Cabotegravir And Rilpivirine

Introduction Overview

Generic Name

cabotegravir and rilpivirine

Brand Name

Cabenuva

Dosage Form

extended-release injection

Drug Class

Antiviral combinations

Pharmacokinetics

Absorption:
Cabenuva contains cabotegravir and rilpivirine as long-acting injectable suspensions administered intramuscularly. Following intramuscular injection into the gluteal muscles, both drugs are slowly absorbed into systemic circulation, achieving therapeutic plasma concentrations that are maintained over extended periods. The extended-release formulation allows for plasma drug concentrations to be sustained for up to one to two months or longer, facilitating monthly or bi-monthly dosing schedules. This slow absorption results in prolonged drug exposure and consistent antiviral activity. Factors such as the injection site, muscle mass, and individual patient variability (e.g., body weight and metabolic rate) can influence absorption kinetics.

Distribution:
Cabotegravir and rilpivirine exhibit extensive distribution throughout the body tissues after absorption. Both agents are highly protein bound, with cabotegravir approximately 99% bound to plasma proteins, primarily albumin and alpha-1-acid glycoprotein. Rilpivirine is also extensively protein-bound (~99.7%), contributing to its long half-life. The high protein binding limits free drug concentrations but allows steady plasma levels to be maintained. Both drugs distribute into lymphatic tissues, a major HIV reservoir. The intramuscular depot injections provide a local reservoir of drug gradually releasing into bloodstream. Volume of distribution for cabotegravir is moderate, reflecting tissue penetration necessary to inhibit viral replication.

Metabolism:
Cabotegravir undergoes metabolism primarily via phase II glucuronidation mediated by the uridine diphosphate glucuronosyltransferase enzyme UGT1A1, with minor contributions from UGT1A9. This conjugation process facilitates drug clearance by generating more hydrophilic metabolites. Rilpivirine is extensively metabolized in the liver via cytochrome P450 enzyme CYP3A4 to multiple inactive metabolites. Because of this metabolic pathway, concomitant use of strong CYP3A4 inducers or inhibitors can significantly alter rilpivirine plasma concentrations, affecting efficacy and safety. The metabolic profiles of both drugs contribute to their relatively long half-lives and steady-state maintenance with monthly or bi-monthly dosing.

Elimination:
The elimination half-life of cabotegravir is approximately 5.6 to 11.5 days after intramuscular injection, resulting in persistent plasma levels enabling extended dosing intervals. Rilpivirine's elimination half-life ranges roughly from 13 to 28 days after intramuscular dosing, also contributing to its long-acting profile. Both drugs undergo predominantly hepatic metabolism, with elimination primarily via feces as metabolites; only a minor fraction is excreted unchanged in urine. Slow release from the intramuscular depot formulations leads to gradual clearance over weeks to months. Clinical significance of this elimination profile includes the importance of adherence to injection schedule to maintain viral suppression and the need for alternative therapies to be initiated promptly upon discontinuation to avoid resistance due to prolonged sub-therapeutic drug levels.

Dosage Forms

Available Dosage Forms:
- Extended-release injectable suspension vials for intramuscular injection.
- Cabenuva is supplied as co-packaged single-dose vials containing cabotegravir and rilpivirine in separate vials.

Specifically:
- Cabotegravir 400 mg/2 mL vial (200 mg/mL suspension)
- Rilpivirine 600 mg/2 mL vial (300 mg/mL suspension)
- Cabotegravir 600 mg/3 mL vial (200 mg/mL suspension)
- Rilpivirine 900 mg/3 mL vial (300 mg/mL suspension)

Dosages for Adults and Adolescents:
- Initiation dosing (monthly schedule): 600 mg cabotegravir + 900 mg rilpivirine intramuscular injections on the last day of oral lead-in or existing antiretroviral therapy.
- Maintenance dosing (monthly): 400 mg cabotegravir + 600 mg rilpivirine every month thereafter.
- Alternate maintenance dosing (every two months): 600 mg cabotegravir + 900 mg rilpivirine injections every two months after two monthly initiation doses.
- Oral lead-in: At least 28 days prior to first injection, patients may take daily oral tablets of cabotegravir and rilpivirine to assess tolerability.

