Регорафениб - это низкомолекулярный ингибитор тирозинкиназы многоцелевого действия, предназначенный для лечения резистентных опухолей, таких как метастатический колоректальный рак, метастатическая стромальная опухоль желудочно-кишечного тракта и гепатоцеллюлярная карцинома.
Показания к применению регорафениба
1. Колоректальный рак
<ссылка>Регорафениб показан для лечения метастатического колоректального рака у пациентов, которые ранее получали химиотерапию на основе фторпиримидина, оксалиплатина и иринотекана, ингибитора фактора роста эндотелия сосудов (анти-VEGF-терапия)., и, если ген KRAS относится к дикому типу (немутированному), ингибитор рецептора эпидермального фактора роста (анти-EGFR терапия).
Американское общество клинической онкологии утверждает, что регорафениб или трифлуридин/типирацил могут рассматриваться в качестве терапии третьей или четвертой линии для пациентов с распространенным колоректальным раком независимо от статуса RAS/BRAF; однако эти препараты особенно рекомендуются пациентам с метастатическим колоректальным раком дикого типа, ранее получавшим лечение фторпиримидином, оксалиплатином, иринотекан, бевацизумаб и анти-СКФ-терапия.
2. Стромальная опухоль желудочно-кишечного тракта
Показан для лечения местнораспространенных, неоперабельных или метастатических стромальных опухолей желудочно-кишечного тракта у пациентов, которые ранее получали лечение иматинибом и сунитинибом (FDA присвоило статус орфанного препарата для лечения этого вида рака).
3. Гепатоцеллюлярная карцинома
Показан для лечения гепатоцеллюлярной карциномы у пациентов, которые ранее получали лечение сорафенибом (FDA присвоило сорафенибу статус орфанного препарата для лечения этого вида рака).
Способ применения и дозы регорафениба
1. Скрининг перед началом лечения
Контролируйте артериальное давление перед началом лечения.
Перед началом лечения определите уровень сывороточных аминотрансфераз (АЛТ и АСТ) и билирубина.
Проверка статуса беременности у женщин с репродуктивным потенциалом.
2. Наблюдение за пациентом
В течение первых 6 недель лечения еженедельно контролируйте артериальное давление, затем каждый цикл или чаще, по клиническим показаниям.
Контролируйте уровень сывороточных аминотрансфераз (АЛТ и АСТ) и билирубина по крайней мере каждые 2 недели в течение первых 2 месяцев лечения, затем ежемесячно или чаще по клиническим показаниям.
3. Другие общие соображения
Прекратите прием регорафениба по крайней мере за 2 недели до плановой операции. Не принимайте регорафениб в течение как минимум 2 недель после серьезной операции и до тех пор, пока не произойдет адекватное заживление раны.
Если регорафениб применяется у пациентов, получающих кумариновые антикоагулянты (например, варфарин), следует чаще контролировать МНО.
4. Способ введения
Принимайте в одно и то же время каждый день после приема пищи с низким содержанием жира (<600>
5. Дозировка
Колоректальный рак
160 мг один раз в день в 1-21-й дни каждого 28-дневного цикла. Продолжайте прием до прогрессирования заболевания или появления неприемлемой токсичности.
Стромальная опухоль желудочно-кишечного тракта
160 мг один раз в день в 1-21-й дни каждого 28-дневного цикла. Продолжайте прием до прогрессирования заболевания или появления неприемлемой токсичности.
Гепатоцеллюлярная карцинома
160 мг один раз в день в 1-21-й дни каждого 28-дневного цикла. Продолжайте прием до прогрессирования заболевания или появления неприемлемой токсичности.
6. Пропущенная доза
Если вы пропустили прием, примите его как можно скорее в тот же день. Не принимайте двойную дозу на следующий день, чтобы восполнить пропущенную дозу.
7. Изменение дозы в зависимости от токсичности
Степень токсичности 3 или 4
При возникновении токсичности 3-й или 4-й степени лечение следует прервать. При токсичности 4-й степени производитель рекомендует прекратить лечение навсегда; производитель заявляет, что лечение может быть возобновлено только после излечения от токсичности 4-й степени, если потенциальная польза превышает риск.
При возобновлении лечения после восстановления после первого проявления токсичности 3-й или 4-й степени (исключая гепатотоксичность или инфекцию) следует использовать уменьшенную дозу до 120 мг в день.
