Lenacapavir initiation with concomitant primidone: A case report with therapeutic drug monitoring

Lenacapavir (LEN), a first-in-class capsid inhibitor, has unique pharmacokinetics that enable twice-yearly dosing. LEN is not extensively metabolized, although it is a substrate of CYP3A4, which introduces drug-drug interactions concerns. As adoption and implementation of LEN for treatment and prevention increase, additional guidance on concomitant medications with LEN is needed. Primidone is a barbiturate type anticonvulsant medication and a moderate-to-strong inducer of CYP3A4. A primary metabolite of primidone, phenobarbital, also induces CYP3A. Consequently, the coadministration of LEN and primidone is not recommended due to the potential induction of CYP3A-mediated metabolism and resultant subtherapeutic LEN concentrations. However, the extent to which LEN concentrations may decrease alongside concomitant primidone is unknown. Herein, we describe a 67-year-old male initiating LEN following switch from a boosted darunavir regimen, alongside long-standing treatment with primidone 50 mg daily. Blood samples were collected throughout the first 6-month dosing interval. Plasma LEN concentrations were quantified using a validated liquid chromatography-tandem mass spectrometry analytical method. LEN concentrations remained above four times the protein adjusted 95% effective concentration during the measured time points. The lowest observed concentration was 24.9 ng/mL at Month 1; the highest observed was 58.3 ng/mL at Month 3. The projected 6-month concentration was 40.6 ng/mL. Observed concentrations were generally consistent with concentrations reported in prior studies in the absence of clinically-significant drug-drug interactions. Viral load measures remained undetectable throughout the dosing interval and following subsequent administrations thereafter. This case provides pharmacokinetic rationale for the coadministration of LEN with primidone and may help guide future clinical decision-making.