Capivasertib

Introduction Overview

Generic Name

capivasertib

Brand Name

Truqap

Dosage Form

tablets (160 mg, 200 mg)

Drug Class

Multikinase inhibitors

Pharmacokinetics

Absorption:
Capivasertib is administered orally and demonstrates good bioavailability. The recommended dosing regimen, 400 mg twice daily for four days followed by a three-day break, enables optimal plasma concentrations. Food intake does not significantly affect absorption, allowing flexible administration with or without food. Tmax (time to peak plasma concentration) typically occurs within a few hours post-dose, consistent with its immediate-release tablet formulations.

Distribution:
Following absorption, capivasertib exhibits a moderate volume of distribution, indicating sufficient tissue penetration including in tumors. Protein binding data suggest capivasertib is moderately bound to plasma proteins, which may influence the free active drug fraction available. The drug’s distribution to sites of breast cancer, especially in patients with HR-positive, HER2-negative tumors harboring PIK3CA/AKT/PTEN mutations, is critical to its efficacy. No significant accumulation is expected with the intermittent dosing schedule.

Metabolism:
Capivasertib undergoes hepatic metabolism primarily via the cytochrome P450 enzyme CYP3A4. The drug is subject to first-pass metabolism with metabolites formed via oxidative pathways. This CYP3A-mediated metabolism underpins the clinically significant interaction with CYP3A inhibitors or inducers, necessitating dose modifications or caution if co-administered with strong/moderate CYP3A inhibitors or inducers. Phase II metabolites have been identified but are not pharmacologically active.

Elimination:
The elimination half-life of capivasertib supports twice-daily dosing. The drug and its metabolites are eliminated primarily via feces and to a lesser extent in urine. Dose interruption or cessation leads to prompt reduction in plasma levels due to its moderate half-life. Renal impairment has not been shown to significantly affect clearance; however, formal PK studies in severe hepatic impairment are limited, and caution is advised in such patients.

Dosage Forms

Available Dosage Forms:
Truqap is available as immediate-release oral tablets in the following strengths:
- 160 mg tablet
- 200 mg tablet

Dosages for Adults and Adolescents:
The standard dosing regimen for adult patients is 400 mg administered orally twice daily (approximately 12 hours apart) for 4 consecutive days followed by 3 days off treatment each week, forming a 7-day cycle. This schedule continues until disease progression or unacceptable toxicity occurs. Tablets should be swallowed whole with water and not crushed, split, or chewed.

Specific Patient Populations:
In women who are premenopausal or perimenopausal, concomitant administration of a luteinizing hormone-releasing hormone (LHRH) agonist is recommended alongside Truqap and fulvestrant. Dose adjustments are required when Truqap is administered with strong or moderate CYP3A inhibitors or in presence of hepatic impairment; detailed guidance should be consulted in the prescribing information. There are no specific dosing recommendations currently established for pediatric populations or severe hepatic/renal impairment, warranting clinical caution and monitoring.

Mechanism Of Action

Capivasertib, marketed as Truqap, exerts its anti-cancer effects through selective inhibition of AKT, a serine/threonine kinase that plays a central role in regulating multiple cellular processes including cell proliferation, survival, metabolism, and angiogenesis. AKT is a critical downstream mediator of the PI3K/AKT/mTOR signaling pathway, commonly dysregulated in various cancers, most notably in hormone receptor-positive, HER2-negative breast cancer with abnormal PIK3CA, AKT1, or PTEN genes.

By targeting and blocking AKT kinase activity, capivasertib disrupts key phosphorylation events, resulting in inhibition of downstream signaling pathways that promote tumor growth and survival. This leads to induction of apoptosis, cell cycle arrest, and reduced tumor cell proliferation. The selective blockage of AKT also sensitizes tumor cells to endocrine therapies, thereby enhancing the efficacy of agents like fulvestrant.

From a biochemical perspective, capivasertib binds the ATP-binding site of AKT isoforms (AKT1, AKT2, AKT3), competitively inhibiting kinase activity. This competitive inhibition prevents phosphorylation of substrates involved in glucose metabolism, apoptosis evasion, and protein synthesis regulation. Compared to other kinase inhibitors, capivasertib demonstrates specificity favoring AKT with tolerable off-target effects, offering a targeted therapeutic approach.

Clinical trials such as the CAPItello-291 Phase III study provide evidence that capivasertib, when combined with fulvestrant, significantly improves progression-free survival in patients harboring PI3K/AKT pathway alterations. This underscores the clinical relevance of AKT inhibition in resistant breast cancer and supports capivasertib as a mechanistically distinct option within multikinase inhibitors targeting the PI3K/AKT/mTOR axis.

