Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of the β-Lactamase Inhibitor Vaborbactam (RPX7009) in Healthy Adult Subjects

Abstract

Vaborbactam (formerly RPX7009) is a member of a new class of β-lactamase inhibitor with pharmacokinetic properties similar to those of many β-lactams, including carbapenems. The pharmacokinetics and safety of vaborbactam were evaluated in 80 healthy adult subjects in a first-in-human randomized, placebo-controlled, double-blind, sequential single- and multiple-ascending-dose study. A total of 10 dose cohorts were enrolled in the study, with 6 subjects randomized to receive 250 to 2,000 mg of vaborbactam and 2 subjects randomized to receive placebo in each cohort. Maximum concentrations for vaborbactam were achieved at the end of the 3-h infusion. Vaborbactam exposure (C_max and area under the concentration-time curve [AUC]) increased in a dose-proportional manner following multiple doses. There was no evidence of accumulation with multiple doses, consistent with the terminal half-life of ∼2 h. Both the volume of distribution (V_ss) and plasma clearance were independent of dose. For the 2,000-mg dose, the plasma clearance was 0.17 ± 0.03 liters/h, the AUC from 0 h to infinity (AUC_0–∞) was 144.00 ± 13.90 mg · h/liter, and the V_ss was 21.80 ± 2.26 mg · h/liter. Urinary recovery was 80% or greater over 48 h across all dose groups. No subjects discontinued the study due to adverse events (AEs), and no serious AEs (SAEs) were observed. All AEs were mild to moderate and similar among the vaborbactam- and placebo-treated subjects, with mild lethargy as the only unique AE reported with the high dose of vaborbactam. Overall, this study revealed the safety, tolerability, and pharmacokinetic profile of vaborbactam and formed the basis for advancement into patient studies in combination with meropenem, including treatment of patients with carbapenem-resistant Enterobacteriaceae (CRE) infections. (This study is registered at ClinicalTrials.gov under identifier NCT01751269.)

INTRODUCTION

Resistance to multiple antimicrobial agents in Gram-negative bacteria threatens the ability of clinicians to treat even the most common human pathogens. Recent data indicate that a growing proportion of US health care facilities have isolated carbapenem-resistant Enterobacteriaceae (CRE) from patients, and virtually every US state with major population centers has reported recovery of such isolates (1). The Centers for Disease Control and Prevention (CDC) recently designated CRE as an urgent antimicrobial resistance threat (1).

Vaborbactam is a member of a new cyclic boronic acid class of β-lactamase inhibitors with activity against serine carbapenemases, especially Klebsiella pneumonia carbapenemase (KPC) (2). Vaborbactam is being developed in combination with meropenem. The combination has potent in vitro and in vivo activities against carbapenem-resistant KPC-producing strains of Enterobacteriaceae (3, 4, 5). Against a panel of 121 carbapenem-resistant KPC-producing strains of K. pneumoniae, the meropenem-vaborbactam MIC₉₀ was 0.5/8 μg/ml (4), and in a neutropenic mouse thigh infection model, the addition of vaborbactam to meropenem produced significant bacterial killing compared to that produced by meropenem alone against carbapenem-resistant KPC-containing Escherichia coli, Enterobacter cloacae, and K. pneumoniae (5). The purpose of this first-in-human study was to determine the safety and pharmacokinetic (PK) profile of vaborbactam following single and multiple ascending doses in healthy adult subjects. A fixed-dose combination product of meropenem (2 g) and vaborbactam (2 g) (meropenem-vaborbactam) is currently under phase 3 clinical investigation for the treatment of complicated urinary tract infection, acute pyelonephritis, and serious infections due to CRE, including hospital-acquired and ventilator-associated pneumonia (ClinicalTrials.gov identifiers NCT02166476 and NCT02168946).

(This work was presented in part at the 24th European Congress of Clinical Microbiology and Infectious Diseases, Barcelona, Spain, 10 to 13 May 2014.)

MATERIALS AND METHODS

Study Design.