Если токсичность 3-й или 4-й степени (исключая гепатотоксичность или инфекцию) рецидивирует при приеме препарата в дозе 120 мг в сутки, снова прервите лечение; при возобновлении приема после выздоровления еще раз снизьте дозу до 80 мг в сутки.
Если суточная доза в 80 мг не переносится пациентом, следует навсегда прекратить лечение.
Токсичность для кожи
For Grade 2 Toxicity
First occurrence (regardless of duration): Reduce dose to 120 mg daily.
No improvement within 7 days after initial reduction, or second occurrence: Interrupt treatment; when restarting, reduce further to 80 mg daily.
Third occurrence: Permanently discontinue if 80 mg daily is not tolerated.
For Grade 3 Toxicity
First occurrence: Interrupt treatment for at least 7 days; after recovery, restart at a reduced dose of 120 mg daily.
Second occurrence: Interrupt treatment again for at least 7 days; after recovery, restart at a further reduced dose of 80 mg daily.
Third occurrence: Permanently discontinue if 80 mg daily is not tolerated.
Hepatotoxicity
For Grade 3 Toxicity (AST and/or ALT >5 times ULN but ≤20 times ULN):
First occurrence: Interrupt treatment; after recovery, restart at a reduced dose of 120 mg daily only if the potential benefit outweighs the risk.
Recurrence: Permanently discontinue treatment.
For Grade 4 Toxicity (AST and/or ALT >20 times ULN):
Any occurrence: Permanently discontinue treatment.
For Grade 2 or higher (AST and/or ALT >3 times ULN) with concurrent bilirubin >2 times ULN.
Any occurrence: Permanently discontinue treatment.
Hypertension
If symptomatic grade 2 hypertension occurs, temporarily interrupt treatment.
Infectious Complications
If grade 3 or 4 infection, or worsening of any grade infection occurs, temporarily interrupt treatment; restart at the same dose after infection resolves.
8. Special Populations
Hepatic Impairment
For patients with mild (total bilirubin ≤ ULN and AST > ULN, or total bilirubin > ULN but ≤1.5 times ULN) or moderate (total bilirubin >1.5 times but ≤3 times ULN, with any AST level) pre-existing hepatic impairment: No dose adjustment required. Monitor closely for adverse reactions.
For patients with severe pre-existing hepatic impairment (total bilirubin >3 times ULN): Not recommended.
Renal Impairment
Mild, moderate, or severe renal impairment: No dose adjustment required.
End-stage renal disease requiring dialysis: Appropriate dosage has not been determined.
Elderly Patients
No specific dosage recommendations at present.
Race
No initial dose adjustment required for Asian patients.
Image from public sources (e.g., FDA website, manufacturer's website) for reference only.
Contraindications of Regorafenib
None known.
Warnings and Precautions for Regorafenib
1. Hepatotoxicity
The prescribing information includes a boxed warning regarding the risk of hepatotoxicity. Severe and sometimes fatal hepatotoxicity has been reported, typically presenting as hepatocellular injury; onset usually occurs within the first 2 months of treatment. Liver function test abnormalities were reported more frequently in Asian patients compared to White patients.
Monitor serum ALT, AST, and bilirubin before treatment initiation, at least every 2 weeks during the first 2 months of treatment, then monthly or more frequently as clinically indicated.
If these levels rise above pretreatment levels, monitor liver function tests weekly until they return to baseline or improve to less than 3 times ULN.
If hepatotoxicity occurs, interrupt treatment, then reduce dose or permanently discontinue based on the severity and persistence of the toxicity.
2. Infectious Complications
Infections have been reported, sometimes fatal. The most common infections included urinary tract infection, nasopharyngitis, mucocutaneous and systemic fungal infections, and pneumonia.
If infection occurs, interrupt treatment based on the severity of the infection.
3. Hemorrhage
Increased risk of bleeding; some fatal events reported.
If severe or life-threatening bleeding occurs, permanently discontinue treatment.
For patients receiving concomitant warfarin, monitor INR more frequently.
4. Gastrointestinal Perforation and Fistula Formation
Gastrointestinal perforation (including 8 deaths) was reported in 0.6% of 4518 patients treated with regorafenib in clinical trials. Gastrointestinal fistula formation has also been reported.
If gastrointestinal perforation or fistula occurs, discontinue treatment.
