CI -19, 6)). In healthy volunteers administered an 80 mg tablet where gastric pH was elevated by dosing of omeprazole for 5 days, osimertinib exposure was not affected (AUC and C_max increase by 7% and 2%, respectively) with the 90% CI for exposure ratio contained within the 80-125% limit.

Distribution

Population estimated mean volume of distribution at steady-state (V_ss/F) of osimertinib is 918 L indicating extensive distribution into tissue. In vitro plasma protein binding of osimertinib is 94.7% (5.3% free). Osimertinib has also been demonstrated to bind covalently to rat and human plasma proteins, human serum albumin and rat and human hepatocytes.

Biotransformation

In vitro studies indicate that osimertinib is metabolised predominantly by CYP3A4, and CYP3A5. However, with current available data, alternative metabolic pathways cannot be fully ruled out. Based on in vitro studies, 2 pharmacologically active metabolites (AZ7550 and AZ5104) have subsequently been identified in the plasma of preclinical species and in humans after oral dosing with osimertinib; AZ7550 showed a similar pharmacological profile to osimertinib while AZ5104 showed greater potency across both mutant and wild-type EGFR. Both metabolites appeared slowly in plasma after administration of osimertinib to patients, with a median (min-max) t_max of 24 (4-72) and 24 (6-72) hours, respectively. In human plasma, parent osimertinib accounted for 0.8%, with the 2 metabolites contributing 0.08% and 0.07% of the total radioactivity with the majority of the radioactivity being covalently bound to plasma proteins. The geometric mean exposure of both AZ5104 and AZ7550, based on AUC, was approximately 10% each of the exposure of osimertinib at steady-state.

The main metabolic pathway of osimertinib was oxidation and dealkylation. At least 12 components were observed in the pooled urine and faecal samples in humans with 5 components accounting for >1% of the dose of which unchanged osimertinib, AZ5104 and AZ7550, accounted for approximately 1.9, 6.6 and 2.7% of the dose while a cysteinyl adduct (M21) and an unknown metabolite (M25) accounted for 1.5% and 1.9% of the dose, respectively.

Based on in vitro studies, osimertinib is a competitive inhibitor of CYP 3A4/5 but not CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6 and 2E1 at clinically relevant concentrations. Based on in vitro studies, osimertinib is not an inhibitor of UGT1A1 and UGT2B7 at clinically relevant concentrations hepatically. Intestinal inhibition of UGT1A1 is possible but the clinical impact is unknown.

Elimination

Following a single oral dose of 20 mg, 67.8% of the dose was recovered in faeces (1.2% as parent) while 14.2% of the administered dose (0.8% as parent) was found in urine by 84 days of sample collection. Unchanged osimertinib accounted for approximately 2% of the elimination with 0.8% in urine and 1.2% in faeces.

Interactions with transport proteins

In vitro studies have shown that osimertinib is not a substrate of OATP1B1 and OATP1B3. In vitro, osimertinib does not inhibit OAT1, OAT3, OATP1B1, OATP1B3, MATE1, OCT2 and MATE2K at clinically relevant concentrations.

Based on in vitro studies osimertinib is a substrate of P-gp and BCRP but at clinical doses, clinically relevant interactions are unlikely. Based on in vitro data, osimertinib is an inhibitor of BCRP and P-gp.

Special populations

In a population based pharmacokinetic analyses (n=1367), no clinically significant relationships were identified between predicted steady-state exposure (AUC_ss) and patient’s age (range: 25 to 91 years), gender (65% female), ethnicity (including White, Asian, Japanese, Chinese and non-Asian-non-White patients), line of therapy and smoking status (n=34 current smokers, n=419 former smokers). Population PK analysis indicated that body weight was a significant covariate with a less than 20% change in osimertinib AUC_ss expected across a body weight range of 88 kg to 43 kg respectively (95% to 5% quantiles) when compared to the AUC_ss for the median body weight of 61 kg. Taking the extremes of body weight into consideration, from <43 kg to >88 kg, AZ5104 metabolite ratios ranged from 11.8% to 9.6% while for AZ7550 it ranged from 12.8% to 8.1%, respectively. Based on population PK analysis, serum albumin was identified as a significant covariate with a <30% change in osimertinib AUC_ss expected across the albumin range of 29 to 46 g/L respectively (95% to 5% quantiles) when compared to the AUC_ss for the median baseline albumin of 39 g/L. These exposure changes due to body weight or baseline albumin differences are not considered clinically relevant.

Hepatic impairment

Osimertinib is eliminated mainly via the liver. In a clinical study, patients with different types of advanced solid tumours and with mild hepatic impairment (Child Pugh A, mean score =5.3, n=7) or moderate hepatic impairment (Child Pugh B, mean score =8.2, n=5) had no increase in exposure compared to patients with normal hepatic function (n=10) after a single 80 mg dose of osimertinib. The geometric mean ratio (90% CI) of osimertinib AUC and C_max was 63.3% (47.3, 84.5) and 51.4% (36.6, 72.3) in patients with mild hepatic impairment and 68.4% (49.6, 94.2) and 60.7% (41.6, 88.6) in patients with moderate hepatic impairment; for the metabolite AZ5104 the AUC and C_max were 66.5% (43.4, 101.9) and 66.3% (45.3, 96.9) in patients with mild hepatic impairment and 50.9% (31.7, 81.6) and 44.0% (28.9, 67.1) in patients with moderate hepatic impairment, compared to the exposure in patients with normal hepatic function. Based on population PK analysis, there was no relationship between markers of hepatic function (ALT, AST, bilirubin) and osimertinib exposure. The hepatic impairment marker serum albumin showed an effect on the PK of osimertinib. Clinical studies that were conducted excluded patients with AST or ALT >2.5x upper limit of normal (ULN), or if due to underlying malignancy, >5.0x ULN or with total bilirubin >1.5x ULN. Based on a pharmacokinetic analysis of 134 patients with mild hepatic impairment, 8 patients with moderate hepatic impairment and 1216 patients with normal hepatic function osimertinib exposures were similar. There are no data available on patients with severe hepatic impairment.

