Tucatinib is a tyrosine kinase inhibitor of HER2. In vitro, tucatinib inhibits phosphorylation of HER2 and HER3, resulting in inhibition of downstream MAPK and AKT signaling and cell proliferation, and showed anti-tumor activity in HER2 expressing tumor cells. In vivo, tucatinib inhibited the growth of HER2 expressing tumors. The combination of tucatinib and trastuzumab showed increased anti-tumor activity in vitro and in vivo compared to either drug alone.
Exposure Response Relationship
Tucatinib exposure-response relationships and the time course of pharmacodynamics response have not been fully characterized.
Cardiac Electrophysiology
No large mean increase in QTc (i.e., > 20 ms) was detected following treatment with TUKYSA at the recommended dose of 300 mg taken orally twice daily.
Tucatinib AUC0-INF and Cmax increased proportionally over a dosage range from 50 mg to 300 mg (0.17 to 1 times the approved recommended dosage). Time to steady state was approximately 4 days. Steady-state pharmacokinetic parameters following administration of TUKYSA 300 mg twice daily for 7 days in patients with mBC and mCRC are described in Table 9. The geometric mean (CV%) tucatinib AUC accumulation ratios ranged from 2.0 (26) fold to 2.5 (28) fold.
| Tumor Type | AUCss (ng*h/mL) | Cmax,ss (ng/mL) | Ctrough,ss (ng/mL) |
| mBC | 5620 (43) | 747 (45) | 288 (59) |
| mCRC | 3370 (49) | 405 (45) | 197 (63) |
Absorption
The median time to peak plasma concentration of tucatinib was approximately 2 hours (range 1 to 4 hours).
Effects of Food
Following administration of a single oral dose of TUKYSA in 11 subjects after a high-fat meal (approximately 58% fat, 26% carbohydrate, and 16% protein), the mean AUC0-INF increased by 1.5-fold, the Tmax shifted from 1.5 hours to 4 hours, and Cmax was unaltered. The effect of food on the pharmacokinetics of tucatinib was not clinically meaningful.
Distribution
The geometric mean (CV%) apparent volume of distribution of tucatinib at steady-state were 903 (42) L and 829 (21) L in patients with mBC and mCRC, respectively. The plasma protein binding was 97.1% at clinically relevant concentrations.
At steady-state, concentrations of tucatinib and its metabolite ONT-993 in the cerebrospinal fluid were comparable to unbound plasma concentrations.
Elimination
At steady-state, tucatinib effective half-life was approximately 11.9 hours and geometric mean (CV%) apparent clearance was 53 (43) L/h in patients with mBC. Tucatinib effective half-life was approximately 16.4 hours and geometric mean (CV%) apparent clearance was 89 (49) L/h in patients with mCRC.
Metabolism
Tucatinib is metabolized primarily by CYP2C8 and to a lesser extent via CYP3A.
Excretion
Following a single oral dose of 300 mg radiolabeled tucatinib, approximately 86% of the total radiolabeled dose was recovered in feces (16% of the administered dose as unchanged tucatinib) and 4.1% in urine with an overall total recovery of 90% within 13 days post-dose. In plasma, approximately 76% of the plasma radioactivity was unchanged, 19% was attributed to identified metabolites, and approximately 5% was unassigned.
Specific Populations
Age (18-77 years), albumin (19 to 52 g/L), creatinine clearance (CLcr: 60 to 89 mL/min (n = 63); CLcr 30 to 59 mL/min (n = 6)), body weight (41 to 146 kg), sex (male (n = 170), female (n = 113)) and race (White (n = 205), Black (n = 37), or Asian (n = 25)) did not have a clinically meaningful effect on tucatinib exposure.
Renal Impairment
No clinically significant differences in the pharmacokinetics of tucatinib were observed in patients with mild to moderate renal impairment (CLcr: 30 to 89 mL/min by Cockcroft-Gault). The effect of severe renal impairment (CLcr: < 30 mL/min) on the pharmacokinetics of tucatinib is unknown.
Hepatic Impairment
Mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment had no clinically relevant effect on tucatinib exposure. Tucatinib AUC0-INF was increased by 1.6 fold in subjects with severe (Child-Pugh C) hepatic impairment compared to subjects with normal hepatic function.
