Sulbactam and Durlobactam

Sulbactam/durlobactam combination is an antibacterial drug.

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 sulbactam/durlobactam and the pharmacokinetic parameters of sulbactam and durlobactam are summarized in Table 1.

Table 1. Pharmacokinetic Properties (Mean ± SD) of the Components of sulbactam/durlobactam combination:

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 2). 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 2. 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 sulbactam/durlobactam after hemodialysis session.

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 sulbactam/durlobactam (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.

Patients with Hepatic Impairment

Sulbactam and durlobactam are primarily cleared renally; therefore, hepatic impairment is not likely to have any effect on sulbactam/durlobactam exposures.

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 sulbactam/durlobactam and OAT1 inhibitors.