Drug Interactions between Dexamethasone Intensol and lenacapavir

GENERALLY AVOID: Coadministration with certain corticosteroids (e.g., dexamethasone (doses > 16 mg daily)), may reduce plasma concentrations and pharmacologic effects of lenacapavir. The proposed mechanism is dexamethasone dose-dependent induction of CYP450 3A4, the primary isoenzyme responsible for lenacapavir metabolism. According to lenacapavir product labeling, concomitant administration of systemic dexamethasone with lenacapavir may result in decreased lenacapavir plasma concentrations potentially leading to loss of lenacapavir virologic response, resistance development, and therefore coadministration is not recommended. Drug studies evaluating the potential interactions following coadministration of lenacapavir with systemic dexamethasone (doses > 16 mg daily) observed dose-dependent CYP450 3A4 induction. Additionally, some literature noted a potential for loss of lenacapavir efficacy following concomitant administration with systemic betamethasone. However, clinical data evaluating this interaction are limited. Coadministration of lenacapavir with another moderate CYP450 3A4 inducer, efavirenz (600 mg once daily), reduced the systemic exposure (AUC) and peak plasma concentration (Cmax) of lenacapavir by 56% and 36%, respectively.

MONITOR CLOSELY: Coadministration with lenacapavir, a moderate CYP450 3A4 inhibitor, may increase the plasma concentrations of dexamethasone and betamethasone, substrates of the CYP450 3A4 isoenzyme. Concomitant administration can increase systemic exposure (AUC) of the corticosteroid(s), increasing the risk for Cushing's syndrome and adrenal syndrome. In pharmacokinetic studies in fed subjects without HIV, coadministration of oral lenacapavir (600 mg twice daily for 2 days, then a single 600 mg dose) with the sensitive CYP450 3A4 substrate midazolam (single 2.5 mg dose orally at the same time as the single lenacapavir dose) led to an increase in midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) by 1.9-fold and 3.6-fold, respectively.

MANAGEMENT: Given its narrow therapeutic index and the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiviral drug levels, concomitant use of lenacapavir, with systemic dexamethasone (doses > 16 mg daily) or systemic betamethasone should generally be avoided. If coadministration is clinically necessary, considering alternative corticosteroids without CYP450 3A4 inducing properties and monitoring lenacapavir's virologic response may be advisable. When dexamethasone is used, some authorities recommend a 2-week washout period before initiating lenacapavir to account for dexamethasone's prolonged inducing effect. In addition, due to the moderate CYP450 3A4 inhibiting properties of lenacapavir, caution is advised if lenacapavir is coadministered with dexamethasone or betamethasone. Lenacapavir's manufacturer recommends initiating with the lowest dose of systemic corticosteroids with gradual titration, while monitoring for corticosteroid safety. Clinicians should be aware that due to lenacapavir's long half-life, the effect may persist for up to 9 months after the last subcutaneous dose, so caution and monitoring for adverse effects are also advised during this time.