Plasma and urine pharmacokinetics of vaborbactam were investigated in a phase 1 healthy-volunteer study (ClinicalTrials.gov identifier NCT01751269). The study was conducted at a phase 1 facility in Adelaide, Australia (CMAX, Royal Adelaide Hospital, North Terrace, Adelaide, Australia). As dose-limiting toxicity was not observed with vaborbactam in repeat dose toxicology studies in dogs up to doses of 1,000 mg/kg of body weight/day (human equivalent dose of 10 g/day) (6), a conservative starting dose of 250 mg (40-fold safety factor) was selected. In addition, preclinical pharmacokinetic studies and allometric scaling suggested that vaborbactam pharmacokinetics would be similar to that of carbapenems. The maximum dose studied (2,000 mg) was based on meeting exposure targets established in nonclinical PK-pharmacodynamics (PD) and resistance development studies (7). A total of 80 patients were enrolled and formed a total of 10 dose cohorts in a 3:1 ratio, with 6 subjects randomized to receive vaborbactam and 2 subjects randomized to receive placebo in each cohort. Subjects participated in only one cohort each. The length of participation in the study for each subject (excluding screening) was approximately 4 days for the single-dose cohorts (cohorts 1 through 6) and 11 to 13 days for the single- and multiple-dose cohorts (cohorts 7 through 10).

The main inclusion criteria for the study were that subjects be male or female of nonchildbearing potential, be a nonsmoker for the previous 6 months, be aged 18 to 55 years, have a body mass index (BMI) within the range of 18.5 to 29.9 kg/m², and have no significant illness. Subjects were excluded if they had a history of being HIV, HBsAg, or hepatitis C virus positive, an excessive drinker (>3 drinks per day or >21 drinks per week), on any medications other than oral contraceptives, or pregnant or lactating, had a creatinine clearance of <80 ml/min, or had a corrected QT, Fridericia's formula (QTcF) of >450 at screening. Additionally, all subjects were required to sign an informed consent approved by a local ethics committee prior to undergoing any screening or study activities. After informed consent was obtained, a medical history, physical examination, and electrocardiography were conducted. Blood was drawn to test for abnormalities and alcohol abuse, and vital signs and concomitant medications were recorded. Subjects were required to complete the screening procedures within 28 days prior to entering the study. If subjects passed the screening procedures and were found to be eligible for the study, they were randomized. Randomization occurred via a computerized randomization scheme created by an unblinded statistician. The randomization scheme was available to only the clinic pharmacy staff who prepared the study drug. It was not available to the sponsor, study subjects, or members of the staff responsible for the monitoring and evaluation of safety assessments.

Subjects randomized to vaborbactam in the first 6 cohorts received single doses of vaborbactam administered as a 3-h constant rate intravenous infusion: 250, 500, 750, 1,000, 1,250, and 1,500 mg. Subjects were confined in the clinic the day prior to infusion until approximately 96 h after the dose on day 1. Patients were not discharged until all follow-up procedures were completed; therefore, the total duration of participation (excluding the screening period) for each subject was approximately 4 days. The remaining 4 cohorts (cohorts 7 through 10) received the following doses of vaborbactam as a 3-h infusion, first as a single dose and subsequently every 8 h for 7 days: 250, 1,000, 1,500, and 2,000 mg. Subjects in cohorts 7 to 10 were confined in the clinic the day prior to infusion until approximately 72 h after the last dose on day 8. Patients were not discharged until all follow-up procedures were completed. The total duration of participation (excluding the screening period) for each subject was approximately 11 days (13 days in cohort 10). The same menu and meal schedule were administered uniformly to subjects in all the cohorts.

This study was conducted in compliance with the protocol and all regulatory requirements in accordance with good clinical practice (GCP), including the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines, and in general conformity with the most recent version of the Declaration of Helsinki. The protocol, the informed consent document, and all relevant supporting data were reviewed and approved by the Bellberry Human Research Ethics Committee. Training of all study staff occurred before any study activities were delegated. Frequent site visits were conducted by sponsor representatives to inspect study data, the subjects' medical records, and electronic case report forms (eCRFs) in accordance with ICH guidelines, GCP requirements, and national regulations and guidelines.

Safety.

Safety was assessed throughout the study via medical history, physical examination, monitoring of vital signs, electrocardiograms (ECGs), and clinical safety labs before and through 96 h after dosing for cohorts 1 through 6 and before and through 72 h after dosing for cohorts 7 through 10. Additionally, safety was monitored by subject self-reports of adverse events (AEs) and specific inquiries to subjects regarding symptoms. Subjects with more than 1 episode of the same adverse event were recorded only once in the per-subject analysis.