5. Skin Effects
Skin and subcutaneous tissue reactions are common, including palmar-plantar erythrodysesthesia syndrome (hand-foot skin reaction) and severe rash requiring dose modification.
If skin toxicity occurs, implement supportive measures; temporary interruption, dose reduction, or permanent discontinuation may be necessary depending on the severity and persistence of the toxicity.
6. Hypertension
Increased risk of hypertension, typically occurring during the first treatment cycle.
Ensure blood pressure is controlled before treatment initiation.
Monitor blood pressure weekly for the first 6 weeks of treatment, then every cycle, or more frequently as clinically indicated. If hypertension is severe or uncontrolled, temporarily or permanently discontinue treatment.
7. Cardiac Ischemia
Cardiac ischemia and myocardial infarction have been reported.
If new or acute onset of cardiac ischemia or myocardial infarction occurs, interrupt treatment. After the acute cardiac ischemic event resolves, treatment may be restarted if the potential benefit outweighs the risk.
8. Reversible Posterior Leukoencephalopathy Syndrome
One case of reversible posterior leukoencephalopathy syndrome was reported among 4800 patients treated with regorafenib in clinical trials.
Consider the possibility of reversible posterior leukoencephalopathy syndrome in patients presenting with headache, seizure, visual disturbance, confusion, or altered mental function. Diagnosis requires magnetic resonance imaging.
Discontinue regorafenib in patients who develop reversible posterior leukoencephalopathy syndrome.
9. Wound Healing Complications
The effect of regorafenib on wound healing has not been specifically studied; however, VEGFR inhibitors may impair wound healing.
Discontinue regorafenib at least 2 weeks before scheduled surgery. The decision to restart treatment after surgery should be based on clinical assessment of adequate wound healing.
The safety of restarting treatment after wound healing is unknown.
10. Fetal/Neonatal Morbidity and Mortality
May cause fetal harm, as evidenced by embryolethality and teratogenicity in animal studies. Avoid pregnancy during treatment and for 2 months after the last dose. If used during pregnancy or if the patient becomes pregnant, apprise of the potential hazard to the fetus.
Use in Specific Populations for Regorafenib
1. Pregnancy
May cause fetal harm.
2. Lactation
In rats, regorafenib is secreted into milk; it is unknown whether it is secreted into human milk. The effects on the nursing infant or on milk production are also unknown. Discontinue breastfeeding during treatment and for 2 weeks after the last dose.
3. Females and Males of Reproductive Potential
Females and males of reproductive potential should use effective contraception during treatment and for 2 months after the last dose.
Impaired fertility was observed in male and female animals.
4. Pediatric Use
Safety and efficacy have not been established.
In animals exposed at levels below those associated with the recommended human dose, dose-dependent dental changes and vascular dilation, as well as persistent growth and thickening of the femoral epiphyseal growth plate, were observed after repeated dosing.
5. Geriatric Use
No overall differences in safety and efficacy compared to younger adults, but the incidence of grade 3 or 4 hypertension was higher in elderly patients.
6. Hepatic Impairment
Mild or moderate hepatic impairment does not affect systemic exposure; however, monitor closely for adverse reactions.
Not studied in patients with severe hepatic impairment (total bilirubin >3 times ULN) and use is not recommended.
7. Renal Impairment
Severe renal impairment (Clcr 15–29 mL/min) does not affect systemic exposure.
Not studied in patients with end-stage renal disease requiring dialysis.
8. Race
Asian patients have a higher incidence of palmar-plantar erythrodysesthesia syndrome (hand-foot skin reaction) and liver function abnormalities; dose adjustment is not recommended.
Adverse Reactions of Regorafenib
Adverse reactions occurring in ≥20% of patients: Pain (including gastrointestinal and abdominal pain), palmar-plantar erythrodysesthesia syndrome (hand-foot skin reaction), asthenia/fatigue, diarrhea, decreased appetite/decreased food intake, hypertension, infection, dysphonia, hyperbilirubinemia, fever, mucositis, weight loss, rash, nausea.
Drug Interactions of Regorafenib
1. Drugs and Food Affecting Hepatic Microsomal Enzymes
Strong CYP3A4 inhibitors: May increase systemic exposure of regorafenib, decrease systemic exposure of M-2 and M-5, and increase the incidence of adverse reactions. Avoid concomitant use.
Strong CYP3A4 inducers: May decrease systemic exposure of regorafenib, increase systemic exposure of M-5, and reduce the efficacy of regorafenib. Avoid concomitant use.
