Dose Selection for Ceftibuten Combined with Avibactam Tomilopil, a Potential Oral Alternative to Carbapenems for Patients with Complicated Urinary Tract Infections

Abstract

There are currently no oral treatment options for infections caused by extended spectrum β‑lactamase‐producing Enterobacterales. Avibactam tomilopil, a novel oral prodrug of avibactam, is being developed in combination with the oral cephalosporin, ceftibuten, as a potential treatment for patients with complicated urinary tract infections (cUTIs). The safety, tolerability, and pharmacokinetic profiles of single and multiple doses of avibactam tomilopil (900 to 1350 mg) and ceftibuten (400 to 1600 mg), alone and/or in combination were evaluated in three Phase 1 trials in healthy participants. Avibactam tomilopil was rapidly metabolized to active avibactam and plasma avibactam exposure increased proportionately with dose. Both avibactam and cis‐ceftibuten had similar plasma half‐lives, and were predominantly renally excreted. While there was negligible food effect on ceftibuten exposures, plasma avibactam exposure in the fed state for a fixed‐dose combination ceftibuten‐avibactam tomilopil tablet was higher compared with the fasted state. Based on joint probability of target attainment simulations using a simultaneous oral ceftibuten‑avibactam tomilopil population pharmacokinetic model, a tablet formulation ceftibuten 400 mg + avibactam tomilopil 1200 mg dosed every 8 h without regard to food is proposed for Phase 3 evaluation in adult patients with cUTIs.

Trial registration: NCT03931876; NCT05554237; NCT06593054.

Introduction

Extended spectrum β‐lactamase (ESBL)‐producing Enterobacterales (ESBL‐E) are a common cause of serious infections and are recognized as an important global health threat, with alarming increases in infection rates reported recently. ¹ , ² , ³ Overall mortality rates are 20% in patients with bloodstream infections caused by these pathogens. The Centers for Disease Control (CDC) reported that cases of ESBL‐E infections increased from 2019 to 2020 in the United States, with increases in both hospital‐onset (32%) and community‐onset (7%) cases. ⁴ The rise has resulted in increased burden on healthcare systems; for instance, ESBL‐E infections have caused hospitalization in the United States to increase by 50% since 2012. ⁵

ESBLs typically confer resistance to third‐generation cephalosporins, and are increasingly co‐expressed with carbapenemases and other antimicrobial resistance mechanisms in multidrug‐resistant (MDR) pathogens. ⁶ , ⁷ Antimicrobial resistance is one of the top 10 global health threats identified by World Health Organization (WHO), ⁸ estimated to have been associated with 4.17 million deaths in 2021worldwide. ⁹ Carbapenem‐resistant Enterobacterales (CRE) have been designated a critical priority for new antibiotic research and development by WHO, ⁸ while the CDC considers CRE among five groups of pathogens designated as “urgent threats” to public health, with ESBL‐E considered a “serious threat.” ¹ Several studies have reported increasing incidence of ESBL‐producing Enterobacterales and CRE in recent years among urinary tract isolates from both hospitalized patients and those in the community. ¹⁰ , ¹¹ , ¹² Currently these infections require treatment with intravenous drugs, including carbapenems and β‐lactam/β‐lactamase inhibitor (BL/BLI) combinations, and there is an unmet need for oral alternatives. WHO recommends the development of new oral treatments for ESBL‐Es and CRE to address gaps in outpatient care, reducing complications and costs compared with in‐hospital parenteral treatment. ¹³ , ¹⁴