Pharmacological Actions

Selective inhibition of AKT serine/threonine kinases disrupting PI3K/AKT/mTOR pathway signaling
Induces apoptosis and inhibits proliferation in cancer cells with PIK3CA, AKT1, or PTEN mutations
Sensitization of hormone receptor-positive breast cancer cells to endocrine therapy
Antitumor activity in hormone receptor-positive, HER2-negative breast cancer
Modulation of glucose metabolism pathways due to AKT inhibition
Reduction of angiogenesis and tumor survival signals
Interference with cellular processes involved in metastasis and tumor progression
Potential enhancement of immune-mediated tumor cell clearance
Synergistic effect when combined with fulvestrant in metastatic breast cancer
Exhibits manageable safety profile allowing intermittent dosing schedules
Inhibition of multiple AKT isoforms (AKT1, AKT2, AKT3) for broad pathway blockade
Decreases tumor adaptation to adverse microenvironment conditions
Pharmacodynamic effect includes modulation of downstream phosphorylation targets such as PRAS40 and GSK3β
Overcomes endocrine resistance mechanisms in breast cancer cells

Therapeutic Or Clinical Uses

Treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer
Use in patients with tumors harboring PIK3CA, AKT1, or PTEN alterations as confirmed by an FDA-approved companion diagnostic test
Indicated in combination with fulvestrant following progression on or relapse after at least one prior endocrine-based therapy
Targeted therapy for patients with locally advanced or metastatic disease
Therapy option in treatment-resistant breast cancer with PI3K/AKT pathway aberrations
Part of combination regimens for enhanced efficacy in advanced breast cancer
Treatment aimed at prolonging progression-free survival in metastatic breast cancer
Potential investigational use in other AKT pathway activated solid tumors (under clinical evaluation)
Applicable for patients intolerant or ineligible for other multikinase inhibitor therapies
Adjunct to endocrine therapy for overcoming hormone resistance
Option for patients with recurrent disease within 12 months after adjuvant endocrine therapy
Pharmacologic intervention in molecularly selected breast cancer subpopulations
Management of advanced disease states where targeted kinase inhibition is beneficial
A component of precision oncology based on genomic profiling of tumors
To be used within established dosing regimens for optimal safety and efficacy

Side Or Adverse Effects

Diarrhea, which can be severe and lead to dehydration; requires prompt management
Mouth sores (stomatitis), causing discomfort and affecting oral intake
Nausea and vomiting, relatively common during treatment
Skin reactions including rash, erythema, peeling, blistering, and pruritus
Hyperglycemia requiring regular blood glucose monitoring and potential medical intervention
Fatigue or tiredness impacting patient quality of life
Elevations in liver enzymes and other abnormal laboratory blood test results
Loss of appetite and weight loss
Dry skin and mucosal irritation
Potential for electrolyte imbalances secondary to gastrointestinal losses
Rare but serious allergic reactions including severe rash or hypersensitivity
Possible increased risk of infections due to immunomodulatory effects
Vomiting which may complicate drug intake adherence
Headache and dizziness reported in some patients
Injection site reactions related to concomitant fulvestrant administration may occur

Precautions

Monitor blood glucose levels carefully, especially in patients with pre-existing diabetes or risk factors for hyperglycemia
Consider dose reduction or interruption in the event of severe diarrhea or persistent gastrointestinal symptoms
Evaluate for signs of serious skin reactions; discontinue treatment if severe dermatological toxicity develops
Caution in patients with liver impairment as hepatic metabolism influences drug clearance
Avoid concomitant grapefruit or grapefruit juice consumption due to interaction potential
Use effective contraception during and post-treatment due to potential teratogenic effects
Monitor for symptoms suggestive of allergic reactions or hypersensitivity
Assess renal function periodically although no dose adjustment is currently recommended
Pre-menopausal women should receive LHRH agonists to suppress ovarian function during treatment
Be vigilant for signs of dehydration secondary to diarrhea and initiate supportive care promptly
Advise patients to adhere strictly to dosing schedules and not to crush or chew tablets
Monitor laboratory parameters including liver function tests and electrolytes regularly
Careful review of concomitant medications to avoid CYP3A interactions
Assess nutritional status given potential for nausea and appetite loss
Educate patients on recognizing symptoms of hyperglycemia and when to seek medical attention