Following each cohort and between the single- and multiple-dose phases of cohort 10, the principal investigator and the sponsor reviewed all pertinent blinded safety data (e.g., physical examinations, vital signs, ECGs, clinical laboratory tests, and AEs, including those from previous cohorts, and determined to (i) continue with the study/cohorts as planned, (ii) continue with the study and add additional safety evaluations, (iii) continue with the study by repeating the dose and adjusting to a dose between the current dose and the next planned dose or adjust to a dose between the current dose and the previous lower dose, or (iv) stop dose escalation of the study. All cohorts proceeded as planned with dose escalations.

Pharmacokinetic samples.

Blood samples for the measurement of vaborbactam concentrations in plasma were obtained predose (time zero) and 1.5, 3, 3.167, 3.333, 3.5, 3.75, 4, 5, 6, 7, 8, 12, and 24 h after the start of infusion. All blood samples (approximately 2 ml) were obtained via an indwelling intravenous cannula, collected into EDTA-containing tubes, immediately placed on ice, and centrifuged at 3,000 × g for 15 min. Supernatant plasma was transferred to screw-cap tubes and stored at −80°C until shipped to the analytical laboratory. Postdose urine was collected during the following intervals: 0 to 4, 4 to 8, 8 to 12, 12 to 24, and 24 to 48 h after the start of infusion. Urine samples were frozen at −80°C until shipment to the analytical laboratory. Plasma and urine samples were analyzed using a validated high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method (MicroConstants, San Diego, CA). The lower limit of quantitation in both matrices was 0.2 mg/liter. The intraday and interday coefficients of variation (CV) for both matrices were 2.4% to 9.8%.

Pharmacokinetic analyses.

Analyses of the plasma and urine were performed using noncompartmental methods (WinNonlin Professional 6.1.1; Pharsight Corp., Mountain View, CA, USA). The pharmacokinetic parameters that were determined included peak (C_max), time to maximum concentration (T_max), area under the curve (AUC), half-life (t_1/2), clearance (CL), volume of distribution (V), renal clearance (CL_R), and nonrenal clearance (CL_NR). Renal clearance (CL_R) was calculated using the following equation: CL_R = Ae_0–τ/AUC_0–τ, where Ae_0–τ is the cumulative amount of compound excreted in the urine over the dosing interval, and AUC_0–τ is the area under the plasma concentration-time curve from time zero to the end of the dosing interval.

Serum protein binding.

Vaborbactam serum protein binding was determined using ultrafiltration at concentrations of 1, 5, 15, and 50 μg/ml. Sera were spiked with vaborbactam and incubated at 37°C for 15 min. Aliquots (500 μl) of spiked or spiked prefiltered serum were added to the upper reservoir of a Centrifree cartridge (YM-30, Millipore, Bedford, MA) and centrifuged at 2,000 × g for 15 min at room temperature. The filtrates were analyzed by liquid chromatography-mass spectrometry. The peak areas were used to calculate serum protein binding as follows: percent serum bound = 100 − (ASF/ASWF × 100), where ASF is the peak area of vaborbactam from spiked serum after ultrafiltration, and ASWF is the peak area of vaborbactam from spiked ultrafiltered serum after ultrafiltration.

RESULTS

Demographics.

Baseline subject demographics are shown in Table 1. Most subjects were white men approximately 30 years of age.

TABLE 1.