A combination of the third‐generation cephalosporin ceftibuten with avibactam tomilopil, a novel oral prodrug of avibactam, is being developed as an innovative oral non‐carbapenem BL/BLI combination treatment for patients facing infections caused by MDR Enterobacterales such as complicated urinary tract infections (cUTIs), including pyelonephritis. ¹⁵ Ceftibuten is a racemic mixture of 90% cis‐ and 10% trans‑ceftibuten; antimicrobial activity of the cis‐isomer is approximately 8‐fold higher than the trans component. ¹⁶ Avibactam tomilopil consists of a carboxyethyl ester of the pivaloyl ester of the sulfuric acid of avibactam. After oral administration and intestinal absorption, the carboxyethyl ester is hydrolyzed, mainly in the liver by carboxylesterase 1, to yield ethanol and the pivaloyl ester of avibactam. Subsequent hydrolysis of the pivaloyl ester liberates avibactam and hydroxypivalic acid with 1:1 molecular yield of avibactam and hydroxypivalic acid. Intravenously administered avibactam is a well‑established β‐lactamase inhibitor with activity against a broad spectrum of β‑lactamases, including ESBLs, AmpC β‐lactamases, and serine carbapenemases. ¹⁷ , ¹⁸ , ¹⁹ Avibactam has been paired with the intravenous β‐lactam antibiotics, ceftazidime and aztreonam, to treat serious infections caused by Gram‑negative bacterial pathogens. ²⁰ , ²¹ The clinical pharmacokinetic and pharmacodynamic properties of ceftibuten (up to 800 mg/day), ²² , ²³ , ²⁴ and of intravenous avibactam in combination with ceftazidime or aztreonam, ²⁵ , ²⁶ have been previously evaluated.

Avibactam is a preferred β‐lactamase inhibitor to partner with ceftibuten, as in vitro studies have reported that ceftibuten‐avibactam is 256‐fold more potent than ceftibuten alone against ESBL‐producing strains and 128‐fold more potent against Klebsiella pneumoniae carbapenemase producers, ²⁷ with limited risk of resistance development through ESBL mutations. ²⁸ In surveillance studies of contemporary Enterobacterales isolates from patients with UTIs, ceftibuten‐avibactam was the most potent oral agent tested, with >97% of ESBL, >90% of MDR, and >70% of CRE isolates inhibited at the ceftibuten‐avibactam minimum inhibitory concentration (MIC) of ≤1 mg/L. ²⁷ , ²⁹ The combination of ceftibuten with avibactam tomilopil is expected to provide an effective and well‐tolerated oral treatment option for infections caused by ESBL‑producing Enterobacterales. While both ceftibuten ²² , ²³ , ²⁴ and intravenous avibactam ²⁵ , ²⁶ have been characterized separately, avibactam tomilopil (the oral prodrug of avibactam) had not been previously studied in humans, and a suitable dose regimen for an oral combination treatment had not been established. Three Phase 1 clinical studies in healthy participants evaluated single and multiple ascending doses and evaluated the relative bioavailability (rBA) of different formulations (oral suspension, separate capsules, and a fixed‐dose combination tablet) of avibactam tomilopil and the ceftibuten‐avibactam tomilopil combination. Participant pharmacokinetic data from the three studies were used to develop a population pharmacokinetic‐guided joint probability of target attainment (jPTA) analysis enabling selection of a dosing regimen for Phase 3 evaluation in patients with cUTI.

Methods

Protocols, protocol amendments, and other relevant documents for the three Phase 1 trials (NCT03931876, NCT05554237, and NCT06593054) were approved by the independent ethics committee (IEC) and/or institutional review board at each study site (The Alfred Hospital Ethics Committee, Melbourne, Australia; Comité d'Ethique Hospitalo‐Facultaire Erasme‐ULB; Clinical Trial College, Belgium Federal Agency for Medicines and Health Products). All participants provided written informed consent that met the requirements of 21 CFR 50, local regulations, the International Council for Harmonisation (ICH) guidelines, the Health Insurance Portability and Accountability Act, and the IEC or study center. All studies were conducted in accordance with the protocol and consensus ethical principles derived from international guidelines, including the Declaration of Helsinki Council and the Council for International Organizations for Medical Sciences International Ethical Guidelines, applicable ICH Good Clinical Practice guidelines, applicable ISO 14155 guidelines, medical device guidelines, and other applicable laws and regulations (including privacy laws).

Study Design and Participants

Three Phase 1 single‐center, randomized studies were conducted in healthy adults to evaluate the safety, tolerability, and pharmacokinetics of avibactam tomilopil and ceftibuten, alone and in combination. Details of the study designs, treatments, and objectives are shown in Table 1.

Table 1.

