Pharmacogenetic and pharmacokinetic profiling of bulevirtide in patients with chronic hepatitis D: A preliminary study

8 Background: Bulevirtide is the first approved entry inhibitor for the treatment of chronic hepatitis D, exerting its antiviral effect through the inhibition of the sodium taurocholate co-transporting polypeptide (NTCP). Despite encouraging clinical efficacy, significant inter-individual variability in drug exposure and therapeutic response has been observed. To date, a few data addressed the extent of bulevirtide plasma level variability with the possible contribution of genetic polymorphisms. This study aimed to assess bulevirtide plasma concentrations, biochemical and virological parameters at multiple time points and the potential influence of NTCP gene variants on the clinical outcome, considering virological and biochemical response at week (W) 48. Materials and methods: A cohort of patients with chronic HDV infection receiving bulevirtide in monotherapy was enrolled. Bulevirtide plasma concentrations and biochemical and virological parameters were quantified at baseline, W4, W12, W24, W36 and W48 using liquid chromatography-mass spectrometry. Pharmacogenetic analysis focused on NTCP single nucleotide polymorphisms (rs8011311 and rs2296651) through PCR-based genotyping. Results: Thirteen patients were enrolled: 76.9% were men, the median age was 50 years, the median BMI was 24.4 kg/m2 and 46.2% had cirrhosis. Median baseline ALT were 75 UI/L and HDV RNA Log 5.53. Stiffness resulted decreased at W48 compared to baseline and W24. The lipid profile resulted not influenced by the treatment and a not statistically significant increase in bile acid was observed. No side effects were reported. Virological outcome was obtained in 3 (23.1%) patients, biochemical outcome in 2 (15.4%) patients and combined response in 1 (7.7%) patient. Median bulevirtide concentrations were 0.4 (IQR 0.3; 2.1) ng/mL at W4, 0.9 (IQR 0.4; 1.9) at W12, 0.6 (IQR 0.3; 1.6) ng/mL at W24, 1.1 (IQR 0.7; 2.6) ng/mL at W36 and 1.2 (IQR 0.7; 7.1) ng/mL at W48. While no co-administered drugs seemed to affect bulevirtide levels, cirrhosis did. Patients with biochemical outcome had slightly higher bulevirtide plasma levels at W36 (1.25 vs. 0.85 ng/mL, p = 0.046). A not significant trend was found for NTCP rs8011311 G > C genetic variant and bulevirtide plasma exposure at W4 (p = 0.069) and at W48 (p = 0.062): Particularly, GC/CC genotype patients had reduced concentrations compared to GG genotype patients. Conclusions: This preliminary study reported for the first time bulevirtide concentrations in patients treated for 48 months and the potential impact of genetic determinants, although a small number of patients was considered. Further studies in larger cohorts are required to achieve personalized dosing strategies enhancing treatment efficacy and safety in HDV-infected patients.