XACDURO Kit for injection Ref.[107381] Active ingredients: Sulbactam Sulbactam and Durlobactam

For sulbactam, the percent time of dosing interval that unbound plasma concentrations of sulbactam exceed the minimum inhibitory concentration (MIC) of A. baumannii has been shown to be the best predictor of efficacy in animal and in vitro models of infection. For durlobactam, the ratio of the 24-hour unbound plasma durlobactam AUC to the sulbactam-durlobactam MIC (fAUC_0–24/MIC) best predicts the activity in in vivo and in vitro models of infection.

Cardiac Electrophysiology

At a dose 4 times the maximum recommended single dose, durlobactam does not prolong the QTc interval to any clinically relevant extent.

Sulbactam and durlobactam pharmacokinetics are similar following single- and multiple-dose administrations. The C_max and AUC of sulbactam increase in proportion to dose (0.5 times the recommended single dose to 1 g single dose). Durlobactam demonstrated dose-proportional pharmacokinetics across the dose range studied (0.25 times the recommended single dose to 2 times the recommended single dose infused over 3 hours every 6 hours).

The pharmacokinetic properties of the components of XACDURO and the pharmacokinetic parameters of sulbactam and durlobactam are summarized in Table 3.

Table 3. Pharmacokinetic Properties (Mean ± SD) of the Components of XACDURO:

AUC_0-6 = area under the plasma concentration time curve from time of dosing to 6 hours post dose; AUC_0-24 = area under the plasma concentration time curve from time of dosing to 24 hours; CL = clearance; C_max = maximum concentration; ELF = epithelial lining fluid; SD = standard deviation, T_1/2 = terminal half-life; V_ss = volume of distribution at steady state
^* Pharmacokinetic parameters are presented at steady state (Day 3) in patients with normal renal function defined as creatinine clearance of greater than or equal to 90 mL/min and less than 130 mL/min at a dosage of 1 g sulbactam and 1 g durlobactam every 6 hours.

Specific Populations

No clinically significant differences in the pharmacokinetics of sulbactam or durlobactam were observed based on age (18-91 years), gender, weight (35-150 kg), and race (White, Black, Asian, American Indian/Alaska Native, Other).

Patients with Renal Impairment

In a single-dose trial evaluating the effect of renal impairment on the pharmacokinetics of sulbactam and durlobactam, dose normalized systemic exposures of sulbactam and durlobactam were higher at all levels of renal impairment compared to healthy subjects with CLcr greater than or equal to 90 mL/min (Table 4). In subjects with end stage renal disease (ESRD) on hemodialysis, the fraction of the dose removed by hemodialysis was 0.41 and 0.33 for sulbactam and durlobactam, respectively.

Table 4. Dose Normalized Fold AUC Increase in Subjects with Renal Impairment Compared to Subjects with CLcr ≥90 mL/min:

To maintain systemic exposures similar to patients with normal renal function, dosage adjustment is recommended for patients with renal impairment. Patients on hemodialysis should receive XACDURO after hemodialysis session [see Dosage and Administration (2.2), Specific Populations (8.6)].

Patients with CLcr 130 mL/min or Greater:

Increased sulbactam and durlobactam clearance have been observed in patients with CLcr of 130 mL/min or greater. A XACDURO (1.0 g sulbactam and 1.0 g durlobactam) dose every 4 hours infused over 3 hours provided sulbactam and durlobactam exposures comparable to those in patients with CLcr 90 to 129 mL/min [see Dosage and Administration (2.2), Use in Specific Populations (8.6)].

Patients with Hepatic Impairment

Sulbactam and durlobactam are primarily cleared renally; therefore, hepatic impairment is not likely to have any effect on XACDURO exposures [see Use in Specific Populations (8.7)].

Drug Interaction Studies

Clinical Studies

No drug-drug interactions were observed among durlobactam, sulbactam, imipenem, and cilastatin in a clinical study in healthy subjects.

In Vitro Studies Where Drug Interaction Potential Was Not Further Evaluated Clinically Cytochrome P450 (CYP) Enzymes

At therapeutic plasma concentrations, durlobactam does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4. Durlobactam showed no potential for in vitro induction of CYP1A2, CYP2B6, or CYP3A4.

No in vitro studies with CYP450 and sulbactam were conducted.

Membrane Transporter Systems

In vitro data showed that sulbactam did not inhibit P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, BSEP, OAT1, OAT3, MATE1, or MATE2-K at therapeutic plasma concentrations. In vitro data also indicated that durlobactam did not inhibit P-gp, BCRP, OATP1B1, OAT1, OAT3, or OCT2 at therapeutic plasma concentrations. Sulbactam and durlobactam are both substrates of OAT1. However, only sulbactam is predicted to have active secretion as a significant portion of total clearance; therefore, inhibition of OAT1 may increase sulbactam plasma concentrations. No clinical studies have been conducted with XACDURO and OAT1 inhibitors [see Drug Interactions (7.1)].

Mechanism of Action

XACDURO is a co-packaged product containing sulbactam and durlobactam. Sulbactam is a beta-lactam antibacterial and Ambler Class A serine beta-lactamase inhibitor that has bactericidal activity due to its inhibition of Acinetobacter baumannii-calcoaceticus complex (ABC) penicillin-binding proteins PBP1 and PBP3, which are essential enzymes required for bacterial cell wall synthesis.

Durlobactam is a diazabicyclooctane non-beta-lactam, beta-lactamase inhibitor, that protects sulbactam from degradation by certain serine-beta-lactamases. Durlobactam alone does not have antibacterial activity against ABC isolates.

