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VIZIMPRO® Tablets (dacomitinib) Clinical Pharmacology

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Dacomitinib is an irreversible inhibitor of the kinase activity of the human EGFR family (EGFR/HER1, HER2, and HER4) and certain EGFR activating mutations (exon 19 deletion or the exon 21 L858R substitution mutation). In vitro dacomitinib also inhibited the activity of DDR1, EPHA6, LCK, DDR2, and MNK1 at clinically relevant concentrations.

Dacomitinib demonstrated dose-dependent inhibition of EGFR and HER2 autophosphorylation and tumor growth in mice bearing subcutaneously implanted human tumor xenografts driven by HER family targets including mutated EGFR. Dacomitinib also exhibited antitumor activity in orally-dosed mice bearing intracranial human tumor xenografts driven by EGFR amplifications.

12.2 Pharmacodynamics

Cardiac Electrophysiology

The effect of dacomitinib on the QT interval corrected for heart rate (QTc) was evaluated using time-matched electrocardiograms (ECGs) evaluating the change from baseline and corresponding pharmacokinetic data in 32 patients with advanced NSCLC. Dacomitinib had no large effect on QTc (i.e., >20 ms) at maximum dacomitinib concentrations achieved with VIZIMPRO 45 mg orally once daily.

Exposure-Response Relationships

Higher exposures, across the range of exposures with the recommended dose of 45 mg daily, correlated with an increased probability of Grade ≥3 adverse events, specifically dermatologic toxicities and diarrhea.

12.3 Pharmacokinetics

The maximum dacomitinib plasma concentration (Cmax) and AUC at steady state increased proportionally over the dose range of VIZIMPRO 2 mg to 60 mg orally once daily (0.04 to 1.3 times the recommended dose) across dacomitinib studies in patients with cancer. At a dose of 45 mg orally once daily, the geometric mean [coefficient of variation (CV%)] Cmax was 108 ng/mL (35%) and the AUC0–24h was 2213 ng∙h/mL (35%) at steady state in a dose-finding clinical study conducted in patients with solid tumors. Steady state was achieved within 14 days following repeated dosing and the estimated geometric mean (CV%) accumulation ratio was 5.7 (28%) based on AUC.

Absorption

The mean absolute bioavailability of dacomitinib is 80% after oral administration. The median dacomitinib time to reach maximum concentration (Tmax) occurred at approximately 6.0 hours (range 2.0 to 24 hours) after a single oral dose of VIZIMPRO 45 mg in patients with cancer.

Effect of Food

Administration of VIZIMPRO with a high-fat, high-calorie meal (approximately 800 to 1000 calories with 150, 250, and 500 to 600 calories from protein, carbohydrate and fat, respectively) had no clinically meaningful effect on dacomitinib pharmacokinetics.

Distribution

The geometric mean (CV%) volume of distribution of dacomitinib (Vss) was 1889 L (18%). In vitro binding of dacomitinib to human plasma proteins is approximately 98% and is independent of drug concentrations from 250 ng/mL to 1000 ng/mL.

Elimination

Following a single 45 mg oral dose of VIZIMPRO in patients with cancer, the mean (CV%) plasma half-life of dacomitinib was 70 hours (21%), and the geometric mean (CV%) apparent plasma clearance of dacomitinib was 24.9 L/h (36%).

Metabolism

Hepatic metabolism is the main route of clearance of dacomitinib, with oxidation and glutathione conjugation as the major pathways. Following oral administration of a single 45 mg dose of [14C] dacomitinib, the most abundant circulating metabolite was O-desmethyl dacomitinib, which had similar in vitro pharmacologic activity as dacomitinib. The steady-state plasma trough concentration of O-desmethyl dacomitinib ranges from 7.4% to 19% of the parent. In vitro studies indicated that cytochrome P450 (CYP) 2D6 was the major isozyme involved in the formation of O-desmethyl dacomitinib, while CYP3A4 contributed to the formation of other minor oxidative metabolites.

Excretion

Following a single oral 45 mg dose of [14C] radiolabeled dacomitinib, 79% of the radioactivity was recovered in feces (20% as dacomitinib) and 3% in urine (<1% as dacomitinib).

