Abstract Body

Molnupiravir, a prodrug of the broadly active, direct-acting antiviral, ribonucleoside analogue EIDD-1931, is a promising COVID-19 drug. Given the primary route of SARS-CoV-2 transmission through respiratory droplets we evaluated EIDD-1931 PK in saliva, nasal secretions and tears of patients with mild-to-moderate COVID-19 through the phase Ib/IIa AGILE platform (NCT04746183).

Patients with PCR-confirmed SARS-CoV-2 infection, within 5?days of symptom onset with mild-to-moderate disease were randomised to oral molnupiravir 300, 600 or 800?mg twice daily. Plasma and non-plasma (saliva, nasal and tear swabs) samples were collected pre-dose, 0.5, 1, 2, and 4 hours post-dose on study days 1 and 5 and molnupiravir and EIDD-1931 measured by LC/MS (lower limit of quantification, 2.5 ng/mL). PK parameters were determined (Phoenix 64, WinNonlin, v. 8.3) and non-plasma:plasma (NP:P) ratios (based on AUC[sub]0-4[/sub]) calculated. Relationships between paired non-plasma and plasma samples were evaluated by linear regression.

Twelve participants (n=4 per dose; 75% female) completed the study contributing 111, 112 and 97 saliva, nasal and tear samples, respectively. Molnupiravir was detected in 11% of saliva samples [median (range) 4.86 ng/mL (2.63-31.44)] and not evaluated in swabs. Quantifiable EIDD-1931, following molnupiravir 300, 600 and 800 mg twice daily were i) saliva: 17.7 (2.8-133), 16.6 (2.9-469), 25.8 (4.0-230) ng/mL, ii) nasal swabs: 182 (18-1700), 136 (18-917), 295 (24-1879) ng/mL and iii) tears: 297 (24-1650), 176 (16-1260), 307 (32-2760) ng/mL. PK parameters are shown (Table 1). Median (range, CV%) pooled NP:P ratio for saliva was 0.03 (0.01-0.11, 60%; n=16). Nasal and tear ratios were 6-fold higher with values of 0.21 (0.05-0.73, 70%; n=17) and 0.22 (0.09-1.05, 92%; n=12), respectively. Non-plasma and plasma concentrations were significantly correlated (r2: 0.360-0.677; p<0.0001). Of measured saliva, nasal and tear samples, 6, 50 and 61%, respectively were within or above the EIDD-1931 EC90 against SARS-CoV-2 in primary human airway epithelia cultures (approximately 0.5-1 µM ? 130-260 ng/mL).

This is the first report of EIDD-1931 PK at sites of initial SARS-CoV-2 exposure in patients with COVID-19. Investigations of PK/PD relationships are warranted; however, these data suggest therapeutic concentrations are potentially achieved in nasal and tear compartments, but not saliva and have important implications for prophylactic coverage.