Overview of Phase 1 Ceftibuten‐Avibactam Tomilopil Studies

Protocol (Trial Registration), Design, Trial Location, and Dates	Population	Objectives	Doses Evaluated	Formulation and Fed/Fasted Status a	PK Analytes, Sampling Schedule, LLOQs
C4691002 (ClinicalTrials.gov ID: NCT03931876) Double‐blind, randomized, parallel‑group, placebo‐controlled study Australia; June–August 2019	Healthy male and female participants aged 18–55 years, with body weight ≥50 kg and BMI 18–32 kg/m2	Safety, tolerability, and PK of single ascending doses of AVP	Placebo (n = 6) AVP 300 mg (n = 8) AVP 900 mg (n = 8) AVP 1350 mg (n = 8)	Oral AVP suspension Fed condition (regular meal)	Analytes: AVP, AVI, HPA Blood: 0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 18, 24, 30, 36, 48, 72 h Urine: 0–4, 4–8, 8–12, 12—24, and 24–36 h collections LLOQs Plasma: 10 ng/mL (AVP, AVI, HPA) Urine: 100 ng/mL (AVP, AVI, HPA)
C4691001 (EudraCT number: 2021‐005428‐39; ClinicalTrials.gov ID: NCT05554237). Double‐blind, randomized, placebo‐controlled two‐part study Belgium; October 2022–June 2023	Healthy male and female participants aged 18–60 years, with body weight >50 kg and BMI 17.5–30.5 kg/m2 Japanese cohort in Part 2: Japanese participants who had four Japanese biologic grandparents who were born in Japan Chinese cohort in Part 2: Chinese participants who were born in mainland China, with both parents of Chinese descent Part 1 (five‐period crossover, single dose; N = 8) Part 2 (five‐cohort, multiple dose; N = 34)	Safety, tolerability and PK of single and multiple ascending doses of CTB and AVP administered as separate oral capsules	Part 1 (single dose)Period 1: CTB 400 mg + AVP 900 mg (n = 6) or placebo + AVP 900 mg (n = 2)Period 2: CTB 800 mg + AVP 1350 mg (n = 6) or placebo + AVP 1350 mg (n = 2)Period 3: CTB 800 mg (n = 6) or placebo (n = 2)Period 4: CTB 1200 mg + AVP 1350 mg (n = 6) or placebo + AVP 1350 mg (n = 2)Period 5: CTB 1600 mg (n = 6) or placebo (n = 2)Part 2 (multiple‐dose q8h for 7 days) Cohort 1: CTB 400 mg + AVP 1350 mg q8h (n = 6) or placebo + AVP 1350 mg q8h (n = 2) Cohort 2: CTB 800 mg + AVP 1350 mg q8h (n = 6) or placebo + AVP 1350 mg q8h (n = 2) Cohort 3: CTB 400 mg + AVP 900 mg q8h (N = 6) OR placebo for CTB 400 mg + AVP 900 mg q8h (N = 2) Cohort 4 (Japanese): CTB 400 mg + AVP 1350 mg q8h (n = 5) or placebo + AVP 1350 mg q8h (n = 1) Cohort 5 (Chinese): CTB 400 mg + AVP 1350 mg q8h (n = 3) or placebo + AVP 1350 mg q8h (n = 1)	Separate CTB and AVP capsules Participants were dosed under the fed condition (regular meal), except for Part 2 Day 7, for which dosing was under the fasted condition	Analytes: AVP, AVI, HPA, cis‐CTBPart 1Blood: 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 14, 24 hPart 2 Blood, Day 1 and Day 6 (fed): 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 h Blood, Day 7 (fasted): 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 h Urine, Day 6 (cohort 1 only): 0–8 h collections LLOQsPlasma: 1 ng/mL (AVP), 10 ng/mL (AVI, HPA), 100 ng/mL (cis‐CTB)Urine: 0.01 µg/mL (AVP, cis‐CTB), 10 ng/mL (AVI, HPA)
C4691003 (EudraCT number: 2023‐507117‐10‐00; ClinicalTrials.gov ID: NCT06593054) Open‐label, single‐dose, randomized, crossover study Healthy male and female participants aged ≥18 years, with body weight >50 kg and BMI 16–32 kg/m2 Belgium; July–October 2024	Healthy male and female participants aged ≥18 years, with body weight >50 kg and BMI 16–32 kg/m2	Safety, tolerability, and relative bioavailability of oral CTB‐AVP tablet compared with oral CTB‐AVP capsule formulations, and the food effect of tablet formulation	Treatment A (CTB‐AVP capsules, fasted condition): CTB 400 mg + AVP 1125 mg separate capsules (n = 12) Treatment B (CTB‐AVP tablet, fasted condition): CTB 402 mg + AVP 1200 mg tablet (n = 13) Treatment C (CTB‐AVP tablet, fed condition): CTB 402 mg + AVP 1200 mg tablet (n = 13) Dosing in each treatment period was followed by a 48‐h washout	Separate CTB and AVP capsules Combined CTB‐AVP tablet Fed and fasted condition (high‐fat meal)	Analytes: AVI, HPA, cis‐CTB Blood (collections repeated for each treatment period): 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8,12, 24, 48 h LLOQs Plasma: 10 ng/mL (AVI, HPA), 100 ng/mL (cis‐CTB) Urine: 0.01 µg/mL (AVI, HPA, cis‐CTB)