Specific Patient Populations:
- Approved for patients aged 12 years and older weighing at least 35 kg (77 lbs).
- Not recommended in patients with known or suspected resistance to cabotegravir or rilpivirine.
- Dosage adjustments have not been established for patients with severe hepatic or renal impairment; caution advised.
- Not recommended for use in pediatric patients under 12 years or those under 35 kg.
- Requires medical supervision during administration; self-injection is not indicated due to potential injection-site reactions and need for clinical monitoring.

Mechanism Of Action

Cabenuva is a fixed-dose combination of two antiviral agents, cabotegravir and rilpivirine, that act synergistically to suppress HIV-1 replication through distinct but complementary mechanisms.

Cabotegravir is an integrase strand transfer inhibitor (INSTI) that targets the HIV-1 integrase enzyme, a critical viral enzyme facilitating the integration of viral DNA into the host cell genome. By inhibiting the strand transfer step of integration, cabotegravir prevents the stable insertion of viral DNA into host chromosomes, thereby blocking a vital step in viral replication and propagation. This inhibition disrupts the establishment of infection in new host cells and suppresses ongoing replication in infected cells.

Rilpivirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that selectively binds to the reverse transcriptase enzyme at a site distinct from the nucleoside binding domain. This binding causes conformational changes that inhibit the enzyme's activity, preventing the conversion of viral single-stranded RNA into double-stranded DNA, an essential early step in HIV replication. By blocking reverse transcriptase, rilpivirine reduces the production of viral DNA necessary for integration and subsequent replication.

Together, cabotegravir and rilpivirine offer a dual blockade of HIV replication at two critical enzymatic steps: reverse transcription and integration. This dual mechanism enhances efficacy and reduces the likelihood of resistance development. The extended-release injectable formulations provide sustained plasma concentrations that maintain consistent viral suppression over monthly or bi-monthly dosing intervals. Clinical trials have demonstrated that this combination maintains virologic suppression comparable to daily oral regimens with improved adherence potential.

Notably, Cabenuva's mechanism contrasts with other antiretroviral therapies that may combine nucleoside reverse transcriptase inhibitors (NRTIs) or protease inhibitors; instead, it leverages long-acting delivery of INSTI and NNRTI. Research continues to explore the pharmacodynamics of this combination, including the impact on viral reservoirs and latent infection.

Pharmacological Actions

Inhibits HIV-1 integrase enzyme, preventing viral DNA integration into host genome (cabotegravir component).
Blocks HIV-1 reverse transcriptase enzyme, inhibiting viral RNA to DNA conversion (rilpivirine component).
Provides sustained antiretroviral activity through long-acting injectable formulations.
Reduces plasma HIV RNA levels to below detectable limits, maintaining viral suppression.
Minimizes viral replication, thereby reducing risk of disease progression and transmission.
Ensures improved treatment adherence due to monthly or bi-monthly dosing schedule.
Decreases the likelihood of viral resistance by dual enzymatic blockade.
Exhibits high plasma protein binding and prolonged half-life, contributing to dosing convenience.
Avoids first-pass metabolism through parenteral administration.
Delivers monotonic plasma drug levels, reducing fluctuations seen with daily oral dosing.
Demonstrates activity against a broad spectrum of HIV-1 subtypes.
Reduces systemic inflammation associated with HIV infection by viral suppression.
Interferes with two essential enzymatic steps, offering robust antiretroviral coverage.
Facilitates simplified treatment regimens, enhancing quality of life for patients.
Has shown efficacy in maintaining viral suppression in clinical studies versus standard oral regimens.

Therapeutic Or Clinical Uses

Treatment of HIV-1 infection in virologically suppressed patients aged 12 years and older weighing at least 35 kg.
Sustains viral suppression in patients switching from stable antiretroviral regimens without treatment failure history.
Provides an alternative to daily oral antiretroviral therapy through a long-acting injectable formulation.
Reduces pill burden and improves adherence in appropriate HIV-1 patients.
Use in patients without known or suspected resistance to cabotegravir or rilpivirine.
Maintenance therapy after initial viral suppression has been achieved with oral agents.
Treatment of patients preferring long-acting injectable formulation to daily oral therapy.
Option for patients with difficulty adhering to daily oral HIV medication schedules.
Potential reduction in HIV transmission risk due to maintained undetectable viral load.
Used in clinical practice to improve patient quality of life and convenience.
Approved by FDA for monthly or every-two-month dosing schedules.
Helpful in treatment programs targeting improved retention in care and adherence.
Can be considered in patients with coexisting conditions where daily medication adherence may be challenging.
Supported by clinical trials demonstrating non-inferior viral suppression compared to oral regimens.
May be integrated into comprehensive HIV treatment plans including monitoring and support.