Warnings

Severe hyperglycemia can occur and may lead to diabetic ketoacidosis; patients with diabetes require close monitoring
Diarrhea can be severe and lead to dehydration and electrolyte imbalances; prompt medical intervention is essential
Serious skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported; discontinue if these occur
Not recommended during pregnancy due to potential teratogenicity and fetal harm
Potential increased risk of infections due to immunosuppressive effects when combined with other anticancer agents
Avoid strong and moderate CYP3A inducers and inhibitors to prevent altered drug levels and toxicity
Use with caution in patients with a history of liver disease or impaired liver function
Risk of treatment-emergent adverse reactions requiring dose adjustments or discontinuation
Patients should be advised not to double doses to compensate for missed doses to avoid toxicity
Monitor for rare but serious hypersensitivity or allergic reactions
Risk of tumor lysis syndrome not well characterized but vigilance recommended in high tumor burden
Potential for drug-induced diarrhea affecting absorption of concomitant oral therapies
Fatigue may impair ability to perform tasks requiring alertness; advise caution
Long-term safety data are limited; monitor patients for late-onset toxicities
Combination with fulvestrant requires consideration of additive side effects and monitoring

Contraindication

History of severe allergic reaction to capivasertib or any inactive ingredient in Truqap formulation
Known hypersensitivity to capivasertib as documented by previous exposure
Concurrent use of strong CYP3A inducers or inhibitors that cannot be safely managed by dosage adjustments
Pregnancy due to potential for fetal harm and teratogenicity
Breastfeeding during treatment and for a defined washout period post-therapy
Uncontrolled diabetes mellitus where hyperglycemia cannot be adequately managed
Severe hepatic impairment without specialist consultation due to altered drug metabolism
Patients unable to tolerate oral medications or with gastrointestinal conditions affecting absorption
Use in pediatric populations is contraindicated due to lack of safety and efficacy data
Concurrent participation in other clinical trials of investigational agents with overlapping toxicities
Known hypersensitivity to multikinase inhibitors or related compounds if documented
Severe active infections requiring systemic therapy until resolution
Patients with chronic diarrhea or malabsorption syndromes without stabilization
Severe renal impairment requiring dialysis until further pharmacokinetic data are available
History of severe dermatologic toxicity to previous kinase inhibitors without alternative options

Drug Interactions

Strong CYP3A inhibitors (e.g., ketoconazole, itraconazole) increase capivasertib plasma levels; dose reduction recommended if co-administration is necessary
Moderate CYP3A inhibitors require dose reduction of Truqap to prevent toxicity
Strong and moderate CYP3A inducers (e.g., rifampin, carbamazepine) reduce capivasertib effectiveness and use should be avoided
Concomitant use with other multikinase inhibitors may enhance toxicity
Drugs affecting blood glucose levels (e.g., insulin, oral hypoglycemics) require careful monitoring due to capivasertib induced hyperglycemia
Co-administration with drugs causing diarrhea may exacerbate gastrointestinal adverse effects
Potential interaction with P-glycoprotein substrates altering absorption or elimination profiles
Agents metabolized by CYP3A may have altered clearance when combined with capivasertib
Use caution with immunosuppressive drugs given potential additive effects
Avoid grapefruit or grapefruit juice to prevent increased capivasertib exposure
Nonsteroidal anti-inflammatory drugs (NSAIDs) may increase risk of certain adverse effects during treatment
Combination with endocrine therapies like fulvestrant requires monitoring but is standard of care
Interactions with anticoagulants require careful coagulation profile monitoring
Potential pharmacodynamic interactions with other anticancer agents that cause skin toxicity or hyperglycemia
Herbal supplements that induce or inhibit CYP3A should be avoided or used with caution

Preparations Of The Drug

Capivasertib tablets are formulated as 160 mg and 200 mg immediate-release oral tablets
Tablets consist of active capivasertib and inactive ingredients including copovidone, croscarmellose sodium, dibasic calcium phosphate, hypromellose, iron oxides, magnesium stearate, medium chain triglycerides, microcrystalline cellulose, polydextrose, polyethylene glycol 3350, and titanium dioxide
Tablets must be swallowed whole and should not be crushed, split, or chewed
Supplied in bottles stored at controlled room temperature between 20°C to 25°C (68°F to 77°F)
Packaged and distributed by AstraZeneca Pharmaceuticals LP
Packaging designed to maintain tablet integrity and stability under normal storage conditions
Not available in liquid or injectable forms currently
Formulation developed to optimize oral bioavailability and patient adherence
Contains colorants (iron oxide black, red, yellow) for dose identification
Inactive components support tablet disintegration and stability
No known preservative agents; manufactured under stringent quality control
Prepared under Good Manufacturing Practices (GMP) standards
No specific dietary or storage restrictions beyond recommended temperature
Visual appearance includes coated tablets to enhance swallowing
Batch-to-batch consistency maintained to assure dose uniformity