Drug Interaction Studies
Clinical Studies
| Concomitant Drug (Dose) | TUKYSA Dose | Ratio (90% CI) of Tucatinib Exposure With and Without Concomitant Drug | |
| Cmax | AUC | ||
| Strong CYP3A Inhibitor Itraconazole (200 mg BID) | 300 mg single dose | 1.3 (1.2, 1.4) | 1.3 (1.3, 1.4) |
| Strong CYP3A/Moderate 2C8 Inducer Rifampin (600 mg once daily) | 0.6 (0.5, 0.8) | 0.5 (0.4, 0.6) | |
| Strong CYP2C8 Inhibitor Gemfibrozil (600 mg BID) | 1.6 (1.5, 1.8) | 3.0 (2.7, 3.5) | |
| a. Tucatinib reduced the renal clearance of metformin without any effect on glomerular filtration rate (GFR) as measured by iohexol clearance and serum cystatin C. | |||
| Concomitant Drug (Dose) | TUKYSA Dose | Ratio (90% CI) of Exposure Measures of Concomitant Drug with/without Tucatinib | |
| Cmax | AUC | ||
| CYP2C8 Substrate Repaglinide (0.5 mg single dose) | 300 mg single dose | 1.7 (1.4, 2.1) | 1.7 (1.5, 1.9) |
| CYP3A Substrate Midazolam (2 mg single dose) | 3.0 (2.6, 3.4) | 5.7 (5.0, 6.5) | |
| P-gp Substrate Digoxin (0.5 mg single dose) | 2.4 (1.9, 2.9) | 1.5 (1.3, 1.7) | |
| MATE1/2-K substratea Metformin (850 mg single dose) | 1.1 (1.0, 1.2) | 1.4 (1.2, 1.5) | |
No clinically significant difference in the pharmacokinetics of tucatinib were observed when used concomitantly with omeprazole (proton pump inhibitor) or tolbutamide (sensitive CYP2C9 substrate).
In Vitro Studies
Cytochrome P450 (CYP) Enzymes: Tucatinib is a reversible inhibitor of CYP2C8 and CYP3A and a time-dependent inhibitor of CYP3A, but is not an inhibitor of CYP1A2, CYP2B6, CYP2C9, CYP2C19, or CYP2D6.
Uridine diphosphate (UDP)-glucuronosyl transferase (UGT) Enzymes: Tucatinib is not an inhibitor of UGT1A1.
Transporter Systems: Tucatinib is a substrate of P-gp and BCRP, but is not a substrate of OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K, or BSEP.
Tucatinib inhibits MATE1/MATE2-K-mediated transport of metformin and OCT2/MATE1-mediated transport of creatinine. The observed serum creatinine increase in clinical studies with tucatinib is due to inhibition of tubular secretion of creatinine via OCT2 and MATE1.
Tucatinib is a tyrosine kinase inhibitor of HER2. In vitro, tucatinib inhibits phosphorylation of HER2 and HER3, resulting in inhibition of downstream MAPK and AKT signaling and cell proliferation, and showed anti-tumor activity in HER2 expressing tumor cells. In vivo, tucatinib inhibited the growth of HER2 expressing tumors. The combination of tucatinib and trastuzumab showed increased anti-tumor activity in vitro and in vivo compared to either drug alone.
Exposure Response Relationship
Tucatinib exposure-response relationships and the time course of pharmacodynamics response have not been fully characterized.
Cardiac Electrophysiology
No large mean increase in QTc (i.e., > 20 ms) was detected following treatment with TUKYSA at the recommended dose of 300 mg taken orally twice daily.
Tucatinib AUC0-INF and Cmax increased proportionally over a dosage range from 50 mg to 300 mg (0.17 to 1 times the approved recommended dosage). Time to steady state was approximately 4 days. Steady-state pharmacokinetic parameters following administration of TUKYSA 300 mg twice daily for 7 days in patients with mBC and mCRC are described in Table 9. The geometric mean (CV%) tucatinib AUC accumulation ratios ranged from 2.0 (26) fold to 2.5 (28) fold.
| Tumor Type | AUCss (ng*h/mL) | Cmax,ss (ng/mL) | Ctrough,ss (ng/mL) |
| mBC | 5620 (43) | 747 (45) | 288 (59) |
| mCRC | 3370 (49) | 405 (45) | 197 (63) |
Absorption
The median time to peak plasma concentration of tucatinib was approximately 2 hours (range 1 to 4 hours).
Effects of Food
Following administration of a single oral dose of TUKYSA in 11 subjects after a high-fat meal (approximately 58% fat, 26% carbohydrate, and 16% protein), the mean AUC0-INF increased by 1.5-fold, the Tmax shifted from 1.5 hours to 4 hours, and Cmax was unaltered. The effect of food on the pharmacokinetics of tucatinib was not clinically meaningful.
Distribution
The geometric mean (CV%) apparent volume of distribution of tucatinib at steady-state were 903 (42) L and 829 (21) L in patients with mBC and mCRC, respectively. The plasma protein binding was 97.1% at clinically relevant concentrations.