AVI, avibactam; AVP, avibactam tomilopil; BMI, body mass index; CTB, ceftibuten; EudraCT, European Union Drug Regulating Authorities Clinical Trials Database; HPA, hydroxypivalic acid; LLOQ, lower limit of quantification; PK, pharmacokinetics; q8h, every 8 h.

^a All post‐dose samples were taken following ceftibuten and/or avibactam tomilopil administration under fed conditions (after a high‐fat, high‐calorie meal in C4691003, and after a standard meal in C4691001 and C4691002).

Exclusion criteria included history of clinically significant hematologic, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease. Detailed inclusion and exclusion criteria for each study are provided as Supplemental Information.

Safety Assessments and Analysis

Safety assessments were conducted during and up to the final visit in each study (7 to 36 days post last treatment administration) and included treatment‐emergent adverse events (TEAEs; all‐causality, treatment‐related, and serious adverse events [SAEs]), clinical laboratory evaluations, and electrocardiograms. In each study, the safety analysis sets included all enrolled participants who received at least one dose of study drug and were analyzed according to the actual treatment received. The safety analysis sets were used for descriptive summaries of all safety data by treatment group.

Pharmacokinetic Assessments

Venous blood samples for the determination of plasma concentrations of avibactam and hydroxypivalic acid (all studies), avibactam tomilopil (C4691001 and C4691002), and cis‐ceftibuten (C4691001 and C4691003) were collected from all participants at prespecified timepoints (Table 1). All post‐dose samples were taken following ceftibuten and/or avibactam tomilopil administration under fed conditions (after a high‐fat, high‐calorie meal in C4691003, and after a standard meal in C4691001 and C4691002), except for Part 2 Day 7 in Study C4691001, and treatment arms A and B in Study C4691003 (Table 1). Urine samples for pharmacokinetic analysis were collected at prespecified intervals for all participants in C4691002 and only for participants in the ceftibuten 400 mg + avibactam tomilopil 1350 mg dosed every 8 h (q8h) cohort in C4691001 Part 2 on Day 6 (Table 1). Samples were analyzed using validated high‐performance liquid chromatography‐tandem mass spectrometry analytical methods in compliance with applicable regulations. Lower limits of quantification in plasma were 1.0 ng/mL (avibactam tomilopil), 10.0 ng/mL (avibactam and hydroxypivalic acid), and 100.0 ng/mL (cis‐ceftibuten). Lower limits of quantification in urine were 0.01 µg/mL (avibactam tomilopil), 0.1 µg/mL (avibactam and hydroxypivalic acid), and 1.00 µg/mL (cis‐ceftibuten).

Noncompartmental Analysis

Pharmacokinetic parameters were derived from concentration–time data using standard noncompartmental methods utilizing using sponsor‐validated electronic noncompartmental analysis software (oNCA, version 2.7.8). The pharmacokinetic analysis sets included all participants in each study who received any amount of avibactam tomilopil and/or ceftibuten and had at least one concentration value reported (pharmacokinetic concentration set), or at least one pharmacokinetic parameter of interest reported (pharmacokinetic parameter set).

