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Safety and Pharmacokinetics of Single and Multiple Ascending Doses of Avibactam Alone and in Combination with Ceftazidime in Healthy Male Volunteers: Results of Two Randomized, Placebo-Controlled Studies

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Abstract

Background and Objective

Avibactam is a novel non-β-lactam β-lactamase inhibitor effective against Ambler class A, C and some class D β-lactamases that is currently in clinical development in combination with ceftazidime for the treatment of serious Gram-negative infections. It restores the in vitro activity of a range of β-lactams, including ceftazidime, against extended-spectrum β-lactamase-producing pathogens. Two phase I studies assessed the safety and pharmacokinetics of avibactam in healthy subjects when administered alone or with ceftazidime.

Methods

The first study (NXL104-1001) was a placebo-controlled, single-ascending dose study assessing avibactam 50, 100, 250, 500, 1000, 1500 or 2000 mg given as a 30-min intravenous infusion. After a 7-day washout, subjects in the 250 and 500 mg dosing groups received a second avibactam dose with concomitant ceftazidime 1000 or 2000 mg, respectively. The second study (NXL104-1002) was performed in two parts. Part 1 assessed multiple-ascending doses of avibactam. Subjects were randomized to receive avibactam 500, 750 or 1000 mg every 8 h (q8 h) over 5 days, or ceftazidime-avibactam 2000–500 mg q8 h over 10 days. Part 2 assessed bioavailability of avibactam after a single oral dose (500 mg) relative to a single 30-min intravenous infusion (500 mg).

Results

No serious or severe adverse events were reported in either study. Avibactam exposure generally increased proportionally to dose and there was no trend for accumulation after multiple doses. Almost all avibactam was excreted largely unchanged in the urine within the first 6 h. Concomitant ceftazidime did not affect avibactam’s safety and pharmacokinetic profile. Avibactam exposure after oral dosing was very low at 6.2 % of that observed after intravenous infusion.

Conclusion

Avibactam was generally well tolerated across all dosing regimens, when given alone or with ceftazidime. Avibactam exposure was dose related in both studies, and avibactam pharmacokinetics were linear and not affected by ceftazidime.

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Acknowledgments

The authors wish to thank Peter J Laud contracted to AstraZeneca from the Statistical Services Unit, Sheffield, for his expert review of the manuscript. These studies have been presented in part at the Interscience Conference on Antimicrobial Agents and Chemotherapy in 2007, and were funded by Novexel. Ceftazidime-avibactam is now being developed by AstraZeneca and Forest Laboratories Inc. a subsidiary of Actavis plc. Medical writing support was provided by Catherine Savage and Rob Campbell of Prime Medica Ltd, Knutsford, Cheshire, UK, funded by AstraZeneca. The design and conduct of the study, as well as analysis of the study data and opinions, conclusions, and interpretation of the data, are the responsibility of the authors.

Conflict of interest

Antoine Tarral, Henri Merdjan and Manickam Rangaraju were employees of Novexel SA at the time of conduct of the studies.

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Author notes

  1. Henri Merdjan

    Present address: Pharsight Consulting Services Europe, Regus Business Centre, 37-39 Avenue Ledru Rollin, CS11237, 75570, Paris Cedex 12, France

  2. Manickam Rangaraju

    Present address: Polyphor Ltd, Allschwil, Switzerland

  3. Antoine Tarral

    Present address: DNDi Drugs for Neglected Diseases Initiative, Geneva, Switzerland

Authors and Affiliations

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    1. Henri Merdjan
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    2. Manickam Rangaraju
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    3. Antoine Tarral
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    Corresponding author

    Correspondence to Henri Merdjan.

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    The authors were formerly employees of Novexel SA.

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    Merdjan, H., Rangaraju, M. & Tarral, A. Safety and Pharmacokinetics of Single and Multiple Ascending Doses of Avibactam Alone and in Combination with Ceftazidime in Healthy Male Volunteers: Results of Two Randomized, Placebo-Controlled Studies. Clin Drug Investig 35, 307–317 (2015). https://doi.org/10.1007/s40261-015-0283-9

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