XACDURO demonstrated in vitro activity against ABC isolates expressing serine beta-lactamases included in Ambler Class A (CTX-M-, TEM-, PER- and SHV-type extended spectrum beta-lactamases [ESBLs], KPC carbapenemase) Class C (ADC-type) and broad spectrum activity against Class D (OXA-type) enzymes.

Resistance

Mechanisms of beta-lactam resistance in ABC isolates may include either the production of beta-lactamases, modification of PBPs or target alteration, up-regulation of efflux pumps or loss of outer membrane porin.

XACDURO is not active against ABC isolates that produce Ambler Class B metallo-beta-lactamases or have modification of active target site of sulbactam (i.e., PBPs). Isolates may also produce in combination multiple beta-lactamases, express varying levels of beta-lactamases, have amino acid PBPs sequence variations or other resistance mechanisms that may contribute to resistance.

Interaction with Other Antimicrobials

In vitro studies showed no antagonism between XACDURO and other antibacterial drugs including ceftazidime-avibactam, imipenem, meropenem, amikacin, colistin, cefepime, ciprofloxacin, minocycline, rifampicin, rifaximin, daptomycin, dalbavancin, oritavancin, tedizolid, fidaxomicin, vancomycin, linezolid, metronidazole, and fluconazole.

Animal Models of Infection

Durlobactam restored activity of sulbactam in animal models of infection (including neutropenic mouse thigh and lung infections) against XACDURO-susceptible A. baumannii strains.

Antimicrobial Activity

XACDURO has been shown to be active against most isolates of the following microorganisms both in vitro and in clinical infections [see Indications and Usage (1.1)].

Acinetobacter baumannii-calcoaceticus complex

Susceptibility Testing

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for XACDURO, please see: https://www.fda.gov/STIC.

Carcinogenesis

Carcinogenicity studies with XACDURO have not been conducted.

Mutagenesis

Durlobactam was negative in genetic toxicology studies including the Salmonella typhimurium bacterial reverse mutation assay, in vivo and in vitro micronucleus assays, and the in vivo Pig-A assay in rats.

Genetic toxicology studies were not conducted with sulbactam or the combination of sulbactam-durlobactam.

Impairment of Fertility

No adverse effects on fertility, reproductive performance, fetal viability, growth, or postnatal development were observed in male and female rats, and female mice for durlobactam at intravenous doses up to 1000 mg/kg/day (approximately 4 times the MRHD based on AUC comparisons) and subcutaneous doses up to 1600 mg/kg/day, (equivalent to 4 times the MRHD based on AUC comparisons) respectively.

Treatment of Hospital-acquired and Ventilator-associated Bacterial Pneumonia Caused by Acinetobacter baumannii-calcoaceticus Complex Organisms

A total of 177 hospitalized adults with documented Acinetobacter baumannii-calcoaceticus complex infections were randomized and treated in a multicenter, active-controlled, investigator-unblinded, independent assessor-blinded, non-inferiority, phase 3 trial (Trial 1, NCT03894046). Patients were treated with either XACDURO (1 g sulbactam and 1 g durlobactam, or renally adjusted dose) intravenously over 3 hours every 6 hours (n=91) or colistin 2.5 mg/kg (or renally adjusted dose) intravenously over 30 minutes every 12 hours after an initial loading dose of colistin 2.5 to 5 mg/kg (n=86). Both treatment arms also received 1 g imipenem/1 g cilastatin (or renally adjusted dose) intravenously every 6 hours as background therapy for potential HABP/VABP pathogens other than Acinetobacter baumannii-calcoaceticus complex. Patients received up to 14 days of therapy.

The primary efficacy endpoint for the study was 28-day all-cause mortality in the patients who received any amount of study medication with a confirmed baseline infection with carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex (CRABC microbiologically modified intent to treat (m-MITT) population). Among 128 patients in the CRABC m-MITT population, 125 patients who did not withdraw consent prior to assessment of survival status at Day 28 were assessed: 63 patients in the XACDURO group and 62 patients in the colistin group.

The demographic and baseline characteristics were comparable between treatment groups among 125 patients in the analysis: 74% male, 50% White, and 44% Asian; the mean age was 63 (±17) years. The majority of patients had pneumonia as the baseline infection (53% VABP and 43% HABP); 2% had bacteremia. The mean Acute Physiology and Chronic Health Evaluation II (APACHE II) score at baseline was 17, and 26% of patients had an APACHE II score ≥ 20. At randomization, 64% of patients had been in the ICU ≥5 days, 26% of patients had been in the ICU for >14 days, and 75% were mechanically ventilated. Approximately 39% of patients had CLcr less than 90 mL/min at baseline. The mean duration of treatment was 9 days for the XACDURO group and 8 days for the colistin group.

Table 5 shows results for the primary endpoint of Day 28 all-cause mortality in the CRABC m-MITT population. XACDURO was non-inferior to colistin with regard to Day 28 all-cause mortality.

Table 5. All-cause Mortality at Day 28 (CRABC m-MITT Population):

CI = Confidence Interval
^* Percentage was calculated using N, the number of patients in the specified population, as the denominator.
^† The 95% CI (2-sided) was computed using a continuity-corrected z statistic.

Clinical cure rates were also evaluated. Clinical cure was defined as complete resolution or significant improvement of signs and symptoms that were present at baseline and no new symptoms, such that no additional gram-negative antimicrobial therapy was warranted. Clinical cure rates in the CRABC m-MITT population at the Test of Cure (TOC) Visit that was 7 days (±2 days) after the end of treatment were 39/63 (61.9%) for XACDURO versus 25/62 (40.3%) for colistin.