ABSTRACT
Background: Despite renal impairment (RI) being a risk factor for severe COVID-19, there are no approved antiviral treatment options for patients with severely impaired kidney function (eGFR less than 30 mL/min/1.73 m2 or kidney failure) in the US. At the time remdesivir (RDV) was initially approved for the treatment of COVID-19, the impact of renal impairment (RI) on pharmacokinetics (PK) of RDV, its metabolites, and the excipient, sulfobutylether beta-cyclodextrin sodium (SBECD), was not known. Method(s): Here, we report the PK data supporting dosing of RDV in COVID-19 patients with severely impaired kidney function. PK samples for RDV and metabolites (GS-704277, GS-441524) were collected in the Phase 3 REDPINE study in hospitalized COVID-19 patients with severely impaired kidney function. Participants in this double-blind study were randomized 2:1 to intravenous (IV) remdesivir (200 mg on Day 1, then 100 mg daily up to Day 5) or IV saline as placebo-to-match. SBECD PK was analyzed in a phase 1 study in non-COVID-19 participants with normal kidney function, mild and moderate RI who received 100 mg dose of remdesivir (containing 3000 mg SBECD). The population PK analysis included observations from healthy and COVID-19 patients with full range of renal function across all adult studies. Result(s): Geometric mean exposures (AUCtau) observed in REDPINE Study as compared to PINETREE Study increased up to 553% for the GS-441524 metabolite (dependent on renal elimination) and to a lesser degree GS-704277 (294%, minor renal elimination) and RDV (78.9%;an increase explained by factors other than renal function, namely, hospitalization and body weight) (Table 1). The increased PK exposures were not associated with new safety signals in this study (n=163 remdesivir, n=80 placebo). Population PK analysis identified baseline eGFR as a significant covariate for GS-704277 and GS-441524 clearance, but not for RDV itself. SBECD PK was characterized by short half-life (t1/2) (1.6 hours in normal renal function to 3.8 hours in moderate RI) and fast plasma clearance (7.9 L/h in normal renal function). Analysis of SBECD in severe RI (REDPINE) is ongoing, but accumulation is not expected based on its observed short plasma t1/2. Conclusion(s): Given the observed PK and the absence of any new safety signals associated with increased metabolite levels in patients with severely impaired kidney function, no dose adjustment is recommended for RDV in COVID-19 patients with eGFR < 30 mL/min/1.73 m2, regardless of the need for dialysis.
ABSTRACT
BACKGROUND: Remdesivir (RDV) is an RNA polymerase inhibitor approved for treatment of COVID-19 (200 mg loading dose, 100 mg qd thereafter) in adult and pediatric patients, primarily metabolized by the high-capacity carboxylesterase 1 pathway (80% of metabolism), and by cathepsin A and CYP3A (10% each). The extensive hepatic contribution to RDV elimination and the prevalence of liver comorbidities in COVID-19 patients warranted a study in participants with hepatic impairment (HI). METHOD(S): This is a phase 1, open-label study of RDV consisting of moderate and severe HI participants and healthy matched controls (HMC) based on age (+/- 10 years), sex, and BMI (+/- 20%). Participants received a single 100 mg IV dose of RDV and remained in the clinic for 8 days. The primary endpoint was pharmacokinetic (PK) parameters of RDV and metabolites. RESULT(S): Preliminary PK and safety data from 10 moderate and 6 severe HI participants and their HMC are available. The average PK fold-change for all analytes and matrices assessed in the study are presented (Table). No serious treatment-related adverse events and no clinically significant changes in participant lab values were reported. CONCLUSION(S): The 1.52 RDV AUCinf fold increase is within expected ranges and justifies no dose adjustment in COVID-19 patients with impaired hepatic function. (Table Presented).
ABSTRACT
P168 Table 1Overall safety showing proportion of participants with AEsParticipants, n (%) Cohort 1n=12 Cohort 2n=12 Cohort 3n=12 Cohort 4n=12 Cohort 8n=5 TotalN=53 Any AE 11 (92) 7 (58) 9 (75) 7 (58) 4 (80) 38 (72) Grade ≥3 AE 6 (50) 2 (17) 1 (8) 4 (33) 2 (40) 15 (28) SAE 5 (42) 2 (17) 0 3 (25) 1 (20) 11 (21) Treatment discontinuation due to AE 2 (17) 0 0 0 0 2 (4) Treatment-emergent death 1 (8) 1 (8) 0 0 1 (20) 3 (6) Grade 3–4 laboratory abnormalities 9 (75) 2 (17) 4 (33) 4 (36) 3 (60) 22 (42) ConclusionsRDV was generally well tolerated in children hospitalised for COVID-19 who were 28 days and older, weighing at least 3 kg. No new safety trends for RDV were identified and a high proportion of participants had clinical improvement. CARAVAN is ongoing for enrolment of full term and preterm neonates.
ABSTRACT
Background: Pregnant people with COVID-19 are at higher risk of severe disease and adverse pregnancy outcomes. Remdesivir (RDV), an antiviral medication that is US FDA-approved for severe COVID-19, has limited data during pregnancy. Here we report preliminary pharmacokinetic (PK) and safety data for RDV in pregnant and non-pregnant women with COVID-19. Methods: IMPAACT 2032 is an ongoing phase IV prospective, open-label, non-randomized opportunistic study of pregnant and non-pregnant women prescribed RDV for COVID-19 treatment as part of clinical care. RDV was administered intravenously at a 200 mg dose on Day 1 followed by 100 mg once-daily through 5 or 10 days of treatment. Enrollment occurred prior to the 4th infusion. Repeat PK sampling was performed through 23 hours post-infusion on infusion day 3, 4 or 5. Baseline demographic and clinical data were recorded from 48 hours pre-1st infusion, and safety data were recorded from 1st infusion through 4 weeks post-last infusion and at labor/delivery for pregnant women. Adverse events (AEs) were graded according to the DAIDS AE Grading Table v2.1. RDV and its plasma metabolites (GS-704277 and GS-441524) were quantified using validated LC/MS methods. PK parameters were estimated using noncompartmental methods (Phoenix WinNonlin®). Results: This preliminary analysis included 18 women: 10 pregnant (median (range) gestational age 28 (22-32) weeks) and 8 non-pregnant (Table). One pregnant woman withdrew consent before completing RDV treatment;3 discontinued RDV early (2 pregnant women due to hospital discharge;1 non-pregnant woman due to grade 2 bradycardia related to RDV). Thirteen women completed 5 days and 1 completed 10 days of treatment. Plasma RDV and metabolite exposures were comparable between 8 pregnant and 6 non-pregnant PK-evaluable women (Table). Among safety-evaluable women (n=18), 8 pregnant and 4 non-pregnant women had ≥1 grade 3/4 AE;1 grade 3 AE was related to RDV in a non-pregnant woman (estimated glomerular filtration rate (eGFR) 30-<60 mL/min). Of 6 women with delivery data available, there were 2 preterm births (<37 weeks) and 1 intrauterine fetal demise (26 weeks), which was unrelated to RDV. Conclusion: Preliminary estimates of RDV, GS-704277 and GS-441524 exposures were generally comparable between pregnant and non-pregnant women, but no formal statistical comparisons were made. PK (including intracellular) and safety investigations in additional women are ongoing.