Population pharmacokinetics and exposure‐response analysis of a single dose of sotrovimab in the early treatment of patients with mild to moderate COVID‐19

Abstract Sotrovimab is a recombinant human monoclonal antibody that has been shown to prevent progression to hospitalization or death in non‐hospitalized high‐risk patients with mild to moderate coronavirus disease 2019 following either intravenous (i.v.) or intramuscular (i.m.) administration. Population pharmacokinetic (PopPK) and exposure‐response (ER) analyses were performed to characterize single dose sotrovimab pharmacokinetics (PK) and the relationship between exposure and response (probability of progression), as well as covariates that may contribute to between‐participant variability in sotrovimab PK and efficacy following i.v. or i.m. administration. Sotrovimab PK was described by a two‐compartment model with linear elimination; i.m. absorption was characterized by a sigmoid absorption model. PopPK covariate analysis led to the addition of the effect of body weight on systemic clearance and peripheral volume of distribution, sex on i.m. bioavailability and first‐order absorption rate (KA), and body mass index on KA. However, the magnitude of covariate effect was not pronounced and was therefore not expected to be clinically relevant based on available data to date. For ER analysis, sotrovimab exposure measures were predicted using the final PopPK model. An ER model was developed using the exposure measure of sotrovimab concentration at 168 h that described the relationship between exposure and probability of progression within the ER dataset for COMET‐TAIL. The number of risk factors (≤1 vs. >1) was incorporated as an additive shift on the model‐estimated placebo response but had no impact on overall drug response. Limitations in the ER model may prevent generalization of these results to describe the sotrovimab exposure‐progression relationship across severe acute respiratory syndrome‐coronavirus 2 variants

Safety and efficacy of treatment with once-daily ledipasvir/sofosbuvir (90/400 mg) for 12 weeks in genotype 1 hcv-infected patients with severe renal impairment.

Background: Despite higher concentrations of the primary circulating sofosbuvir (SOF) metabolite, GS‐331007, in patients with severe renal impairment, retrospective case series and claims database analyses have suggested substantial use of ledipasvir (LDV)/SOF in this population with no untoward effects described. The current study evaluated the safety, efficacy, and pharmacokinetics (PK) of LDV/SOF (90/400 mg) once‐daily for 12 weeks in patients with genotype (GT) 1 HCV‐infection and severe renal impairment. Methods: Treatment naïve or experienced patients with or without compensated cirrhosis and creatinine clearance (CLcr) ≤ 30 mL/min (Cockcroft‐Gault equation), not on dialysis, received open‐label treatment with LDV/SOF once daily for 12 weeks. Virologic response, pharmacokinetics (PK), and safety, including echocardiograms, were assessed. Results: Of the 18 patients enrolled and treated, the majority were male (67%), 10 (56%) were African‐American, 8 (44%) had BMI \u3e30 kg/ m2 and mean (range) CLcr at baseline was 24 9 (9 0‐39 6) mL/min. In terms of liver disease characteristics, all 18 had GT1 HCV infection (14 GT1a and 4 GT1b), 14 (78%) were treatment naïve, and 2 (11%) had cirrhosis. All patients completed 12 weeks of LDV/SOF treatment. There were no early discontinuations nor any on‐treatment virologic failures. The SVR4 rate is 100% (18/18). Preliminary PK data in subjects with severe renal impairment demonstrate that the exposure of SOF and GS‐331007 were approximately 2.6‐ and 5.1‐fold higher, respectively, than in subjects in the LDV/SOF Phase 3 studies; LDV exposure was similar in both populations. The most common adverse events (AEs) were fatigue (22%), headache (22%), and hyperkalemia (22%). Six serious AEs were reported among 4 patients (22%), including 2 renal events; no SAEs were considered related to study drugs. Preliminary analysis of echocardiogram data from the first 8 subjects demonstrated stable parameters from screening through the end of treatment. Complete SVR12, PK, and echocardiogram results will be presented. Conclusions: Treatment with LDV/SOF (90/400 mg) for 12 weeks in genotype 1 patients with and without cirrhosis and severe renal impairment resulted in 100% SVR4 rate. The regimen was safe and well‐tolerated with no treatment discontinuations and no treatment‐related SAEs

Sofosbuvir plus velpatasvir combination therapy for treatment- Experienced patients with genotype 1 or 3 hepatitis c virus infection

Background: Effective treatment options are needed for patients with genotype 1 or 3 hepatitis C virus (HCV) infection in whom previous therapy has failed. Objective: To assess the efficacy and safety of sofosbuvir plus velpatasvir, with and without ribavirin, in treatment-experienced patients. Design: Randomized, phase 2, open-label study. (ClinicalTrials .gov: NCT01909804) Setting: 58 sites in Australia, New Zealand, and the United States. Patients: Treatment-experienced adults with genotype 3 HCV infection without cirrhosis (cohort 1) and with compensated cirrhosis (cohort 2) and patients with genotype 1 HCV infection that was unsuccessfully treated with a protease inhibitor with peginterferon and ribavirin (50% could have compensated cirrhosis) (cohort 3). Intervention: All patients received 12 weeks of treatment that included 400 mg of sofosbuvir once daily. Patients in each cohort were randomly assigned to 25 mg of velpatasvir once daily with or without ribavirin or 100 mg of velpatasvir once daily with or without ribavirin. Measurements: Proportion of patients with sustained virologic response at week 12 after treatment (SVR12). Results: In cohort 1, SVR12 rates were 85% with 25 mg of velpatasvir, 96% with 25 mg of velpatasvir plus ribavirin, 100% with 100 mg of velpatasvir, and 100% with 100 mg of velpatasvir plus ribavirin. In cohort 2, SVR12 rates were 58% with 25 mg of velpatasvir, 84% with 25 mg of velpatasvir plus ribavirin, 88% with 100 mg of velpatasvir, and 96% with 100 mg of velpatasvir plus ribavirin. In cohort 3, SVR12 rates were 100% with 25 mg of velpatasvir, 97% with 25 mg of velpatasvir plus ribavirin, 100% with 100 mg of velpatasvir, and 96% with 100 mg of velpatasvir plus ribavirin. The most common adverse events were headache, fatigue, and nausea. Limitation: Treatment assignments were not blinded, and no inferential statistics were planned. Conclusion: Treatment with 400 mg of sofosbuvir plus 100 mg of velpatasvir for 12 weeks was well-Tolerated and highly effective in treatment-experienced patients with genotype 1 or 3 HCV infection