Side Or Adverse Effects

Injection site reactions including pain, redness, swelling, itching, bruising, warmth, or formation of a hard lump.
Fever and flu-like symptoms following injection.
Nausea and gastrointestinal discomfort.
Musculoskeletal pain including bone, joint, or muscle aches.
Fatigue and sleep disturbances.
Headache and dizziness post-administration.
Rash potentially indicating hypersensitivity or allergic reaction.
Severe allergic reactions such as hives, swelling of face, lips, tongue, or throat, difficulty breathing.
Serious drug reactions affecting multiple systems such as skin rash, swollen glands, muscle aches, weakness, unusual bruising, or jaundice.
Psychiatric symptoms including mood changes, depression, suicidal thoughts or behaviors.
Hepatotoxicity symptoms like loss of appetite, nausea, vomiting, upper right abdominal pain, dark urine, clay-colored stools, and jaundice.
Anxiety, light-headedness, sweating, stomach pain, or mouth numbness shortly after injection.
Potential for long-lasting drug effects up to 12 months after last injection necessitating monitoring.
Rare but serious injection site abscess or cellulitis.
Potential interactions leading to decreased efficacy or increased adverse effects when combined with other medications.

Precautions

Assess for hypersensitivity reactions to cabotegravir, rilpivirine or any components before initiation.
Use caution in patients with liver disease including hepatitis B or C due to risk of hepatotoxicity.
Monitor liver function tests periodically during treatment.
Evaluate mental health status and monitor for depression or mood changes.
Avoid use in patients with a history of treatment failure or known resistance to cabotegravir or rilpivirine.
Ensure patient adherence to injection schedule to avoid the risk of developing HIV resistance.
Counsel patients about potential injection site reactions and management.
Not approved for patients younger than 12 years or weighing less than 35 kg.
Not a cure for HIV or AIDS; continued adherence to treatment plan is essential.
Assess drug interactions comprehensively before initiating therapy.
Do not use concurrently with other antiretroviral agents without medical supervision.
Consider alternate therapies for patients unable to tolerate initial oral lead-in dosing.
Pregnancy and breastfeeding require careful evaluation due to limited data and HIV transmission risk.
Storage and handling precautions including refrigeration of injectable suspensions.
Patients should remain under healthcare provider supervision throughout treatment.

Warnings

Do not administer to patients with known hypersensitivity to cabotegravir, rilpivirine, or any excipients of the injection kit.
Serious injection site reactions, including severe pain, swelling, and redness, may occur and require medical evaluation.
Potential for liver toxicity requires monitoring of hepatic function throughout treatment.
Depression and mood disorders, including suicidal ideation, have been reported and warrant psychiatric assessment.
Residual drug concentrations may persist for up to 12 months after discontinuation, complicating management of treatment failure or switching regimens.
Prompt initiation of alternative antiretroviral therapy within one month after final injection is critical to prevent viral resistance.
The medication is not effective in patients with viral resistance to either cabotegravir or rilpivirine.
Missed or delayed injections beyond seven days require special management to avoid sub-therapeutic plasma levels.
Do not use in combination with other HIV therapies unless directed by a healthcare provider.
Avoid concomitant use with medications that strongly induce UGT1A1 or CYP3A4 enzymes which may reduce drug concentrations.
Pregnancy safety is not established; potential risks versus benefits must be carefully considered.
Breastfeeding is contraindicated due to potential HIV transmission through breast milk.
Healthcare providers must monitor patients closely during and after injections for adverse reactions.
Injection technique and site must be adhered to strictly to minimize local adverse effects.
Patients with psychiatric history or liver disease require special caution and monitoring.