Specific Populations

Patients with Renal Impairment

Based on population pharmacokinetic analyses, mild (60 mL/min ≤ CLcr <90 mL/min; N=590) and moderate (30 mL/min ≤ CLcr <60 mL/min; N=218) renal impairment did not alter dacomitinib pharmacokinetics, relative to the pharmacokinetics in patients with normal renal function (CLcr ≥90 mL/min; N=567). The pharmacokinetics of dacomitinib has not been adequately characterized in patients with severe renal impairment (CLcr <30 mL/min) (N=4) or studied in patients requiring hemodialysis.

Patients with Hepatic Impairment

In a dedicated hepatic impairment trial, following a single oral dose of 30 mg VIZIMPRO, dacomitinib exposure (AUCinf and Cmax) was unchanged in subjects with mild hepatic impairment (Child-Pugh A; N=8) and decreased by 15% and 20%, respectively in subjects with moderate hepatic impairment (Child-Pugh B; N=9) when compared to subjects with normal hepatic function (N=8). Based on this trial, mild and moderate hepatic impairment had no clinically important effects on pharmacokinetics of dacomitinib. In addition, based on a population pharmacokinetic analysis of 1381 patients, in which 158 patients had mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin > 1 to 1.5 × ULN with any AST) and 5 patients had moderate hepatic impairment (total bilirubin > 1.5 to 3 × ULN and any AST), no effects on pharmacokinetics of dacomitinib were observed. The effect of severe hepatic impairment (total bilirubin > 3 to 10 × ULN and any AST) on dacomitinib pharmacokinetics is unknown [see Use in Specific Populations (8.7)].

Drug Interaction Studies

Clinical Studies

Effect of Acid-Reducing Agents on Dacomitinib

Coadministration of a single 45 mg dose of VIZIMPRO with multiple doses of rabeprazole (a proton pump inhibitor) decreased dacomitinib Cmax by 51% and AUC0–96h by 39% [see Dosage and Administration (2.4) and Drug Interactions (7.1)].

Coadministration of VIZIMPRO with a local antacid (Maalox® Maximum Strength, 400 mg/5 mL) did not cause clinically relevant changes dacomitinib concentrations [see Dosage and Administration (2.4) and Drug Interactions (7.1)].

The effect of H2 receptor antagonists on dacomitinib pharmacokinetics has not been studied [see Dosage and Administration (2.4) and Drug Interactions (7.1)].

Effect of Strong CYP2D6 Inhibitors on Dacomitinib

Coadministration of a single 45 mg dose of VIZIMPRO with multiple doses of paroxetine (a strong CYP2D6 inhibitor) in healthy subjects increased the total AUClast of dacomitinib plus its active metabolite (O-desmethyl dacomitinib) in plasma by approximately 6%, which is not considered clinically relevant.

Effect of Dacomitinib on CYP2D6 Substrates

Coadministration of a single 45 mg oral dose of VIZIMPRO increased dextromethorphan (a CYP2D6 substrate) Cmax by 9.7-fold and AUClast by 9.6-fold [see Drug Interactions (7.2)].

In Vitro Studies

Effect of Dacomitinib and O-desmethyl Dacomitinib on CYP Enzymes: Dacomitinib and its metabolite O-desmethyl dacomitinib do not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4/5. Dacomitinib does not induce CYP1A2, CYP2B6, or CYP3A4.

Effect of Dacomitinib on Uridine 5' diphospho-glucuronosyltransferase (UGT) Enzymes: Dacomitinib inhibits UGT1A1. Dacomitinib does not inhibit UGT1A4, UGT1A6, UGT1A9, UGT2B7, or UGT2B15.

Effect of Dacomitinib on Transporter Systems: Dacomitinib is a substrate for the membrane transport protein P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). Dacomitinib inhibits P-gp, BCRP, and organic cation transporter (OCT)1. Dacomitinib does not inhibit organic anion transporters (OAT)1 and OAT3, OCT2, organic anion transporting polypeptide (OATP)1B1, and OATP1B3.

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