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tucatinib
Tucatinib is a reversible and selective tyrosine kinase inhibitor of HER2. In vivo, tucatinib inhibited the growth of HER2 expressing tumors. The combination of tucatinib and trastuzumab showed increased anti-tumor activity compared to either drug alone. In vitro, tucatinib inhibits phosphorylation of HER2 and HER3, resulting in inhibition of downstream cell signaling and cell proliferation, and induces death in HER2 driven tumor cells.
| Time to reach steady state | approximately 4 days |
| PPB | 97.1% |
| Cross blood brain barrier? |
Yes |
Primarily by CYP2C8 and to a lesser extent by CYP3A
| Active metabolites |
Yes |
| Inactive metabolites |
Yes |
| Feces | 86% (16% unchanged drug) |
| Urine |
4% |
| Half-life | 8.7 hours |
- Breast cancer
Refer to the product monograph for a full list and details of approved indications
Emetogenic Potential:
The following table lists adverse effects that occurred in a phase 3 trial of tucatinib versus placebo in combination with trastuzumab and capecitabine in patients with locally advanced unresectable or metastatic HER2- positive breast cancer, where incidences were ≥ 5% compared to placebo. Severe, life-threatening and post-marketing adverse effects from other sources are also included.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Cardiotoxicity (rare) | E | |||
| Dermatological | Palmar-plantar erythrodysesthesia syndrome (PPES) (63%) (may be severe; 13%) | E | |||
| Rash (20%) | E | ||||
| Gastrointestinal | Anorexia, weight loss (25%) | E | |||
| Diarrhea (81%) (may be severe; 12%) | E | ||||
| Mucositis (32%) | E | ||||
| Nausea, vomiting (58%) (generally mild) | E | ||||
| General | Fatigue (45%) | E | |||
| Hematological | Anemia (21%) | E | |||
| Hemorrhage (epistaxis 12%) (rare - rectal or vaginal) | E | ||||
| Hepatobiliary | Hepatotoxicity (42%) (may be severe; 9%) | E | |||
| Infection | Infection (including septic stock - rare) | E | |||
| Metabolic / Endocrine | Hyperglycemia (rare) | E | |||
| Hypoglycemia (rare) | E | ||||
| Musculoskeletal | Musculoskeletal pain (15%) | E | |||
| Nervous System | Peripheral neuropathy (13%) | E | |||
| Seizure (rare) | E D | ||||
| Renal | Creatinine increased (14%) | E | |||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most common side effects for tucatinib include diarrhea, palmar-plantar erythrodysesthesia syndrome (PPES), nausea, vomiting, fatigue, hepatotoxicity, mucositis, anorexia, weight loss, anemia, rash and musculoskeletal pain.
Severe diarrhea accompanied by dehydration, hypotension and acute kidney injury have been reported and may be fatal. The median onset of the first episode of diarrhea was 12 days and median time to resolution was 8 days. Diarrhea led to dose reductions of tucatinib in 6% of patients and discontinuation of tucatinib in 1% of patients.
Hepatotoxicity, including severe hepatotoxicity, has been reported. The median time to onset of any grade ALT, AST, or bilirubin increase was 36 days with 84% of events resolving with a median time of 22 days. Hepatotoxicity led to dose reduction of tucatinib in 8% of patients and discontinuation of tucatinib in 1.5% of patients.
Increased serum creatinine due to inhibition of renal transport of creatinine without affecting glomerular function was reported. The mean increase in serum creatinine was 30% within the first 21 days of treatment. Increases persisted throughout treatment and were reversible upon treatment completion.
Refer to protocol by which patient is being treated.
- Patients with brain metastases requiring immediate local therapy should undergo local CNS directed therapy prior to being treated with tucatinib, if appropriate.
(in combination with trastuzumab and capecitabine)
Refer to the CAPETUCA+TRAS Regimen Monograph for dosing information on trastuzumab and capecitabine
| Dose Level | Tucatinib Dose (mg/BID) |
| 0 | 300 |
| -1 | 250 |
| -2 | 200 |
| -3 | 150 |
| -4 | Permanently discontinue |
| Toxicity | Grade | Tucatinib Dose* | |
| Diarrhea | Grade 3, without antidiarrheal treatment | Initiate or intensify appropriate medical therapy. Hold until recovery to ≤ grade 1. Restart at same dose level. | |
| Grade 3, with antidiarrheal treatment | Initiate or intensify appropriate medical therapy. Hold until recovery to ≤ grade 1. Restart at 1 dose level ↓. | ||
| Grade 4 | Permanently discontinue | ||
| Hepatotoxicity | Bilirubin >1.5 to 3 x ULN | Hold until recovery to ≤ grade 1. Restart at same dose level. | |
|
ALT or AST > 5 to 20 x ULN OR Bilirubin > 3 to 10 x ULN |
Hold until recovery to ≤ grade 1. Restart at 1 dose level ↓. | ||
|
ALT or AST > 20 X ULN OR Bilirubin > 10 x ULN |
Permanently discontinue | ||
|
ALT or AST > 3 x ULN AND Bilirubin > 2 x ULN |
|||
| Other Adverse Reactions | Grade 3 | Hold until recovery to ≤ grade 1. Restart at 1 dose level ↓. | |
| Grade 4 | Permanently discontinue | ||
*Trastuzumab and capecitabine may also require dosage modification.
