Article by Dave Griffin
Traditionally, β-lactamase inhibitors (BLIs) have been developed in combination with a single, carefully chosen β-lactam (BL). The selection of the partner BL was generally based on the similarity of its pharmacokinetic (PK) properties to that of the BLI so that both agents would be present at the site of infection, allowing the inhibitor to protect the integrity of the BL. This made sense since the spectrum of β-lactamase inhibitory activity of the early BLIs (i.e., clavulanic acid, sulbactam and tazobactam) was generally limited.
Whilst significant improvements in potency, spectrum of activity, PK properties and safety profile of the BL class has been made over the years, this has been largely mirrored by the evolution of the β-lactamases. The recent approvals of avibactam, relebactam and vaborbactam combined with ceftazidime, imipenem and meropenem, respectively, have dramatically improved treatment options for serious Gram-negative bacterial infections[1-3]. Further progress is now being made and it is anticipated that many new BLIs will become available for clinical use within the next decade, thus providing additional therapeutic options for infections caused by multidrug resistant pathogens.
Partnering a BLI with a single BL may, however, be problematic in that the combination may not be efficacious against all potential infecting organisms, nor may it be the best combination if several β-lactamases are being produced, as affinities of these enzymes for the BLI will differ. So, despite a BLI having improved inhibitory activity, combining it with a single BL may eventually limit its use should resistance develop. This was seen with ceftazidime/avibactam where, shortly after release into clinical use, resistance emerged during treatment in some Enterobacterales and Pseudomonas aeruginosa. Resistance occurred through single amino acid substitutions in some β-lactamases, including the KPC enzymes that hydrolyse carbapenems[4, 5].
These issues have raised the question whether a BLI could be developed as a stand-alone agent (i.e., not combined with a specific partner BL). Whilst no regulatory pathway for such an approach currently exists, regulators have not excluded this development pathway. A dedicated symposium was held in June 2021 at the World Microbe Forum in which both the European Medicines Agency (EMA) and the US Food and Drugs Administration (FDA) discussed their position on stand-alone BLI development.
Dr Mair Powell, representing the EMA, stated that there is no regulatory issue that would preclude the approval of a stand-alone BLI in the European Union (EU). The Summary of Product Characteristics (SmPC) would need to state the specific BLs with which the BLI can be used, and, for each partner BL, the indication and posology would need to be listed separately. Potential partner BLs would need to be identified using appropriate microbiological studies, much the same as done when developing BL/BLI combinations, and only BLs that are approved for use in the EU can be referred to in the BLI SmPC. If a partner BL has multiple doses, Dr Powell recommended that the highest EMA-approved dose regimen should be chosen in conjunction with the BLI to cover all the claimed indications and to avoid concerns about inadequate dosing. The PK profile of the BLI alone and the BL/BLI combination must be determined for each potential partner BL to assess any interactions, and separate population PK models will need to be developed for the BLI with each partner BL. To avoid complex BLI posology, the EMA recommends that only one BLI regimen is chosen, based on the partner BL requiring the highest BLI exposure for an acceptable Probability of Target Attainment.
If both the BL and BLI are already approved in Europe at the doses intended for the combined administration, and there are no significant PK interactions, then the EMA may not require a clinical trial to be conducted. If the BLI is unlicensed in Europe, then at least one randomised controlled trial in one site-specific infection approved for one partner BL will be required. It will not be necessary, however, to demonstrate clinical benefit of adding the BLI to the BL (i.e., BL-resistant pathogens do not have to be sufficient in number), nor will the usual requirements for non-inferiority margins to support an infection-site specific indication have to be met, thereby reducing the sample size needed. Furthermore, it will not be necessary to conduct efficacy trials with every proposed partner BL if PK/pharmacodynamic (PD) analyses provide robust support for the dosage regimens, and at least some of the indications already approved for the partner BLs may be applied for based on PK/PD considerations only.
The FDA are currently less committed to the acceptability of a stand-alone BLI development route but, nevertheless, did not rule this out. Dr Sumati Nambiar, representing the FDA’s opinion, stated that whilst a stand-alone BLI may be approvable and may offer benefits in certain situations, there are many factors that will need to be considered. The FDA’s primary concern, as with any medication, relates to medication errors and inappropriate use. Examples of concerns cited by Dr Nambiar included administration of the BLI alone, ensuring correct dosing if the regimens for the BL and BLI differ, and stability/compatibility of the two agents together.
However, the FDA also consider that, if the BL and BLI have differing PK characteristics, a stand-alone BLI may allow co-administration with a BL when this may not be possible as a fixed dose combination. It could also allow for greater flexibility in dose adjustment (e.g., in cases of renal impairment) and may allow therapy to be tailored based on specific organisms and their expressed resistance mechanisms.
In summary, the EMA position is that a stand-alone BLI would be acceptable in the EU and that only a very limited clinical efficacy programme may be required. The SmPC, however, will need to restrict the partner BLs to those already approved in EU, where PK and PK/PD data support the dosing regimens and the indications and posology for each BL will need to be listed separately. The FDA, on the other hand, were more hesitant stating that development of a stand-alone BLI, whilst untested, is potentially an option but that this has unique challenges that will need to be considered carefully. Maintaining a dialogue with both agencies, and obtaining scientific advice prior to embarking on, and during, a development programme will be, as always, critical to success.
tranScrip has considerable experience in the development of BL/BLIs and in the planning of development programmes, obtaining scientific advice, and helping its clients achieve successful product registrations.
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1. Griffin, D.R.J., β-lactamase inhibitors: then to now. https://www.transcrip-partners.com/news/b-lactamase-inhibitors-then-now, 2021.
2. Abodakpi, H., A. Wanger, and V.H. Tam, What the Clinical Microbiologist Should Know About Pharmacokinetics/Pharmacodynamics in the Era of Emerging Multidrug Resistance: Focusing on beta-Lactam/beta-Lactamase Inhibitor Combinations. Clin Lab Med, 2019. 39(3): p. 473-485.
3. Tooke, C.L., et al., beta-Lactamases and beta-Lactamase Inhibitors in the 21st Century. J Mol Biol, 2019. 431(18): p. 3472-3500.
4. Papp-Wallace, K.M., The latest advances in beta-lactam/beta-lactamase inhibitor combinations for the treatment of Gram-negative bacterial infections. Expert Opin Pharmacother, 2019. 20(17): p. 2169-2184.
5. Vazquez-Ucha, J.C., et al., New Carbapenemase Inhibitors: Clearing the Way for the beta-Lactams. Int J Mol Sci, 2020. 21(23).