Contraindication

Known hypersensitivity to cabotegravir or rilpivirine or any components of the formulation.
History of severe allergic reactions to this drug combination.
Patients with known or suspected HIV-1 resistance mutations to cabotegravir or rilpivirine.
Concurrent use with agents that strongly induce UGT1A1 or CYP3A4 enzymes leading to sub-therapeutic drug levels.
Use in pediatric patients younger than 12 years or weighing less than 35 kg due to lack of safety and efficacy data.
Patients experiencing active hepatitis with severe liver impairment should avoid use.
Inability to adhere to injection schedule or to attend regular clinical visits.
Pregnant or breastfeeding women where risks outweigh benefits or alternative regimens are available.
Concomitant use with other antiretroviral drugs not approved for combination with Cabenuva.
Patients with active serious psychiatric illness uncontrolled by treatment.
Use with caution in patients with QT prolongation or on medications known to prolong the QT interval.
Known hypersensitivity to any vial components, including the excipients or ingredients in prefilled syringes.
Contraindicated in patients with ongoing severe injection site infections or cellulitis.
Not for pre-exposure prophylaxis (PrEP); indicated only for treatment of established HIV-1 infection.

Drug Interactions

Concurrent use with strong inducers of UGT1A1 or CYP3A4 (e.g., rifampin, rifabutin, rifapentine) may significantly reduce plasma concentrations of cabotegravir and rilpivirine, decreasing antiviral efficacy.
Co-administration with certain antibiotics such as clarithromycin, erythromycin, or azithromycin may alter rilpivirine metabolism.
Dexamethasone (multiple doses) can induce metabolism and lower drug levels.
Drugs that prolong the QT interval (e.g., droperidol, disopyramide) may increase risk of cardiac arrhythmias when used concomitantly.
Antiseizure medications such as carbamazepine, oxcarbazepine, phenobarbital, and phenytoin induce metabolic pathways reducing Cabenuva levels.
Herbal supplements like St. John's wort significantly reduce plasma concentrations through enzyme induction.
Apalutamide and enzalutamide may decrease concentrations of both agents via enzyme induction.
Methadone can alter rilpivirine levels, necessitating monitoring.
Viekira Pak (combination of dasabuvir, ombitasvir, paritaprevir, ritonavir) interacts via CYP pathways affecting drug levels.
Co-administration with other antiretrovirals not approved with Cabenuva may lead to adverse interaction or treatment failure.
Concomitant use with medications that affect hepatic enzymes needs caution given metabolism via UGT1A1 and CYP3A4.
Interactions may persist due to prolonged drug half-life; careful review is needed if switching therapies.
Adjustment of antiretroviral regimen warranted when co-administering interacting drugs to maintain virologic suppression.
Clinical monitoring for therapeutic efficacy and toxicities recommended when combining with interacting agents.
Counsel patients to disclose all medications including over-the-counter and herbal products to healthcare providers.

Preparations Of The Drug

Cabenuva is supplied as two separate extended-release injectable suspension vials: cabotegravir and rilpivirine.
Cabotegravir vial strengths: 400 mg/2 mL (200 mg/mL) and 600 mg/3 mL (200 mg/mL).
Rilpivirine vial strengths: 600 mg/2 mL (300 mg/mL) and 900 mg/3 mL (300 mg/mL).
Each co-pack contains the two single-dose vials with administration supplies including syringes, vial adapters, labels, and needles (23-gauge, 1½ inch).
The vials have rubber stoppers that are not made from natural rubber latex.
Kits must be stored refrigerated between 2°C to 8°C (36°F to 46°F) and should not be frozen.
Before administration, vials must be brought to room temperature (not exceeding 25°C or 77°F).
Preparations not used within 6 hours after reaching room temperature should be discarded.
Suspensions must be drawn into syringes and administered as soon as possible; syringes and medication not used within 2 hours must be discarded.
Injection is intramuscular, administered by healthcare providers in the gluteal muscle.
The two injections are administered either in the same buttock muscle spaced approximately 2 cm apart or one injection in each buttock.
The product is not intended for self-administration due to need for clinical observation post-injection.
The extended-release formulation provides sustained plasma drug levels facilitating monthly or bi-monthly dosing.
Packaging includes educational materials and instructions for healthcare providers regarding reconstitution and administration.
Manufacturer: ViiV Healthcare, Durham, NC 27701, USA.