Chemical formula: C₂₆H₂₄N₈O₂ Molecular mass: 480.532 g/mol PubChem compound: 51039094
Tucatinib is a reversible, potent and selective tyrosine kinase inhibitor of HER2. In cellular signalling assays, tucatinib is >1000-fold more selective for HER2 compared to epidermal growth factor receptor. In vitro, tucatinib inhibits phosphorylation of HER2 and HER3, resulting in inhibition of downstream cell signalling and cell proliferation, and induces death in HER2 driven tumour cells. In vivo, tucatinib inhibits the growth of HER2 driven tumours and the combination of tucatinib and trastuzumab showed enhanced anti-tumour activity in vitro and in vivo compared to either medicinal product alone.
Multiple doses of tucatinib 300 mg twice a day did not have an effect on the QTc interval in a TQT study in healthy subjects.
Plasma tucatinib exposure (AUCinf and Cmax) demonstrated dose proportional increases at oral doses from 50 to 300 mg (0.17 to 1 time the recommended dose). Tucatinib exhibited 1.7-fold accumulation for AUC and 1.5-fold accumulation for Cmax following administration of 300 mg tucatinib twice daily for 14 days. Time to steady-state was approximately 4 days.
Following a single oral dose of 300 mg tucatinib, the median time to peak plasma concentration was approximately 2.0 hours (range 1.0 to 4.0 hours).
Following administration of a single dose of tucatinib in 11 subjects after a high-fat meal (approximately 58% fat, 26% carbohydrate, and 16% protein), the mean AUCinf increased by 1.5-fold, the Tmax shifted from 1.5 hours to 4.0 hours, and Cmax was unaltered. The effect of food on the pharmacokinetics of tucatinib was not clinically meaningful, thus tucatinib may be administered without regard to food.
The apparent volume of distribution of tucatinib was approximately 1670 L in healthy subjects after a single dose of 300 mg. The plasma protein binding was 97.1% at clinically relevant concentrations.
Tucatinib is metabolized primarily by CYP2C8 and to a lesser extent via CYP3A and aldehyde oxidase.
Tucatinib is a substrate of CYP2C8 and CYP3A.
Tucatinib is a reversible inhibitor of CYP2C8 and CYP3A and a time-dependent inhibitor of CYP3A, at clinically relevant concentrations.
Tucatinib has low potential to inhibit CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and UGT1A1 at clinically relevant concentrations.
Tucatinib is a substrate of P-gp and BCRP. Tucatinib is not a substrate of OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K, and 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.
Following a single oral dose of 300 mg, tucatinib is cleared from plasma with a geometric mean halflife of approximately 8.5 hours and apparent clearance of 148 L/h in healthy subjects.
Tucatinib is predominantly eliminated by the hepatobiliary route and is not appreciably renally eliminated. Following a single oral dose of 300 mg 14C-tucatinib, approximately 85.8% of the total radiolabelled dose was recovered in faeces (15.9% of the administered dose as unchanged tucatinib) and 4.1% in urine with an overall total recovery of 89.9% within 312 hours post-dose. In plasma, approximately 75.6% of the plasma radioactivity was unchanged, 19% was attributed to identified metabolites, and approximately 5% was unassigned.
Based on population pharmacokinetic analysis according to demographic characteristics, age (<65 years (N=211); ≥65 years (N=27)), albumin (25.0 to 52.0 g/L), creatinine clearance (CLcr 60 to 89 mL/min (N=89); CLcr 30 to 59 mL/min (N=5)), body weight (40.7 to 138.0 kg), and race (White (N=168), Black (N=53), or Asian (N=10)) did not have a clinically meaningful effect on tucatinib exposure. There are no data for subjects with severely impaired renal function.
The pharmacokinetics of tucatinib have not been evaluated in a dedicated renal impairment study.
Mild (Child–Pugh A) and moderate (Child-Pugh B) hepatic impairment had no clinically relevant effect on tucatinib exposure. Tucatinib AUCinf was increased by 1.6-fold in subjects with severe (Child-Pugh C) hepatic impairment compared to subjects with normal hepatic function. There are no data for breast cancer patients with severely impaired hepatic function.
Effect of Other Drugs on Tucatinib:
| Concomitant Drug (Dose) | Tucatinib 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) | |
Effect of Tucatinib on Other Drugs:
| Concomitant Drug (Dose) | Tucatinib 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 twice daily | 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) | |
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.
No clinically significant difference in the pharmacokinetics of tucatinib were observed when used concomitantly with omeprazole (proton pump inhibitor) or tolbutamide (sensitive CYP2C9 substrate).
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.
Carcinogenicity studies have not been conducted with tucatinib.
Tucatinib was not clastogenic or mutagenic in the standard battery of genotoxicity assays.
In repeat-dose toxicity studies in rats, decreased corpora lutea/corpus luteum cyst, increased interstitial cells of the ovary, atrophy of the uterus, and mucification of the vagina were observed at doses of ≥6 mg/kg/day administered twice daily, equivalent to 0.09 times the human exposure based on AUC0-12 at the recommended dose. No histological effects were observed on male or female reproductive tracts in cynomolgus monkeys or on male reproductive tracts in rats at doses resulting in exposures up to 8 times (in monkey) or 13 times (in rat) the human exposure at the recommended dose based on AUC0-12.
Embryo-foetal development studies were conducted in rabbits and rats. In pregnant rabbits, increased resorptions, decreased percentages of live foetuses, and skeletal, visceral, and external malformations were observed in foetuses at ≥90 mg/kg/day; at this dose, maternal exposure is approximately equivalent to the human exposure at the recommended dose based on AUC. In pregnant rats, decreased maternal body weight and body weight gain were observed at doses of ≥90 mg/kg/day. Foetal effects of decreased weights and delayed ossification were observed at ≥120 mg/kg/day; at this dose, maternal exposure is approximately 6-fold higher than human exposure at the recommended dose based on AUC.
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