Review of Clinical Pharmacokinetics of Avibactam, A Newly Approved non-β lactam β-lactamase Inhibitor Drug, In Combination Use With Ceftazidime

Abstract

Avibactam, a potent non-β lactam β-lactamase inhibitor, was recently approved in the USA for combination use with ceftazidime, a cephalosporin antibiotic drug. The addition of avibactam potentiates the antimicrobial drug ceftazidime, which otherwise would have been susceptible to β-lactamases produced by variety of Gram negative pathogens. The focus of this review was to provide clinical pharmacokinetic data of avibactam to cover absorption, distribution, metabolism, and excretion aspects including any potential for avibactam to show drug-drug interactions in the clinic. Based on the review of the data, the pharmacokinetics of avibactam was generally stationary in the studied dosing regimen. The elimination half-life (approximately 1.4- 3.2 h) and volume of distribution at steady state (15.4-26.3 L) were found similar across the studies and therefore, provided the complementary pharmacokinetic attributes for combination use with ceftazidime. Renal excretion was the major pathway for the clearance of avibactam. In summary, any degree of renal dysfunction is expected to alter the pharmacokinetics of avibactam – this consideration should be factored in dosage adjustments while dosing in patients with renal impairment. Concomitant drugs that may influence renal mechanism of elimination of avibactam should be avoided and/or monitored for any impact on the pharmacokinetics of avibactam.

Key words

Avibactam - ceftazidime - β-lactamase - pharmacokinetics - pharmacodynamics - drug-drug interaction