At steady-state, concentrations of tucatinib and its metabolite ONT-993 in the cerebrospinal fluid were comparable to unbound plasma concentrations.
Elimination
At steady-state, tucatinib effective half-life was approximately 11.9 hours and geometric mean (CV%) apparent clearance was 53 (43) L/h in patients with mBC. Tucatinib effective half-life was approximately 16.4 hours and geometric mean (CV%) apparent clearance was 89 (49) L/h in patients with mCRC.
Metabolism
Tucatinib is metabolized primarily by CYP2C8 and to a lesser extent via CYP3A.
Excretion
Following a single oral dose of 300 mg radiolabeled tucatinib, approximately 86% of the total radiolabeled dose was recovered in feces (16% of the administered dose as unchanged tucatinib) and 4.1% in urine with an overall total recovery of 90% within 13 days post-dose. In plasma, approximately 76% of the plasma radioactivity was unchanged, 19% was attributed to identified metabolites, and approximately 5% was unassigned.
Specific Populations
Age (18-77 years), albumin (19 to 52 g/L), creatinine clearance (CLcr: 60 to 89 mL/min (n = 63); CLcr 30 to 59 mL/min (n = 6)), body weight (41 to 146 kg), sex (male (n = 170), female (n = 113)) and race (White (n = 205), Black (n = 37), or Asian (n = 25)) did not have a clinically meaningful effect on tucatinib exposure.
Renal Impairment
No clinically significant differences in the pharmacokinetics of tucatinib were observed in patients with mild to moderate renal impairment (CLcr: 30 to 89 mL/min by Cockcroft-Gault). The effect of severe renal impairment (CLcr: < 30 mL/min) on the pharmacokinetics of tucatinib is unknown.
Hepatic Impairment
Mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment had no clinically relevant effect on tucatinib exposure. Tucatinib AUC0-INF was increased by 1.6 fold in subjects with severe (Child-Pugh C) hepatic impairment compared to subjects with normal hepatic function.
Drug Interaction Studies
Clinical Studies
| Concomitant Drug (Dose) | TUKYSA Dose | Ratio (90% CI) of Tucatinib Exposure With and Without Concomitant Drug | |
| Cmax | AUC | ||
| Strong CYP3A Inhibitor Itraconazole (200 mg BID) | 300 mg single dose | 1.3 (1.2, 1.4) | 1.3 (1.3, 1.4) |
| Strong CYP3A/Moderate 2C8 Inducer Rifampin (600 mg once daily) | 0.6 (0.5, 0.8) | 0.5 (0.4, 0.6) | |
| Strong CYP2C8 Inhibitor Gemfibrozil (600 mg BID) | 1.6 (1.5, 1.8) | 3.0 (2.7, 3.5) | |
| a. Tucatinib reduced the renal clearance of metformin without any effect on glomerular filtration rate (GFR) as measured by iohexol clearance and serum cystatin C. | |||
| Concomitant Drug (Dose) | TUKYSA Dose | Ratio (90% CI) of Exposure Measures of Concomitant Drug with/without Tucatinib | |
| Cmax | AUC | ||
| CYP2C8 Substrate Repaglinide (0.5 mg single dose) | 300 mg single dose | 1.7 (1.4, 2.1) | 1.7 (1.5, 1.9) |
| CYP3A Substrate Midazolam (2 mg single dose) | 3.0 (2.6, 3.4) | 5.7 (5.0, 6.5) | |
| P-gp Substrate Digoxin (0.5 mg single dose) | 2.4 (1.9, 2.9) | 1.5 (1.3, 1.7) | |
| MATE1/2-K substratea Metformin (850 mg single dose) | 1.1 (1.0, 1.2) | 1.4 (1.2, 1.5) | |
No clinically significant difference in the pharmacokinetics of tucatinib were observed when used concomitantly with omeprazole (proton pump inhibitor) or tolbutamide (sensitive CYP2C9 substrate).
In Vitro Studies
Cytochrome P450 (CYP) Enzymes: Tucatinib is a reversible inhibitor of CYP2C8 and CYP3A and a time-dependent inhibitor of CYP3A, but is not an inhibitor of CYP1A2, CYP2B6, CYP2C9, CYP2C19, or CYP2D6.
Uridine diphosphate (UDP)-glucuronosyl transferase (UGT) Enzymes: Tucatinib is not an inhibitor of UGT1A1.
Transporter Systems: Tucatinib is a substrate of P-gp and BCRP, but is not a substrate of OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K, or BSEP.
Tucatinib inhibits MATE1/MATE2-K-mediated transport of metformin and OCT2/MATE1-mediated transport of creatinine. The observed serum creatinine increase in clinical studies with tucatinib is due to inhibition of tubular secretion of creatinine via OCT2 and MATE1.
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