Randomized pharmacokinetic and drug-drug interaction studies of ceftazidime, avibactam, and metronidazole in healthy subjects

Abstract

We assessed pharmacokinetic and safety profiles of ceftazidime-avibactam administered ± metronidazole, and whether drug-drug interactions exist between ceftazidime and avibactam, or ceftazidime-avibactam and metronidazole. The first study (NCT01430910) involved two cohorts of healthy subjects. Cohort 1 received ceftazidime-avibactam (2000-500 mg) as a single infusion or as multiple intravenous infusions over 11 days to evaluate ceftazidime-avibactam pharmacokinetics. Cohort 2 received ceftazidime, avibactam, or ceftazidime-avibactam over 4 days to assess drug-drug interaction between ceftazidime and avibactam. The second study (NCT01534247) assessed interaction between ceftazidime-avibactam and metronidazole in subjects receiving ceftazidime-avibactam (2000-500 mg), metronidazole (500 mg), or metronidazole followed by ceftazidime-avibactam over 4 days. In all studies, subjects received a single-dose on the first and final days, and multiple-doses every 8 h on intervening days. Concentration-time profiles for ceftazidime and avibactam administered as single- or multiple-doses separately or together with/without metronidazole were similar. There was no evidence of time-dependent pharmacokinetics or accumulation. In both interaction studies, 90% confidence intervals for geometric least squares mean ratios of area under the curve and maximum plasma concentrations for each drug were within the predefined interval (80-125%) indicating no drug-drug interaction between ceftazidime and avibactam, or ceftazidime-avibactam and metronidazole. There were no safety concerns. In conclusion, pharmacokinetic parameters and safety of ceftazidime, avibactam, and metronidazole were similar after single and multiple doses with no observed drug-drug interaction between ceftazidime and avibactam, or ceftazidime-avibactam and metronidazole.

Keywords: Avibactam; ceftazidime; drug–drug interaction; infectious disease; pharmacokinetics.

Figures

Figure 1

Geometric mean (±SD) plasma concentration-time profiles of (A) ceftazidime and (B) avibactam following single and multiple doses in the CAZ-AVI PK part of the CAZ and AVI drug–drug interaction study. Linear (top) and semilog scales (bottom) are shown. AVI, avibactam; CAZ, ceftazidime; SD, standard deviation.

Figure 2

Geometric mean (±SD) plasma concentration-time profiles in the CAZ and AVI interaction part of the CAZ and AVI drug–drug interaction study for (A) ceftazidime 2000 mg when administered singly and in combination with avibactam 500 mg, on linear (top) and semilog scales (bottom), and (B) avibactam 500 mg when administered singly and in combination with ceftazidime 2000 mg, on linear (top) and semilog scales (bottom). AVI, avibactam; CAZ, ceftazidime; SD, standard deviation. *Compared with other subjects in the ceftazidime–avibactam group, one subject had very low concentrations of CAZ on Day 4, and the data were excluded from the Day 4 analysis. Pharmacokinetic parameters for avibactam on Day 4 in the same subject appeared similar to those in other subjects in the same group and were therefore included in the analysis.

Figure 3

Geometric mean (SD) plasma concentration-time profiles on Day 4 of the CAZ-AVI and MTZ interaction study for ceftazidime (A) and avibactam (B) when administered as ceftazidime 2000 mg-avibactam 500 mg or ceftazidime 2000 mg-avibactam 500 mg plus metronidazole 500 mg, and for metronidazole (C) when administered as metronidazole 500 mg or ceftazidime 2000 mg-avibactam 500 mg plus metronidazole 500 mg. Linear (top) and semilog scales (bottom) are shown. AVI, avibactam; CAZ, ceftazidime; MTZ, metronidazole; SD, standard deviation. aOne subject did not receive the infusion of metronidazole alone as he withdrew consent prior to commencing treatment in period 3 (see main text). bOne subject had a metronidazole infusion 20-min longer than planned on Day 4 during the ceftazidime 2000 mg-avibactam 500 mg plus metronidazole 500 mg treatment, and the metronidazole data were excluded from the Day 4 analysis.

Figure 4

No drug–drug interaction was observed between ceftazidime and avibactam as demonstrated by the geometric LS mean (90% CI) ratios (shown as percentages) of (A) ceftazidime pharmacokinetic parameters when administered in combination as ceftazidime 2000 mg-avibactam 500 mg or separately as ceftazidime 2000 mg alone, and (B) avibactam pharmacokinetic parameters when administered in combination as ceftazidime 2000 mg-avibactam 500 mg or separately as avibactam 500 mg alone. Predefined intervals for no interaction effect are indicated by the dotted lines (data from CAZ and AVI interaction part of the CAZ and AVI drug–drug interaction study, n = 27). AVI, avibactam; AUC, area under the curve; AUC(0-τ), AUC during the dosing interval; CAZ, ceftazidime; CI, confidence interval; Cmax, maximum plasma concentration; LS, least-squares; PK, pharmacokinetic.

Figure 5

No drug–drug interaction was observed between ceftazidime–avibactam and metronidazole as demonstrated by the geometric LS mean (90% CI) ratios (shown as percentages) for pharmacokinetic parameters of (A) ceftazidime and (B) avibactam when administered as ceftazidime 2000 mg-avibactam 500 mg plus metronidazole 500 mg or ceftazidime 2000 mg-avibactam 500 mg, and (C) metronidazole when administered as ceftazidime 2000 mg-avibactam 500 mg plus metronidazole 500 mg or metronidazole 500 mg. Predefined intervals for no interaction effect are indicated by dotted line (data from CAZ-AVI and MTZ interaction study, n = 28) AVI, avibactam; AUC, area under the curve; AUC(0-τ), AUC during the dosing interval; CAZ, ceftazidime; CI, confidence interval; Cmax, maximum plasma concentration; LS, least-squares; MTZ, metronidazole; PK, pharmacokinetic.