• References

• 1 Wang DY, Abboud MI, Markoulides MS. et al. The road to avibactam: the first clinically useful non-β-lactam working somewhat like a β-lactam. Future Med Chem 2016; 8: 1063-1084
• 2 Aktas Z, Kayacan C, Oncul O. In vitro activity of avibactam (NXL104) in combination with beta-lactams against Gramnegative bacteria, including OXA-48 beta-lactamase-producing Klebsiella pneumoniae. Int J Antimicrob Agents 2012; 39: 86-89
• 3 Ehmann DE, Jahic H, Ross PL. et al. Kinetics of avibactam inhibition against Class A, C, and D beta-lactamases. J Biol Chem 2013; 288: 27960-27971
• 4 Lagace-Wiens PR, Tailor F, Simner P. et al. Activity of NXL104 in combination with beta-lactams against genetically characterized Escherichia coli and Klebsiella pneumoniae isolates producing class A extended-spectrum beta-lactamases and class C beta-lactamases. Antimicrob Agents Chemother 2011; 55: 2434-2437
• 5 Ehmann DE, Jahic H, Ross PL. et al. Avibactam is a covalent, reversible, non-beta-lactam beta-lactamase inhibitor. Proc Natl Acad Sci USA 2012; 109: 11663-11668
• 6 Lahiri SD, Mangani S, Durand-Reville T. et al. Structural insight into potent broad-spectrum inhibition with reversible recyclization mechanism: avibactam in complex with CTX-M- 15 and Pseudomonas aeruginosa AmpC beta-lactamases. Antimicrob Agents Chemother 2013; 57: 2496-2505
• 7 Singh R, Kim A, Tanudra MA. et al. Pharmacokinetics/pharmacodynamics of a beta-lactam and beta-lactamase inhibitor combination: A novel approach for aztreonam/avibactam. The Journal of antimicrobial chemotherapy 2015; 70: 2618-2626
• 8 Sy S, Zhuang L, Xia H. et al. Prediction of in vivo and in vitro infection model results using a semimechanistic model of avibactam and Aztreonam combination against multidrug resistant organisms. CPT: Pharmacometrics & systems pharmacology 2017; 6: 197-207
• 9 Zhanel GG, Lawson CD, Adam H. et al. Ceftazidime-avibactam: A novel cephalosporin/β-lactamase inhibitor combination. Drugs. 2013; 73: 159-177
• 10 Barber KE, Ortwine JK, Akins RL. Ceftazidime/Avibactam: Who Says You Can't Teach an Old Drug New Tricks?. J Pharm Pharm Sci 2016; 19: 448-464
• 11 AVYCAZ® (ceftazidime and avibactam) for injection, for intravenous use. Product prescribing information ttp://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206494s000lbl.pdf Distributed by Forrest Pharmaceuticals, 2015. Accessed on March 3, 2017
• 12 Sader HS, Castanheira M, Flamm RK. Antimicrobial Activity of Ceftazidime-Avibactam When Tested against Gram-negative Bacteria Isolated from Patients Hospitalized with Pneumonia in United States Medical Centers (2011-2015). Antimicrob Agents Chemother 2017; Jan 9 pii: AAC.02083-16. DOI: 10.1128/AAC.02083.
• 13 Marshall S. HujerAM Rojas LJ. et al. Can ceftazidime/avibactam and aztreonam overcome β-lactam resistance conferred by metallo-β-lactamases in Enterobacteriaceae?. Antimicrob Agents Chemother 2017; Feb 6 pii: AAC.02243-16. DOI: 10.1128/AAC.02243-16.
• 14 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 2015; 35: 307-317
• 15 Zasowski EJ, Rybak JM, Rybak MJ. The b-Lactams strike back: Ceftazidime-Avibactam. Pharmacotherapy 2015; 35: 755-770
• 16 Vishwanathan K, Mair S, Gupta A. et al. Assessment of the mass balance recovery and metabolite profile of avibactam in humans and in vitro drug-drug interaction potential. Drug Metab Dispos 2014; 42: 932-942
• 17 Das S, Li J, Armstrong J. et al. Randomized pharmacokinetic and drug-drug interaction studies of ceftazidime, avibactam, and metronidazole in healthy subjects. Pharmacol Res Perspect 2015; 3: e00172. doi:10.1002/prp2.172
• 18 Li J, Learoyd M, Qiu F. et al. A Randomized, Phase I Study to Assess the Safety, Tolerability and Pharmacokinetics of Ceftazidime-Avibactam in Healthy Chinese Subjects. Clin Drug Investig 2016; 36: 119-126
• 19 Nicolau DP, Siew L, Armstrong J. et al. Phase 1 study assessing the steady-state concentration of ceftazidime and avibactam in plasma and epithelial lining fluid following two dosing regimens. J AntimicrobChemother 2015; 70: 2862-2869
• 20 Veillette JJ, Truong J, Forland SC. Pharmacokinetics of ceftazidime-avibactam in two patients with kpc-producing klebsiella pneumoniae bacteremia and renal impairment. Pharmacotherapy. 2016; 36: e172-e177
• 21 Merdjan H, Tarral A, Das S. et al. Phase 1 study assessing the pharmacokinetic profile and safety of avibactam in patients with renal impairment. J ClinPharmacol 2017; 57: 211-218
• 22 Tarral A, Merdjan H. Effect of age and sex on the pharmacokinetics and safety of avibactam in healthy volunteers. ClinTher 2015; 37: 877-886
• 23 Buckman SA, Krekel T, Muller AE. et al Ceftazidime-avibactam for the treatment of complicated intra-abdominal infections. Expert Opin Pharmacother 2016; 17: 2341-2349
• 24 Lam YW, Duroux MH, Gambertoglio JG. et al. Effect of protein binding on serum bactericidal activities of ceftazidime and cefoperazone in healthy volunteers. Antimicrob Agents Chemother 1988; 32: 298-302
• 25 Dallow J, Otterson LG, Huband MD. et al. Microbiological interaction studies between ceftazidime/avibactam and pulmonary surfactant and between ceftazidime/avibactam and antibacterial agents of other classes. Int J Antimicrob Agents 2014; 44: 552-556
• 26 Maeda K, Tian Y, Fujita T. et al. Inhibitory effects of p-aminohippurate and probenecid on the renal clearance of adefovir and benzylpenicillin as probe drugs for organic anion transporter (OAT) 1 and OAT3 in humans. Eur J Pharm Sci 2014; 59: 94-103
• 27 Srinivas NR. Influence of Morbidly obesity on the clinical pharmacokinetics of various anti-infective drugs: Reappraisal using recent case studies-issues, dosing implications, and considerations. Am J Ther 2016 Jan 13, [Epub ahead of print]
• 28 Tominaga N, Edeki T, Li J. et al. Phase I study assessing the safety, tolerability, and pharmacokinetics of avibactam and ceftazidime-avibactam in healthy Japanese volunteers. Journal of infection and chemotherapy 2015; DOI: 10.1016/j.jiac.2015.04.006.
• 29 Chahine EB, Sourial M, Ortiz R. Ceftazidime/ Avibactam: A new antibiotic for Gram-Negative Infection, Clinical Review. The Consultant Pharmacist 2015; Vol. 30 (No 12) 695–705 DOI: 10.4140/TCP.n.2015.695..
• 30 Das S, Armstrong J, Mathews D. et al. Randomized, placebo-controlled study to assess the impact on QT/QTc Interval of supratherapeutic doses of ceftazedime-avibactam or ceftroline fosamil-avibactam. J Clin Pharm 2013; 54: 331-340
• 31 Riccobene TA, Su SF, Rank D. Single-and multiple-dose study to determine the safety, tolerability, and pharmacokinetics of ceftroline fosamil in combination with avibactam in healthy subjects. Antimcrob. Agents Chemother 2013; 57: 1496-1504
• 32 Merdjan H, Tarral A, Girard AM et al. Safety, Single dose pharmacokinetics and pharmacodynamics of β-Lactamase inhibitor NXL104 in healthy young male adults [Abstract A -809). Paper presented at: 47th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17-20, 2007, Chicago, IL
• 33 Bradley JS, Armstrong J, Arrieta A. et al. Phase I study assessing the pharmacokinetic profile, safety, and tolerability of a single dose of ceftazidime-avibactam in hospitalized pediatric patients. Antimicrobial Agents and Chemotherapy 2016; 60: 6252-6259
• 34 Lagace-Wiens P, Walkty A, Karlowsky JA. Cetazidime-avibactam; an evidence-based review of its pharmacology and potential use in the treatment of Gram-negative bacterial infections. Core evidence 2014; 9: 13-25 doi:10.2147/CE.540698
• 35 Srinivas NR. Clinical Pharmacology Considerations for Development of β Lactamase Inhibitor Combination with Antibiotics. Drug Res (Stuttg) 2018; Apr 9 DOI: 10.1055/a-0590-3791.