Dose proportionality in Study C4691002 was assessed using the power model. Log‐transformed pharmacokinetic parameters maximum plasma concentration (C_max), area under the plasma drug concentration–time curve (AUC), and log‑transformed dose were used to estimate the slope parameter and the 95% confidence interval (CI) for the slope. Dose proportionality was to be concluded if the 95% CIs around the slope estimate included the value of 1.

Population Pharmacokinetic Analysis and Simulation

Structural Model Development, Interindividual, and Residual Variability

Population pharmacokinetic models for cis‐ceftibuten (CTB‐PO model) and avibactam tomilopil (AVI‐PO model) were developed separately using analyte concentration data from C4691001 and C4691002. The sequence of model development stages and the covariate selection are described in the Supplemental Appendix (Population Pharmacokinetic Analysis and Simulation section; Figure S1 and Table S1). The CTB‐PO and AVI‐PO models were then used to describe a combined dataset that contained cis‐ceftibuten and avibactam concentrations for each participant at pre‐determined timepoints (CTB/AVP‐PO model). The model was later updated with C4691003 concentration–time data. As the studies employed different formulations and food conditions, with drugs dosed together or separately (Table 1), appropriate covariates were added in the final model to explain the variability observed between studies.

Population modeling was performed using the nonlinear mixed‐effects modeling approach in NONMEM version 7.5.0 and PsN version 5.3.0 (ICON Plc, Dublin, Ireland). ³⁰ , ³¹ First‐order conditional estimation method with interaction was used. R version 4.2.1 was used for data manipulation, simulations, and graph creation. ³²

Base Population Models

Based on previous knowledge ²² , ²³ , ²⁶ , ³³ and data obtained from aforementioned three healthy adult studies, several structural models were evaluated during the model development process, including one‐ and two‐compartment models with and without absorption lag time, with and without varying numbers of transit compartments, and first‐order elimination for both cis‐ceftibuten and avibactam.

The models were parameterized in terms of absorption rate constant (K_a) or transit rate constant (K_tr), apparent oral clearance (CL/F), apparent central volume of distribution (V_c/F), apparent inter‐compartmental clearance (Q/F), and where appropriate, apparent peripheral volume of distribution (V_p/F). Oral doses of ceftibuten and avibactam tomilopil were administered into an absorption depot compartment. Avibactam tomilopil dose was scaled to the equivalent avibactam dose, using molecular weight fraction. Body weight and creatinine clearance (CrCL; calculated using the Cockcroft–Gault equation ³⁴ ) were included as covariates in the base model to improve model stability. As ceftibuten ³³ and avibactam ³⁵ are largely excreted unchanged in urine, renal function affects plasma clearance of both drugs. All CrCL estimates were standardized to the observed population median value (i.e., 112  mL/min) and adjusted by body weight. The effect of CrCL on CL/F was described by a power function with the exponent value estimated. Body weight was standardized as 70 kg and its effect on CL/F, V_c/F, Q/F, and V_p/F was described by a fixed exponent power function using standard allometric scaling values of 0.75 and 1.0 on clearance and volume of distribution terms, respectively. ³⁶ , ³⁷ , ³⁸ This covariate structure with allometric scaling and body surface area (BSA)‐normalized CrCL (nCrCL) enables the separation of size‑related effects and renal function and reflects biological processes, consistent with established pharmacokinetic principles. ³⁶ , ³⁹ , ⁴⁰

Plasma cis‐ceftibuten and avibactam are mainly excreted unchanged in the urine, the relationships between total body clearance and CrCL has been previously studied for cis‐ceftibuten CL/F ³³ and avibactam CL/F. ²⁵ , ⁴¹ Intraindividual variability (IIV) was included in the pharmacokinetic parameters using multiplicative exponential random effects, with results denoted as coefficient of variation (CV%). Residual variability was modeled as an additive model in the log domain, and results were expressed as a CV%.

Covariate Model Development and Final Model

With the differences in the study design, meal conditions, formulations used, and limited number of healthy adult participants in each study; the covariate information was limited. Inclusion of significant covariates was guided by assessing clinical relevance, graphical evaluation of covariate–parameter relationships, a decrease in the objective function value (−2 log likelihood) and precision of the parameter estimates.