Baseline demographics

Parameter	Single ascending dose		Multiple ascending doses
	All vaborbactam (n = 42)	Pooled placebo (n = 14)	All vaborbactam (n = 24)	Pooled placebo (n = 8)
Race (n [%])
White	39 (93)	13 (93)	22 (92)	7 (88)
White/Maori			1 (4)
Maori	1 (2)		1 (4)
Native Hawaiian or other Pacific Islander		1 (7)
Asian	2 (5)			1 (13)
Sex (n [%])
Femalea	2 (5)		2 (8)
Male	40 (95)	14 (100)	22 (92)	8 (100)
Age (yrs)
Mean (SD)	30.2 (10.8)	26.5 (7.6)	30.0 (10.0)	26.9 (4.8)
Median	26.0	25.0	26.0	26.0
Range	18–55	19–49	21–49	20–33
Height (cm)
Mean (SD)	178.7 (7.3)	182.8 (4.4)	178.0 (5.8)	179.5 (7.7)
Median	179.5	181.0	179.5	182.0
Range	158–192	177–193	164–189	169–188
Weight (kg)
Mean (SD)	79.40 (9.25)	81.35 (10.72)	80.37 (10.99)	76.14 (13.57)
Median	81.80	79.45	81.35	72.90
Range	62.4–99.1	68.5–107.6	62.4–99.1	60.2–99.6
BMI (kg/m2)
Mean (SD)	24.86 (2.66)	24.36 (3.10)	25.33 (3.03)	23.53 (3.17)
Median	24.55	24.70	25.50	22.85
Range	19.0–29.6	19.4–28.9	19.1–29.8	20.2–29.7
Creatinine clearance (ml/min)
Mean (SD)	137.69 (27.20)	134.87 (17.01)	149.29 (29.44)	131.11 (26.03)
Median	137.75	133.40	149.95	120.65
Range	91.8–205.9	110.3–165.8	99.6–201.0	99.4–170.0

^aOnly women of nonchildbearing potential were enrolled.

Pharmacokinetics. (i) Protein binding.

The average serum protein binding level across the range studied was 33%. The protein binding levels were similar at all concentrations tested.

(a) Single-dose pharmacokinetics.

Vaborbactam plasma concentrations are shown in Fig. 1, and the pharmacokinetic parameters are shown in Table 2. The mean C_max values ranged from 5.03 ± 0.860 μg/ml for the 250-mg dose to 41.6 ± 4.75 μg/ml for the 2,000-mg dose; the corresponding mean AUC_0–∞ ranged from 16.6 ± 3.24 to 144 ± 13.9 μg · h/ml. The exposure of vaborbactam (C_max and AUC_0–∞) following single dosing increased proportional to dose (Figs. 1 and 2, Table 2). The mean vaborbactam plasma clearance ranged from 12.8 ± 2.36 to 15.6 ± 2.63 liters/h, and the mean volume at steady state (V_ss) ranged from 20.2 ± 2.43 to 25.4 ± 2.96 liters (Table 2). The mean weight-normalized vaborbactam CL ranged from 0.16 ± 0.02 to 0.20 ± 0.03 liters/h/kg, and the mean weight-normalized V_ss ranged from 0.27 ± 0.04 to 0.33 ± 0.042 liters/kg (Table 2). The mean values for percent urinary excretion (fe_0–24) ranged from 80.3 ± 9.94% to 105 ± 15.1% (Table 2). The mean values for CL_R ranged from 11.5 ± 2.58 to 15.1 ± 2.55 liters/h (Table 2). The mean values for CL_NR ranged from 1.00 to 2.90 liters/h. In general, the CL_R constituted ∼80% to 90% of the total clearance of vaborbactam.

FIG 1.

Mean (± SD) vaborbactam plasma concentration-versus-time profiles following 3-h intravenous infusions of 250 to 2,000 mg in healthy volunteers.

TABLE 2.

Pharmacokinetic parameters of vaborbactam following a single dose or 7 days of multiple doses^a

