A RANDOMISED PHASE i PHARMACOKINETIC STUDY COMPARING HIGH-CONCENTRATION, LOW-VOLUME, and CITRATE-FREE SB5 (40 MG/0.4 ML) with PRIOR SB5 FORMULATION, and ADALIMUMAB BIOSIMILAR, in HEALTHY MALE SUBJECTS

Background: SB5, an adalimumab (ADL) biosimilar, was developed in a low-concentration (40 mg/0.8 mL, SB5-LC) aligned with the reference ADL product. Pharmacokinetics (PK) equivalence of SB5 and reference ADL was demonstrated in a Phase I study conducted in healthy subjects1. Equivalent efficacy and comparable safety between 40 mg/0.8 mL SB5 and 40 mg/0.8 mL reference ADL were demonstrated in a Phase III study conducted in patients with rheumatoid arthritis2. High-concentration, low-volume, citrate-free SB5 (40 mg/0.4 mL, SB5-HC) has been developed as a part of life cycle management in line with the reference ADL formulation. Objectives: To compare the PK, safety, and tolerability of the newly developed SB5-HC (40 mg/0.4 mL) to prior SB5-LC (40 mg/0.8 mL) in healthy male subjects. Methods: This study was a randomised, single-blind, two-arm, parallel group, single-dose study in healthy male subjects. Subjects were randomised in a ratio of 1:1 to receive a single dose of either SB5-HC or SB5-LC by subcutaneous injection on Day 1 and then observed for 57 days during which the PK, safety, and immunogenicity were evaluated. The serum concentration of ADL was measured using an enzyme-linked immunosorbent assay. The primary PK parameters were area under the concentration-time curve from time zero to infnity (AUCinf) and maximum serum concentration (Cmax). Equivalence for the primary PK parameters was to be concluded if the 90% confdence intervals (CIs) for the ratio of geometric least squares means (LSMeans) of the treatment groups compared were completely contained within the pre-defned equivalence margin of 0.80 to 1.25 using an analysis of variance. Results: Of 188 randomised subjects, 187 subjects were analysed as PK Analysis Set (PKS) (n=93 in SB5-HC and n=94 in SB5-LC). One subject was excluded from the PKS in SB5-HC group (major protocol deviation for not being withdrawn in the event of confrmed COVID-19). The geometric LSMeans ratios for the comparison of SB5-HC and SB5-LC for AUCinf and Cmax were 0.920 and 0.984, respectively, and the corresponding 90% CIs were within the pre-defned equivalence margin of 0.80 to 1.25 (Table 1), indicating the two treatment groups are bioequivalent. There were no deaths, serious adverse events or discontinuation of the study due to treatment-emergent adverse events (TEAEs) during the study. The proportions of subjects who experienced TEAEs were comparable between the two treatment groups (44.7% in SB5-HC vs 51.1% in SB5-LC). The most frequent TEAEs were headache (10.6% in SB5-HC vs 12.8% in SB5-LC). Conclusion: This study demonstrated PK equivalence between SB5-HC and SB5-LC in healthy subjects. Both SB5-HC and SB5-LC were generally well tolerated with similar safety profiles.

Doxycycline inhibits SARS-CoV-2 replication in vitro

Introduction and Aim: We examined the effect of pre-and/or post-infection doxycycline on human nasal epithelial cell viability and SARS-CoV-2 (clinical strain IHUMI-3) replication in vitro. Materials and Methods: Human nasal epithelial cells, an in vivo SARS-CoV-2 target, were derived from healthy donor nasal epithelial stem/progenitor cells via in vitro differentiation. The cells were exposed to doxycycline at 0, 0.1, 0.5, 1, 5, 10, 50, and 100 μM before and/or after IHUMI-3 inoculation to determine the optimal inhibitory concentration. Viral replication was evaluated using quantitative reverse-transcription PCR, and doxycycline 50% cytotoxic concentration (CC50) and half-maximal effective concentration (EC50) were calculated. The peak serum concentration (Cmax) resulting from typical oral (100 or 200 mg) or intravenous (100 mg) doxycycline doses was estimated, and the Cmax/EC50 ratio was calculated as an index of potential clinical utility. Results: Doxycycline exhibited low cytotoxicity (CC50 > 100 μM) in human nasal epithelial cells and inhibited SARS-CoV-2 replication (EC50: 5.2 ± 3.3 μM) in a dose-dependent manner when administered pre-and/or post-infection. Reasonable oral or intravenous doses will help achieve effective concentrations in vivo. Conclusion: Early administration of this well-characterized, safe, and accessible drug may limit person-to-person transmission and prevent progression to severe coronavirus disease.