Effects of meal condition and formulation on absorption parameters (Ktr and bioavailability [F1]) were evaluated as covariates. The effect on F1 and/or CL/F of ceftibuten or avibactam tomilopil being administered alone was also evaluated. A prediction‐corrected visual predictive check was performed using the developed population pharmacokinetic models.

Dose‐exposure nonlinearity was described using a power model on rBA (F1 = [cis‐ceftibuten or avibactam tomilopil mg dose/Dref]^θ, where Dref is the reference dose 400 mg for ceftibuten or 1350 mg for avibactam tomilopil).

Simulations to Select Ceftibuten‐Avibactam Tomilopil Dose for Phase 3 Evaluation

The CTB/AVP‐PO joint pharmacokinetic model was modified for jPTA simulations to include relationships between CrCL and CL/F for ceftibuten and avibactam in participants with decreased renal function. Pharmacokinetic and pharmacodynamic indices for ceftibuten and avibactam for jPTA simulations were based on a murine neutropenic thigh infection study (data on file). For ceftibuten, the index was time over the dosing interval that free cis‐ceftibuten concentration exceeded a target MIC (f T > MIC). For avibactam, the index was free avibactam AUC during 24 h at steady state (fAUC_{0 − 24, ss}). Target values for these indices were 50% to >99% fT > MIC for cis‐ceftibuten, and 50–100 µg h/mL fAUC_{0 − 24 , ss} for avibactam. The jPTA at each MIC was defined as the proportion of simulated patients with a cUTI who met the target criteria for both ceftibuten and avibactam simultaneously. Plasma‐free fractions of cis‐ceftibuten and avibactam were assumed as 61% and 92%, respectively.

Individual cis‐ceftibuten and avibactam concentration–time profiles were simulated to obtain the pharmacokinetic/pharmacodynamic parameters in patients with cUTIs (N = 1000) receiving a range of ceftibuten‐avibactam tomilopil doses administered q8h. Covariates for patients with cUTI were obtained from a previous aztreonam‐avibactam population pharmacokinetic analysis in patients with cUTI. ⁴² Using the simulated concentration–time profiles, fT > MIC and fAUC_{0−24, ss} were calculated on Day 10 for MIC values that ranged from 0.12 to 4 mg/L. Separate simulations evaluated the impact of the meal condition (fasted or fed) on jPTA at a specific dose combination. To assess the impact of variability due to patient factors, sensitivity analyses were performed with simulations using IIVs that were inflated by 50% for CL/F and Vc/F for both cis‐ceftibuten and avibactam.

Results

Participants

Study C4691002 enrolled 30 participants in three cohorts, of whom 24 received single‑dose avibactam tomilopil (in three escalating dose groups) and six received placebo. All 30 participants were included in the safety analysis set, and all 24 participants treated with avibactam tomilopil were included in the pharmacokinetic analysis set. For Study C4691001, 42 participants were enrolled, eight in Part 1 (single‑dose CTB + avibactam tomilopil, ceftibuten alone, or placebo + avibactam tomilopil in a five‐period crossover) and 34 in Part 2 in five cohorts (multiple‑dose ceftibuten + avibactam tomilopil or placebo + avibactam tomilopil, including Chinese and Japanese cohorts). All 42 participants were included in the safety analysis set. The pharmacokinetic analysis set for Part 1 included six participants in each dose group. The pharmacokinetic analysis set for Part 2 included 26 participants on Day 1 and 23 participants on Days 6 and 7. Study C4691003 enrolled 13 participants, 12 of whom completed all treatment and follow‐ups. Twelve participants received ceftibuten and avibactam tomilopil capsules in the fasted condition, 13 received ceftibuten and avibactam tomilopil capsules in the fed condition, and 13 received ceftibuten‐avibactam tomilopil tablets in the fed condition. All participants were included in the safety and pharmacokinetic analysis sets. Participants’ demographic and baseline characteristics, included in the population pharmacokinetic analysis, are summarized in Table 2.

Table 2.