Parameter	PK values for vaborbactam dose (mg)b
	250		500	750	1,000		1,250	1,500		2,000
	S (n = 12)	M (n = 6)	S (n = 6)	S (n = 6)	S (n = 12)	M (n = 5)	S (n = 6)	S (n = 12)	M (n = 6)	S (n = 6)	M (n = 6)
Cmax (μg/ml)	5.03 ± 0.86	4.81 ± 1.04	9.97 ± 0.95	15.30 ± 2.76	21.80 ± 3.83	21.30 ± 6.63	27.80 ± 3.67	32.90 ± 5.77	33.40 ± 4.48	41.60 ± 4.75	40.90 ± 4.68
T1/2 (h)	1.17 ± 0.15	1.17 ± 0.13	1.35 ± 0.22	1.24 ± 0.33	1.41 ± 0.28	1.43 ± 0.36	1.32 ± 0.47	1.40 ± 0.31	1.65 ± 0.26	1.51 ± 0.08	1.66 ± 0.10
AUC0–τ (μg · h/ml)	16.2 ± 3.17	16.30 ± 3.56	34.50 ± 4.87	50.60 ± 7.51	76.70 ± 13.20	74.60 ± 17.90	97.20 ± 14.80	110.00 ± 18.90	118.00 ± 15.30	140.00 ± 13.50	145.00 ± 15.80
AUC(0–∞), μg · h/ml)	16.6 ± 3.24		35.60 ± 5.21	51.80 ± 8.03	79.30 ± 14.20		100.00 ± 17.40	114.00 ± 20.00		144.00 ± 13.90
CL (liters/h)	15.6 ± 2.63	15.20 ± 2.56	14.30 ± 2.28	14.80 ± 2.24	13.10 ± 2.59	14.10 ± 3.42	12.80 ± 2.36	13.50 ± 2.17	12.90 ± 1.71	14.00 ± 1.40	14.00 ± 1.78
CLR (liters/h)	12.70 ± 2.71	12.70 ± 3.68	11.80 ± 1.63	13.00 ± 2.08	12.10 ± 2.43	11.70 ± 3.75	11.50 ± 2.58	11.80 ± 1.88	11.20 ± 1.72	15.10 ± 2.55	12.80 ± 2.05
CLNR (liters/h)	2.85 ± 3.11	2.49 ± 3.27	2.55 ± 1.92	1.72 ± 0.80	0.97 ± 0.92	2.31 ± 1.21	1.33 ± 1.31	1.42 ± 1.17	1.68 ± 0.13	−1.07 ± 2.13	1.15 ± 0.68
Vss (liters)	24.5 ± 5.81		25.40 ± 2.96	23.20 ± 3.97	21.00 ± 3.03		20.20 ± 2.43	23.00 ± 4.76		21.80 ± 2.26
Vdβ (liters)	26.2 ± 5.30	25.70 ± 5.57	27.70 ± 4.64	23.20 ± 3.97	25.90 ± 3.80	28.00 ± 5.66	20.20 ± 2.43	26.90 ± 5.39	30.30 ± 3.48	30.60 ± 4.45	33.40 ± 4.52
CL (liters/h/kg)	0.20 ± 0.03	0.20 ± 0.02	0.19 ± 0.02	0.19 ± 0.04	0.17 ± 0.02	0.18 ± 0.02	0.18 ± 0.04	0.16 ± 0.02	0.15 ± 0.01	0.17 ± 0.03	0.17 ± 0.02
Vss (liters/kg)	0.31 ± 0.06		0.33 ± 0.04	0.30 ± 0.09	0.28 ± 0.02		0.29 ± 0.05	0.28 ± 0.05		0.27 ± 0.04
Vdβ (liters/kg)	0.33 ± 0.06	0.34 ± 0.06	0.37 ± 0.07	0.34 ± 0.10	0.33 ± 0.06	0.36 ± 0.05	0.33 ± 0.10	0.33 ± 0.07	0.37 ± 0.07	0.38 ± 0.07	0.41 ± 0.05
Urinary recovery (%)	81.30 ± 16.60	79.90 ± 16.30	80.30 ± 9.94	86.40 ± 5.05	89.90 ± 6.97	82.80 ± 10.30	86.90 ± 9.71	86.60 ± 7.22	86.80 ± 2.48	105.00 ± 15.10	91.60 ± 5.36

^aValues shown are means ± SD.

^bS, single dose; M, multiple dose.

FIG 2.

Linear regression of vaborbactam exposure as a function of dose.

(b) Multiple-dose pharmacokinetics.