Renal impairment

In a clinical study, patients with severe renal impairment (CLcr 15 to less than 30 mL/min; n=7) compared to patients with normal renal function (CLcr greater than or equal to 90 mL/min; n=8) after a single 80 mg oral dose of osimertinib showed a 1.85-fold increase in AUC (90% CI; 0.94, 3.64) and a 1.19-fold increase in C_max (90% CI: 0.69, 2.07). Furthermore, based on a population pharmacokinetic analysis of 593 patients with mild renal impairment (CLcr 60 to less than 90 mL/min), 254 patients with moderate renal impairment (CLcr 30 to less than 60 mL/min), 5 patients with severe renal impairment (CLcr 15 to less than 30 mL/min) and 502 patients with normal renal function (greater than or equal to 90 mL/min), osimertinib exposures were similar. Patients with CLcr less than or equal to 10 mL/min were not included in the clinical studies.

Patients with brain metastases

PET images following administration of microdoses of [¹¹C]osimertinib in EGFR mutation-positive NSCLC patients with brain metastases (n=4) and healthy volunteers (n=7) demonstrated that the brain to plasma ratio (Kp) was similar and that [¹¹C]osimertinib crossed the blood brain barrier rapidly and was homogeneously distributed across all regions of the brain in both patients and healthy volunteers.

The main findings observed in repeat dose toxicity studies in rats and dogs comprised atrophic, inflammatory and/or degenerative changes affecting the epithelia of the cornea (accompanied by corneal translucencies and opacities in dogs at ophthalmology examination), GI tract (including tongue), skin, and male and female reproductive tracts with secondary changes in spleen. These findings occurred at plasma concentrations that were below those seen in patients at the 80 mg therapeutic dose. The findings present following 1 month of dosing were largely reversible within 1 month of cessation of dosing with the exception of partial recovery for some of the corneal changes.

Lens fibre degeneration was found in the 104-week carcinogenicity rat study at exposures 0.2-times the human AUC, at the recommended clinical dose of 80 mg once a day. Lens opacities were first noted from week 52 of this study and showed a gradual increase in incidence and severity with increased duration of dosing. The clinical relevance of this finding cannot be ruled out.

Osimertinib penetrated the intact blood-brain barrier of the cynomolgus monkey (intravenous dosing), rat and mouse (oral administration).

Non-clinical data indicate that osimertinib and its metabolite (AZ5104) inhibit the h-ERG channel, and QTc prolonging effect cannot be excluded.

Osimertinib did not cause genetic damage in in vitro and in vivo assays. Osimertinib showed no carcinogenic potential when administered orally to Tg rasH2 transgenic mice for 26 weeks. An increased incidence of proliferative vascular lesions (angiomatous hyperplasia and haemangioma) in the mesenteric lymph node was observed in the rat 104-week carcinogenicity study at exposures 0.2 times the AUC at the recommended clinical dose of 80 mg once daily, and is unlikely to be relevant for humans.

Reproductive toxicity

Degenerative changes were present in the testes in rats and dogs exposed to osimertinib for ≥1 month and there was a reduction in male fertility in rats following exposure to osimertinib for 3 months. These findings were seen at clinically relevant plasma concentrations. Pathology findings in the testes seen following 1 month dosing were reversible in rats; however, a definitive statement on reversibility of these lesions in dogs cannot be made.

Based on studies in animals, female fertility may be impaired by treatment with osimertinib. In repeat dose toxicity studies, an increased incidence of anoestrus, corpora lutea degeneration in the ovaries and epithelial thinning in the uterus and vagina were seen in rats exposed to osimertinib for ≥1 month at clinically relevant plasma concentrations. Findings in the ovaries seen following 1 month dosing were reversible. In a female fertility study in rats, administration of osimertinib at 20 mg/kg/day (approximately equal to the recommended daily clinical dose of 80 mg) had no effects on oestrus cycling or the number of females becoming pregnant, but caused early embryonic deaths. These findings showed evidence of reversibility following a 1 month off-dose.

In a modified embryofoetal development study in the rat, osimertinib caused embryolethality when administered to pregnant rats prior to embryonic implantation. These effects were seen at a maternally tolerated dose of 20 mg/kg where exposure was equivalent to the human exposure at the recommended dose of 80 mg daily (based on total AUC). Exposure at doses of 20 mg/kg and above during organogenesis caused reduced foetal weights but no adverse effects on external or visceral foetal morphology. When osimertinib was administered to pregnant female rats throughout gestation and then through early lactation, there was demonstrable exposure to osimertinib and its metabolites in suckling pups plus a reduction in pup survival and poor pup growth (at doses of 20 mg/kg and above).