2. Drugs Metabolized by Hepatic Microsomal Enzymes
In vitro studies suggest that regorafenib and/or its active metabolites inhibit certain CYP isoenzymes; patient studies showed no clinically important effects on AUC or concentration of probe substrates for CYP2C8, 2C19, or 3A4 isoenzymes, while the AUC of a CYP2C9 probe substrate was increased by 25%.
3. Drugs Affected by Transporter Systems
BCRP substrates: May increase systemic exposure of BCRP substrates. Monitor for toxicity of BCRP substrates closely.
P-gp substrates: No clinically important interactions are expected; in vitro studies suggest regorafenib inhibits P-gp, but clinical data show no effect on the pharmacokinetics of a P-gp probe substrate.
4. Drugs Affecting Transporter Systems
Drugs affecting P-gp or BCRP: May affect exposure of M-2 and M-5; clinical significance has not been determined.
Mechanism of Action of Regorafenib
At clinically relevant concentrations, regorafenib inhibits multiple receptor tyrosine kinases in vitro, including vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2, VEGFR-3), platelet-derived growth factor receptors (PDGFR-α, PDGFR-β), fibroblast growth factor receptors (FGFR1, FGFR2), and tyrosine kinase with immunoglobulin and epidermal growth factor homology (TIE-2).
It also inhibits other receptor kinases involved in normal cellular functions and pathological processes (e.g., RET, c-Kit, DDR2, TrkA, EphA-2, Raf-1, b-Raf, mutant b-Raf, SAPK2, Ptk5, Bcr-Abl, CSF-1R).
Inhibits tumor angiogenesis in vivo; inhibits tumor growth and metastasis in mouse cancer models.
The major circulating metabolites M-2 and M-5 are equipotent to regorafenib in biochemical and cellular assays.
Pharmacokinetics of Regorafenib
1. Absorption
Bioavailability: Peak plasma concentration of regorafenib is reached approximately 4 hours after oral administration.
Food effect: Co-administration with a high-fat meal (945 calories, 54.6 g fat) increased regorafenib AUC by 48% and decreased AUC of active metabolites M-2 and M-5 by 20% and 51%, respectively. Co-administration with a low-fat meal (319 calories, 8.2 g fat) increased AUC of regorafenib, M-2, and M-5 by 36%, 40%, and 23%, respectively.
2. Distribution
Extent: It is unknown whether regorafenib distributes into human milk.
Plasma protein binding: >99% for regorafenib, M-2, and M-5.
3. Metabolism
Primarily metabolized by CYP3A4 and UGT1A9. The major circulating metabolites M-2 (N-oxide metabolite) and M-5 (N-oxide and N-desmethyl metabolite) have similar steady-state concentrations and in vitro activity to the parent drug. Metabolism of regorafenib to M-2 is mediated by CYP3A4; the enzyme(s) that convert M-2 to M-5 have not been identified. Regorafenib undergoes enterohepatic circulation.
4. Elimination
Elimination pathways: Primarily excreted in feces (71%; 47% as parent drug, 24% as metabolites), with a lesser amount excreted in urine (19%).
Half-life: Approximately 28 hours for regorafenib, 25 hours for M-2, and 51 hours for M-5.
Pharmacokinetics in Special Populations for Regorafenib
In patients with hepatocellular carcinoma and mild or moderate hepatic impairment, systemic exposures of regorafenib, M-2, and M-5 were similar to those in patients with normal hepatic function. In patients with mild renal impairment, systemic exposures of regorafenib, M-2, and M-5 were similar to those in patients with normal renal function.
Age, body weight, race, and gender have no significant effect on the pharmacokinetics of regorafenib.
Storage of Regorafenib
Oral tablets, store at 25°C (excursions permitted between 15-30°C). Store in the original container, keep tightly closed, and keep the desiccant inside; 7 weeks after first opening the bottle, discard any unused tablets.
Important Reminders
1. Immediately inform the clinician of signs and symptoms of infection (e.g., fever, severe cough or sore throat, difficulty breathing, burning or pain during urination, unusual vaginal discharge or irritation).
2. Inform the clinician of signs and symptoms of unusual bleeding, such as bruising, dizziness.
3. Immediately inform the clinician if severe abdominal pain, persistent bloating, chills, nausea, vomiting, dehydration, or high fever occurs.