| Baseline Liver Function | Tucatinib Dose |
| Child Pugh A or B | No dosage adjustment necessary |
| Child Pugh C | 200 mg BID |
| Baseline Creatinine Clearance | Tucatinib Dose |
| CrCl ≥ 30 mL / min | No dosage adjustment necessary |
| CrCl < 30 mL / min |
Use is not recommended. Tucatinib is used in combination with capecitabine and trastuzumab, and capecitabine is contraindicated in severe renal impairment. |
No dose adjustment is required in patients ≥ 65 years of age. No overall differences in effectiveness was observed in patients ≥ 65 years compared to younger patients. Patients ≥ 65 years were more likely to experience a serious adverse event such as diarrhea and vomiting and more likely to discontinue treatment compared to younger patients <65 years.
The safety and efficacy of tucatinib in pediatric patients has not been established.
- Swallow tablets whole, do not chew, crush, or split prior to swallowing.
- Take approximately 12 hours apart at the same time each day with or without a meal.
- Tucatinib and capecitabine may be taken at the same time.
- If a dose is missed or vomited, administer the next dose at its usual time.
- Store original container at a controlled room temperature between 20ºC and 25ºC
- Protect from moisture.
- Patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.
-
Use with caution in patients with known chronic liver disease, carriers of hepatitis B or C or with pre-existing liver function test abnormalities (total bilirubin > 1.5 × ULN, or AST/ALT > 2.5 × ULN, or AST/ALT > 5 × ULN if liver metastases were present) as they were excluded from clinical trials.
- Patients should exercise caution when driving or operating a vehicle or potentially dangerous machinery.
Other Drug Properties:
-
Carcinogenicity:
No information available
-
Clastogenicity:
No
-
Mutagenicity:
No
-
Teratogenicity:
Documented in animals
- Tucatinib is not recommended for use in pregnancy. Adequate contraception should be used by both sexes during treatment, and for at least 1 week after the last dose.
- It is not known if tucatinib is present in semen. Male patients should not donate or store semen during treatment and for at least 1 month after the last dose.
-
Excretion into breast milk:
Probable
Breastfeeding is not recommended during treatment and for at least 1 week after the last dose.
-
Fertility effects:
Probable
Documented in animals
Tucatinib is metabolized by and a reversible inhibitor of CYP2C8 and CYP3A. It is substrate of P-gp and BCRP and inhibits MATE1/MATE2-K mediated transport of metformin and OCT2/MATE1- mediated transport of creatinine.
No clinically significant drug interactions have been observed when tucatinib is co-administered with omeprazole.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| Moderate or Strong CYP2C8 Inducers (e.g. rifampin) | ↓ tucatinib concentration and/or efficacy | ↑ metabolism of tucatinib | Avoid concomitant use |
| Strong CYP3A4 inducers (i.e. phenytoin, rifampin etc) | ↓ tucatinib concentration and/or efficacy | ↑ metabolism of tucatinib | Avoid concomitant use |
| Moderate or Strong CYP2C8 Inhibitors (e.g. clopidogrel, gemfibrozil) | ↑ tucatinib concentration and/or toxicity | ↓ metabolism of tucatinib | Avoid concomitant use with strong inhibitors. If co-administration is unavoidable, reduce tucatinib starting dose to 100 mg twice daily and increase monitoring for tucatinib-related toxicity. After discontinuation of the strong CYP2C8 inhibitor for 3 elimination half-lives, resume tucatinib at dose taken prior to initiating the inhibitor. If co-administered with a moderate inhibitor, increase monitoring for toxicity. |
| CYP3A4 substrates (e.g. cyclosporine, pimozide, tacrolimus, triazolo-benzodiazepines, dihydropyridine calcium-channel blockers, certain HMG-CoA reductase inhibitors) | ↑ substrate concentration and/or toxicity | ↓ metabolism of substrate | Avoid concomitant use. If co-administration is unavoidable, consider dose modification of CYP3A substrates with narrow therapeutic indices and/or increased monitoring for potential adverse reactions. |
| P-glycoprotein substrates (i.e. verapamil, digoxin, morphine, ondansetron) | ↑ substrate concentration and/or toxicity | ↑ substrate exposure | Caution when co-administered with P-gp substrates with narrow therapeutic indices. Refer to the prescribing information of sensitive P-gp substrates for dose adjustment recommendations. |
| Monitor Type | Monitor Frequency |
|---|---|
CBC |
Baseline and as clinically indicated |
Liver function tests |
Baseline, every 3 weeks during treatment and as clinically indicated |
Renal function tests |
Baseline and as clinically indicated |
| Clinical toxicity assessment for fatigue, gastrointestinal effects, cutaneous reactions, infection, anemia, bleeding, neuropathy or seizure | As clinically indicated |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
Exceptional Access Program (EAP Website)
- tucatinib - in combination with trastuzumab and capecitabine for advanced breast cancer, according to clinical criteria
Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med 2020; 382:597-609.
Product Monograph: TukysaTM (Tucatinib). McKesson Specialty Distribution Inc., June 2020.
February 2023 updated Supplementary public funding section
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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