Tagrisso Flashcards
What is the therapeutic indication of Tagrisso
TAGRISSO as monotherapy is indicated for:
* the adjuvant treatment after complete tumour resection in adult patients with stage IB-IIIA non-small cell lung cancer (NSCLC) whose tumours have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations (see section 5.1).
* the first-line treatment of adult patients with locally advanced or metastatic NSCLC with activating EGFR mutations.
* the treatment of adult patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC.
What is the Posology and method of administration of Tagrisso?
Treatment with TAGRISSO should be initiated by a physician experienced in the use of anticancer therapies.
When considering the use of TAGRISSO, EGFR mutation status (in tumour specimens for adjuvant treatment and tumour or plasma specimens for locally advanced or metastatic setting) should be determined using a validated test method.
The recommended dose is 80 mg osimertinib once a day.
Patients with locally advanced or metastatic lung cancer should receive treatment until disease progression or unacceptable toxicity.
Dosing interruption and/or dose reduction may be required based on individual safety and tolerability. If dose reduction is necessary, then the dose should be reduced to 40 mg taken once daily.
What are the contraindication’s of tagrisso?
Hypersensitivity to the active substance or to any of the excipients.
St. John’s Wort should not be used together with TAGRISSO.
What is the mechanism of action of tagrisso?
Osimertinib is a Tyrosine Kinase Inhibitor (TKI). It is an irreversible inhibitor of EGFRs harboring sensitising-mutations (EGFRm) and TKI-resistance mutation T790M.
What are the Pharmadynamic effects of Tagrisso?
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 IC50s 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 IC50s 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.
What are the pharmacokinetic properties of Tagrisso?
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 AUC and Cmax 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.
How is Tagrisso absorbed in the body?
Following oral administration of TAGRISSO, peak plasma concentrations of osimertinib were achieved with a median (min-max) tmax of 6 (3-24) hours, with several peaks observed over the first 24 hours in some patients. The absolute bioavailability of TAGRISSO 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 Cmax 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 Cmax increase by 7% and 2%, respectively) with the 90% CI for exposure ratio contained within the 80-125% limit.
How is Tagrisso Distributed in the body?
Population estimated mean volume of distribution at steady-state (Vss/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.
What is the Biotransformation of Tagrisso?
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 TAGRISSO while AZ5104 showed greater potency across both mutant and wild-type EGFR. Both metabolites appeared slowly in plasma after administration of TAGRISSO to patients, with a median (min-max) tmax 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.
How is Tagrisso eliminated from the body?
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.
