Bulevirtide blocks the entry of HBV and HDV into hepatocytes by binding to and inactivating NTCP, a bile salt liver transporter serving as essential HBV/HDV entry receptor.
The pharmacokinetic properties of bulevirtide were characterised after intravenous and subcutaneous administration. The exposure of bulevirtide increased disproportionally while the clearance and volume of distribution decreased with higher doses.
The estimated volume of distribution is smaller than total body water. In vitro plasma protein binding is high with >99% of bulevirtide bound to plasma proteins.
No biotransformation study was performed for bulevirtide. Bulevirtide is a linear peptide consisting of L-amino acids, and it is expected to be degraded to smaller peptides and individual amino acids. No active metabolites are expected.
Based on the results of in vitro interaction studies, bulevirtide did not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4.
No in vitro induction of CYP1A2, CYP2B6 or CYP3A4 by bulevirtide was observed.
Based on the in vitro studies, no clinically relevant interaction is expected for most common efflux transporters (MDR1, BCRP, BSEP, MATE1 and MATE2K) and uptake transporters (OATP2B1, OAT1, OAT3, OCT1 and OCT2). A specific in vitro interaction was identified with the organic anion transporting polypeptides, OATP1B1 and OATP1B3 with IC50 values of 0.5 and 8.7µM, respectively.
No bulevirtide excretion into urine was detected in healthy volunteers. Elimination via target (NTCP) binding is assumed to be the main route. Both distribution and elimination after multiple dosing were reduced compared to values estimated after the first dose. Accumulation ratios for 2 mg dose for Cmax and AUC were approximately 2-fold. Steady state is assumed to be achieved within the first weeks of administration. After reaching peak concentrations, plasma levels declined with t1/2 of 4-7 hours.
No studies have been conducted with bulevirtide in patients with renal impairment.
No studies have been conducted with bulevirtide in patients with moderate and severe hepatic impairment.
No data is available in patients older than 65 years of age.
No data is available in patients younger than 18 years of age.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single and repeated dose toxicity, and toxicity to reproduction and development.
No genotoxicity and carcinogenicity studies were conducted due to the nature and mechanism of action of the product.
A pre- and post-natal development study (PPND) has been completed in rats and did not show any bulevirtide-related toxicity.
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