Following 7 days of vaborbactam infused over 3 h every 8 h (q8h) at doses ranging from 250 to 2,000 mg, mean C_max values ranged from 4.81 ± 1.04 μg/ml for the 250-mg dose to 40.9 ± 4.68 μg/ml for the 2,000 mg dose. The corresponding mean AUC_0–τ ranged from 16.3 ± 3.56 to 145 ± 15.8 μg · h/ml. The exposure of vaborbactam (C_max and AUC_0–τ) following multiple doses increased proportionally with the administered dose (Fig. 2). Vaborbactam plasma concentrations did not accumulate following repeated dosing. The mean CL following multiple doses ranged from 12.9 ± 1.71 to 15.2 ± 2.56 liters/h, and the mean V ranged from 25.7 ± 5.57 to 33.4 ± 4.52 liters (Table 2). The mean weight-normalized vaborbactam CL ranged from 0.15 ± 0.01 to 0.20 ± 0.02 liters/h/kg, and the mean weight-normalized V values ranged from 0.34 ± 0.06 to 0.41 ± 0.05 liters/kg. The mean values for the percent urinary excretion (fe_0–8) (dosing interval) following 7 days of q8h dosing ranged from 79.9 ± 16.3% to 91.6 ± 5.36%. Urinary excretion of vaborbactam following repeated dosing was equal to that following a single dose (Table 2). The mean values for CL_R following multiple doses ranged from 11.2 ± 1.72 to 12.8 ± 2.05 liters/h (Table 2). The mean values for CL_NR ranged from 1.20 to 2.50 liters/h (Table 2). As was observed following a single dose, CL_R constituted ∼80% to 90% of the total clearance of vaborbactam. The mean ratio of day 7/day 1 renal clearance ranged from 0.862 ± 0.129 to 1.02 ± 0.165. The results suggest that vaborbactam renal clearance did not change following repeated dosing.

(ii) Safety and tolerability.

There were no deaths or other serious adverse events. One subject in cohort 8 terminated the study prior to completion; this subject withdrew consent due to personal reasons following the first dose of vaborbactam (1,000 mg).

(a) Single ascending dose.

Treatment-emergent adverse events were reported for 25 of 56 (45%) subjects. This included 19 of 42 (45%) subjects following intravenous dose administration of vaborbactam and 6 of 14 (43%) subjects following administration of placebo. A total of 50 treatment-emergent adverse events were reported during the single-ascending-dose part of the study (Table 2). The most common treatment-emergent AE during the single-dose phase was headache; however, there was no evidence of increasing incidence with increasing doses of vaborbactam, and the overall incidence was similar to that of placebo (8 of 42 [19%] subjects following all doses of vaborbactam and 3 of 14 [21%] subjects following placebo). Adverse events deemed to be related (possibly or probably) to the study drug were reported in 9 of 42 (21%) subjects receiving vaborbactam and 2 of 14 (14%) subjects receiving placebo. There were no differences between dose levels of vaborbactam. All AEs deemed to be related to the study drug were mild (10 AEs) or moderate (4 AEs) in severity, with the 4 AEs of moderate intensity occurring in 3 subjects (myalgia [1 subject, placebo], musculoskeletal [buttock] pain [1 subject, vaborbactam 750 mg], pain in extremity [thigh] [1 subject, vaborbactam 750 mg], and infusion site thrombosis [1 subject, vaborbactam 2,000 mg]). There was no evidence for an increasing incidence of AEs with increasing doses of vaborbactam.

(b) Multiple ascending doses.

Treatment-emergent AEs (n = 109) were reported for 29 of 32 (91%) subjects. This included 23 of 24 (96%) subjects following multiple intravenous dose administrations of vaborbactam and 6 of 8 (75%) subjects following multiple-dose administration of placebo (Tables 3 and 4). The most common treatment-emergent AEs during the multiple-dose phase were catheter site complications associated with blood draw catheters unrelated to study drug dosing. Infusion site reactions (associated with intravenous dosing catheters) were reported with a similar incidence in subjects who received active treatment and in subjects who received placebo. There was no evidence for an increasing incidence of AEs with increasing dose of vaborbactam other than mild lethargy that was observed in the highest dose group. AEs deemed to be related (possibly or probably) to the study drug were reported by 14 of 24 (58%) subjects, with no differences between dose levels of vaborbactam. Three of eight (38%) subjects receiving placebo reported AEs that were deemed related to study treatment. All AEs deemed to be related to the study drug were mild (27 AEs) or moderate (3 AEs), with no treatment-related AEs of severe intensity. The 3 AEs of moderate severity deemed to be related to the study drug occurred in 3 subjects (infusion site phlebitis [1 subject, vaborbactam 250 mg, and 1 subject, vaborbactam 2,000 mg] and infusion site erythema [1 subject, placebo]).

TABLE 3.

