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Pharmaceutical Development of a Broad-Spectrum Antibacterial Candidate for Multidrug-Resistant Infections

Introduction

The World Health Organization (WHO) has identified antimicrobial resistance (AMR) as one of the top ten global public health threats. Despite concerted global efforts, AMR infections caused 4.95 Mn deaths in 2019. A clinical-stage biopharmaceutical company has been working on AMR since 2016 in collaboration with Syngene. They have developed a small molecule, a novel bacterial topoisomerase inhibitor that selectively restrains bacterial DNA replication by inhibiting DNA gyrase and topoisomerase IV. The clinical drug candidate demonstrates broad-spectrum activity against the major WHO published list of “global priority” pathogens1 . The client collaborated with Syngene for formulation development from the discovery of the molecule to the First in Humans (FIH) development stage.

Collaborative work at Syngene

Cross-functional teams from discovery chemistry, drug metabolism, drug product development collaborated to develop the clinical antibiotic candidate.

The client conducted structure-activity Relationship (SAR) studies, followed by synthesizing the compounds during the discovery stage with Syngene’s discovery chemistry team. The formulation team then performed salt and polymorph screening of the drug candidate.

The drug product development team conducted the formulation development of the drug candidate (for preclinical studies), followed by peroral pharmacokinetic studies by Syngene’s drug metabolism team. A few studies were conducted by the client to understand the pharmacokinetic profiles in dogs

Challenging science

The major challenges encountered during formulation development included poor solubility and low bioavailability2 . The drug exhibited aqueous solubility of less than 1 mg/mL, making it difficult to dissolve effectively. Additionally, it was identified that the drug was actively transported out of the cell, significantly impacting its bioavailability. During formulation development, scientists encountered additional challenges.

Evaluation of various formulations
  • Multiple formulation strategies – including solubilization, amorphous solid dispersion, and nanosuspension – were evaluated to enhance oral bioavailability. However, these approaches proved unsuccessful.
  • Dissolution studies (pH shift studies) were conducted to assess the impact of various formulations on the pH shift in the gut’s acidic environment. The root cause was identified and attributed to the probable precipitation of the formulation when it transits from the stomach to the intestinal region.
  • Excipients with transporter inhibitor activity were screened to counteract the molecule being pumped out of the cell. Further optimization studies were conducted to determine the appropriate excipient concentration, which was subsequently proposed for pharmacokinetic studies.
In Vivo Evaluation

A high dose formulation (plasma concentration, Cmax) was achieved during oral formulation in the preclinical stage. However, dose-proportional oral bioavailability was not achieved. Optimization studies were conducted to address this, resulting in a finalized formulation that demonstrated good oral bioavailability and dose margins for toxicology studies.

The outcome

Optimized Formulation Achievements –  The p-GP inhibitorbased formulation was successfully optimized to sustain stability in both gastric and intestinal fluids, as demonstrated by in-vitro and in-vivo studies. This formulation achieved the desired oral exposure, addressing the bioavailability challenges of efflux transport.

Progress Toward First-in-Human (FIH) Studies – Syngene’s drug product development team is developing a proof-ofconcept oral formulation for First-in-Human studies and will manufacture a GMP-compliant drug product.

Clinical Trial Success – Drug doses were administered intravenously during the Single Ascending Dose (SAD) clinical trial in healthy volunteers. It was safe and well-tolerated (primary endpoint) and achieved dose-proportional exposures (secondary endpoint).

Scientific Collaboration and Recognition – A paper with a client is published in Nature Communication, showcasing the innovation and success of the drug development process.

References

WHO’s amr-factsheet.pdf Antimicrobial Resistance: Addressing a Global Threat to Humanity | PLOS MedicineEffect of P-glycoprotein (P-gp) Inducers on Exposure of P-gp Substrates: Review of Clinical Drug–Drug Interaction Studies

1 Carbapenem-resistant Enterobacteriaceae, carbapenem-resistant Pseudomonas aeruginosa, carbapenem-resistant Acinetobacter baumannii and methicillinresistant Staphylococcus aureus

2 Bioavailability refers to the proportion of a drug that enters the bloodstream when introduced into the body and is available for therapeutic action.

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