A Randomized, Placebo-Controlled Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Inhaled Ribavirin Administered Via Air-Jet Nebulizer in Healthy Volunteers

RATIONALE: Ribavirin is an inosine monophosphate dehydrogenase inhibitor. Studies suggest ribavirin aerosol could be a safe and efficacious treatment option in the fight against coronaviruses. It is currently approved for treatment of lower respiratory tract infections due to respiratory syncytial virus in pediatrics. However, treatment is long and continuous (12-18 hours per day, 3-7 days) limiting wider clinical utility. A reduction in treatment time would mean ribavirin could become a practical treatment option for SARS-CoV-2. The primary objective of this study was to evaluate the safety and pharmacokinetics (PK) of four, single-dose regimens of ribavirin aerosol in healthy volunteers. METHODS : Thirty-two subjects entered this phase Ia, randomized, doubleblinded, placebo-controlled, study. Four successive cohorts received ribavirin (active) or placebo. Cohort 1 received 50 mg/mL ribavirin/placebo (10 ml total volume);2 - 50 mg/mL ribavirin/placebo (20 ml total volume);3 - 100 mg/mL ribavirin/placebo (10 ml total volume);4 - 100 mg/mL ribavirin/placebo (20 ml total volume). All treatments were aerosolized and administered over 20 or 40 min for the 10ml and 20 ml volumes respectively. Randomization to cohorts took place on day 1, followed by intense safety monitoring and PK sampling on days 1, 2, 3 and 40. Treatment-emergent adverse events (TEAEs) were summarized by cohort and treatment group. PK parameters were analyzed using non-compartmental methods for maximal plasma concentration (Cmax), time to maximal plasma concentration (Tmax), area under the curve (AUC), and elimination half life (t1/2). RESULTS : Subjects were (mean ± SD, active vs placebo) aged 57 ± 4.5 vs 60 ± 2.5 years;83% vs 88% were female;and 75% vs 50% were Caucasian. 12.5% (3/24) and 25% (2/8) of subjects experienced at least one TEAE (2 moderate;5 mild) in active and placebo groups respectively. TEAEs were unrelated to study treatment. No clinically significant safety concerns were reported. Table I provides a summary of PK parameters. PK results were linear and well-behaved across the four single-dose regimens, demonstrating systemic exposure with minimal systemic effects. Ribavirin absorption reached Cmax within 2 hrs across all cohorts. The t1/2 was similar across all cohorts. CONCLUSIONS : Four single-dose regimens of ribavirin aerosol demonstrated systemic exposure with minimal systemic effects. These results support preliminary efficacy and safety data in COVID-19 patients and continued clinical development of ribavirin aerosol as a treatment option for SARS-CoV-2 and its variants. (Table Presented).

Pharmacotherapy of rhino-orbital-cerebral mucormycosis

The aim of this study is Recently there is an alarming increase in the incidence of mucormycosis in patients diagnosed with Covid-19. In this short review, we will discuss the basic principles of mucormycosis treatment, antifungal agents used along with update on pharmacotherapeutic guidelines recommended for management of mucormycosis. Searching the Pubmed with the key words “mucormycosis and covid 19 ”, “ Treatment of mucormycosis”, “ antifungal used in Mucormycosis revealed many articles, and the relevant articles were screened. Mucormycosis is an aggressive disease which is difficult to diagnose in early stage with high morbidity and mortality. Multimodal therapeutic approach consisting of early diagnosis, urgent surgical and medical intervention and elimination of predisposing factors is key to successful management of this condition. First-line antifungal agent is high-dose liposomal amphotericin B although amphotericin B deoxycholate may be the viable option in resource limited settings.