Commonly occurring treatment-emergent AEs that occurred in >5 (10%) subjects who received active vaborbactam treatment: single ascending dose

Parameter	Treatment
	Pooled placebo (n = 14)	250 mg (n = 6)	500 mg (n = 6)	750 mg (n = 6)	1,000 mg (n = 6)	1,250 mg (n = 6)	1,500 mg (n = 6)	2,000 mg (n = 6)	All vaborbactam (n = 42)	All subjects (n = 56)
Subjects (n [%])	3 (21)	1 (17)	0 (0)	2 (33)	2 (33)	1 (17)	1 (17)	1 (17)	8 (19)	11 (20)
No. of headache events	4	1	0	2	2	1	2	1	9	13

TABLE 4.

Commonly occurring treatment-emergent AEs that occurred in >5 (10%) subjects who received active vaborbactam treatment: multiple ascending doses

AE	Treatment
	Pooled placebo (n = 8)	250 mg (n = 6)	1,000 mg (n = 6)	1,500 mg (n = 6)	2,000 mg (n = 6)	All vaborbactam (n = 24)	All subjects (n = 32)
Infusion site phlebitis
Subjects (n [%])	4 (50)	3 (50)	1 (17)	2 (33)	4 (67)	10 (42)	14 (44)
No. of AEs	5	4	1	4	5	14	19
Headache
Subjects (n [%])	1 (13)	2 (33)	0 (0)	2 (33)	3 (50)	7 (29)	8 (25)
No. of AEs	1	2	0	3	4	9	10
Catheter site paina
Subjects (n [%])	0 (0)	3 (50)	0 (0)	3 (50)	1 (17)	7 (29)	7 (22)
No. of AEs	0	3	0	4	1	8	8
Catheter site hematomaa
Subjects (n [%])	1 (13)	1 (17)	0 (0)	1 (17)	2 (33)	4 (17)	5 (16)
No. of AEs	2	1	0	1	2	4	6
Catheter site phlebitisa
Subjects (n [%])	2 (25)	2 (33)	1 (17)	0 (0)	0 (0)	3 (13)	5 (16)
No. of AEs	3	2	2	0	0	4	7
Lethargy
Subjects (n [%])	0 (0)	0 (0)	1 (17)	0 (0)	4 (67)	5 (21)	5 (16)
No. of AEs	0	0	1	0	4	5	5
Dermatitis contact
Subjects (n [%])	0 (0)	0 (0)	1 (17)	1 (17)	1 (17)	3 (13)	3 (9)
No. of AEs	0	0	1	1	1	3	3

^aCatheter site adverse events refer to catheters used for PK blood draws only.

There were no differences in safety as assessed by clinical laboratory tests (hematology, biochemistry, coagulation, and urinalysis), vital signs, or ECG assessments between subjects who had received vaborbactam and those who received placebo during either the single- or multiple-ascending-dose periods (data not shown).

DISCUSSION

The safety, tolerability, and pharmacokinetics of vaborbactam following single and multiple doses ranging from 250 to 2,000 mg were investigated in healthy adult subjects. The exposure of vaborbactam (C_max and AUC) increased proportionately with dose. C_L and V for vaborbactam did not change with repeated dosing, and there was no evidence of accumulation of vaborbactam in plasma following 7 days of repeated q8h dosing. Vaborbactam was measurable at high concentrations in the urine, with ∼80% to 90% of the administered dose recovered unchanged following single or multiple doses. Vaborbactam was well tolerated, and no safety concerns were identified. Other than mild lethargy observed in the highest-dose group, there were no dose-related trends in safety assessments in subjects who received vaborbactam. There were also no differences in safety assessments between single- and multiple-dosing cohorts.

Vaborbactam is being developed in combination with meropenem. The combination has shown potent in vitro and in vivo activity against carbapenem-resistant KPC-containing strains of Enterobacteriaceae. The pharmacokinetic profile of vaborbactam is very similar to that previously reported for meropenem (8). Overall, these data show the safety, tolerability, and pharmacokinetic profile of the novel cyclic boronic acid β-lactamase inhibitor vaborbactam and form the basis for advancement into patient studies, including treatment of patients with CRE infection.

Funding Statement

This work, including the efforts of David C. Griffith, Jeffery S. Loutit, Elizabeth E. Morgan, Stephanie Durso, and Michael N. Dudley, was funded in part by HHS | DHHS Office of the Secretary (OS) (HHSO100201400002).

This project was funded in part by federal funds from the Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority, under contract HHSO100201400002.