カボテグラビル

Q1: What is the mechanism of action of cabotegravir?

A1: Cabotegravir is a potent integrase strand transfer inhibitor (INSTI) that acts by binding to the integrase enzyme of HIV-1. This binding prevents the integration of viral DNA into the host cell's genome, thus blocking viral replication. [, , , ]

Q2: How does the inhibition of HIV-1 integrase by cabotegravir affect the virus lifecycle?

A2: By inhibiting integrase, cabotegravir prevents the formation of proviral DNA, which is essential for the production of new viral proteins and the establishment of a persistent infection. [, , ]

Q3: Does cabotegravir demonstrate activity against HIV-2?

A3: Yes, in vitro studies have demonstrated that cabotegravir exhibits antiviral activity against HIV-2 isolates, with EC50 values in the low to subnanomolar range, comparable to its activity against HIV-1. []

Q4: What is the molecular formula and weight of cabotegravir?

A4: Cabotegravir has the molecular formula C28H27F2N7O4 and a molecular weight of 555.56 g/mol. []

Q5: How do structural modifications of cabotegravir influence its activity and solubility?

A5: While the exact SAR of cabotegravir's solubility is not fully elucidated in these papers, research suggests that specific structural features contribute to its low aqueous solubility, which is crucial for its long-acting formulation. [] One study investigating resistance mechanisms identified that specific mutations in the HIV integrase enzyme, like L74I/Q148R, can reduce cabotegravir's susceptibility. []

Q6: How is cabotegravir formulated for long-acting administration?

A6: Cabotegravir is formulated as a nanosuspension for long-acting intramuscular (IM) injection. This formulation allows for slow drug release from the muscle, resulting in sustained therapeutic concentrations for extended periods. [, , ]

Q7: How does the stability of cabotegravir in its injectable formulation compare to other formulations?

A7: The long-acting injectable formulation of cabotegravir exhibits a significantly longer half-life compared to the oral formulation, allowing for less frequent dosing intervals (monthly or even bimonthly). [, ] This difference in half-life is attributed to the slow release of the drug from the intramuscular depot.

Q8: How is cabotegravir absorbed, distributed, metabolized, and excreted (ADME)?

A8: Cabotegravir is primarily metabolized by UDP-glucuronosyltransferase (UGT) 1A1 and UGT1A9 enzymes in the liver. [] Following oral administration, approximately 27% of the dose is recovered in the urine, primarily as the glucuronide metabolite (M1). [] Cabotegravir demonstrates minimal intestinal and renal metabolism. []

Q9: What is the impact of renal impairment on cabotegravir exposure?

A9: Severe renal impairment (creatinine clearance <30 mL/min) does not significantly impact plasma cabotegravir exposure. Therefore, dose adjustment is not required in patients with renal impairment who are not on dialysis. []

Q10: How does a high-fat meal affect the pharmacokinetics of cabotegravir?

A10: A high-fat meal moderately increases cabotegravir exposure (area under the curve and maximum concentration) by approximately 14%, which is not considered clinically significant. []

Q11: How does obesity impact the exposure of long-acting cabotegravir and rilpivirine?

A12: Studies using physiologically based pharmacokinetic modeling suggest that obesity can reduce the exposure of both drugs, particularly in individuals with a BMI > 35 kg/m2. This reduction might lead to suboptimal drug concentrations, especially with less frequent dosing schedules. []

Q12: Does age affect the pharmacokinetics of long-acting cabotegravir and rilpivirine?

A13: PBPK modeling studies suggest that older individuals may have higher exposure to LA cabotegravir/rilpivirine compared to younger individuals. This difference highlights the need to consider age-related pharmacokinetic variations in this population. []

Q13: What is the impact of oral lead-in on long-acting cabotegravir pharmacokinetics?

A14: Studies have shown that the use of an oral lead-in before initiating long-acting cabotegravir injections does not significantly affect the drug's overall exposure. This finding supports the optional use of oral lead-in. []

Q14: What preclinical studies have been conducted to evaluate the efficacy of long-acting cabotegravir?

A15: Preclinical studies in macaque models demonstrated that long-acting cabotegravir provided high protection against both rectal and vaginal HIV transmission at clinically achievable drug concentrations. These findings supported the drug's development for pre-exposure prophylaxis (PrEP). [, ]

Q15: What are the key findings from clinical trials evaluating long-acting cabotegravir for HIV treatment and prevention?

A16:* HPTN 083 & HPTN 084: Demonstrated superior efficacy of long-acting cabotegravir compared to daily oral tenofovir disoproxil fumarate–emtricitabine (TDF–FTC) for PrEP in men who have sex with men (MSM), transgender women, and cisgender women in sub-Saharan Africa. [, ] * ECLAIR: Phase IIa study showcasing the safety, tolerability, and acceptability of cabotegravir LA for PrEP in healthy men. []* LATTE: Phase IIb study demonstrating the efficacy of daily oral cabotegravir + rilpivirine compared to efavirenz + 2 NRTIs in treatment-naïve adults with HIV-1. []* LATTE-2: Phase IIb study showing comparable efficacy of long-acting cabotegravir + rilpivirine (dosed every 4 or 8 weeks) to daily oral ART in treatment-naïve adults with HIV-1. [] * FLAIR: Phase III study demonstrating non-inferiority of monthly long-acting cabotegravir + rilpivirine versus daily oral dolutegravir/abacavir/lamivudine for maintaining virologic suppression in treatment-naïve individuals. []* ATLAS: Phase III study confirming the efficacy of monthly cabotegravir + rilpivirine injections in maintaining HIV suppression in treatment-experienced patients. []* ATLAS-2M: Supported the efficacy of cabotegravir + rilpivirine injections administered every 8 weeks. []

Q16: What are the known resistance mechanisms to cabotegravir?

A17: Resistance to cabotegravir can emerge through mutations in the HIV-1 integrase gene. While the L74I polymorphism alone doesn't significantly impact cabotegravir susceptibility, the combination of L74I with Q148R mutations can lead to reduced susceptibility. [] Additionally, mutations like E138A/G140A/G163R/Q148R or E138K/G140A/S147G/Q148K have been shown to confer high-level resistance to both cabotegravir and bictegravir, highlighting potential cross-resistance within the INSTI class. []

Q17: Does the HIV-1 subtype influence the risk of treatment failure with cabotegravir + rilpivirine?

A18: Yes, clinical trials have shown that individuals infected with HIV-1 subtypes A6/A1, initially classified as A1, have an increased risk of virologic failure when treated with cabotegravir + rilpivirine. This finding emphasizes the importance of considering HIV-1 subtype when prescribing this treatment. [, ]

Q18: What are the most common side effects associated with long-acting cabotegravir injections?

A19: The most commonly reported side effect is injection site reactions (ISRs), including pain, induration, and swelling. These reactions are typically mild to moderate in severity and tend to decrease in frequency with subsequent injections. [, ]

Q19: What analytical techniques are used to quantify cabotegravir in biological samples?

A20: Several analytical methods, including high-performance liquid chromatography (HPLC) coupled with mass spectrometry (MS) and tandem mass spectrometry (MS/MS), have been developed and validated for the quantification of cabotegravir in biological samples. [, , ] These methods demonstrate high sensitivity, accuracy, and reproducibility for therapeutic drug monitoring.

Q20: Why is the low solubility of cabotegravir important for its long-acting formulation?

A21: The low solubility of cabotegravir in aqueous solutions is a key factor contributing to its slow and sustained release from the intramuscular injection site, allowing for a longer duration of action and less frequent dosing. [, ]