Demographic and Baseline Characteristics of Participants Included in the Population Pharmacokinetic Analysis

	Single‐Dose AVP Study (C4691002)	Single‐ and Multiple‐Dose CTB ± AVP Study (C4691001)	Relative Bioavailability Single‐Dose Crossover Study (C4691003)	Overall (N = 71)
Sex, n (%)
Male	15 (62.5)	31 (91.2)	11 (84.6)	57 (80.3)
Female	9 (37.5)	3 (8.8)	2 (15.4)	14 (19.7)
Race, n (%)
Black	0	1 (2.9)	3 (23.1)	4 (5.6)
Asian	7 (29.2)	9 (26.5)	0	16 (22.5)
White	12 (50)	24 (70.6)	8 (61.5)	44 (62)
Other	5 (20.8)	0	0	5 (7)
Not reported	0	0	2 (15.4)	2 (2.8)
Age, years
Mean (SD)	25 (7.57)	36.6 (9.76)	39.1 (9.64)	33.1 (10.7)
Median (range)	23 (18–53)	34.5 (21–59)	39 (25–56)	32 (18–59)
BSA (m2)
Mean (SD)	1.86 (0.171)	1.95 (0.182)	1.93 (0.244)	1.91 (0.193)
Median (range)	1.85 (1.54–2.25)	1.98 (1.49–2.29)	1.97 (1.48–2.28)	1.93 (1.48–2.29)
CrCL (mL/min)
Mean (SD)	127 (17.6)	124 (22.1)	111 (30.2)	122 (22.8)
Median (range)	129 (95.1–157)	123 (74.5–179)	110 (58.5–175)	124 (58.5–179)
Body weight (kg)
Mean (SD)	73.5 (11.3)	77.5 (12.1)	78.7 (15.6)	76.4 (12.5)
Median (range)	72.2 (55.1–99.6)	78.5 (51.6–101)	82.6 (50.1–98.6)	76.6 (50.1–101)
nCrCL (mL/min/1.73 m2)
Mean (SD)	118 (16.0)	110 (16.0)	97.9 (16.1)	111 (17.3)
Median (range)	118 (82.4–145)	108 (79.9–160)	95.4 (68.3–133)	109 (68.3–160)

AVP, avibactam tomilopil; BSA, body surface area; CTB, ceftibuten; CrCL, creatinine clearance; nCrCL, normalized creatinine clearance; SD, standard deviation.

Safety of Avibactam Tomilopil and Ceftibuten

TEAEs of avibactam tomilopil and ceftibuten across the studies are summarized in Tables S2–S7. All TEAEs were of mild or moderate severity. There were no severe TEAEs, SAEs, or deaths. Across all three studies, the most common TEAEs (Tables S3–S6) were classified as gastrointestinal disorders (e.g., nausea and diarrhea), nervous system disorders (e.g., headache), and general disorders and administration site conditions (e.g., vessel puncture site reaction).

Single‐Dose Studies

Twelve all‐cause TEAEs were reported in 8/24 (33.3%) participants treated with single‐dose avibactam tomilopil in Study C4691002, including five treatment‑related TEAEs in three (12.5%) participants (three treatment‐related TEAEs were mild and two were moderate); no dose‐related trends in TEAEs were observed. In the placebo group, one all‐cause TEAE in one participant (12.5%) and no treatment‐related TEAEs were reported (Table S2). In Study C4691001 Part 1, 20 all‐cause TEAEs were reported in 6/8 (75.0%) participants treated with single doses of ceftibuten and/or avibactam tomilopil or placebo (Tables S3 and S4), including 10 treatment‐related TEAEs in five (62.5%) participants (all mild intensity). In Study C4691003, 26 all‐cause TEAEs were reported in nine (69.2%) participants who received ceftibuten‐avibactam tomilopil, of which 11 events in five (38.5%) participants were treatment related (all mild intensity); all‐cause TEAEs are summarized in Table S5. In the single‐dose studies, no participants discontinued any study due to TEAEs, and there were no clinically significant changes in laboratory assessments, vital signs, or electrocardiograms.

Multiple‐Dose Evaluation (C4691001 Part 2)

In Study C4691001 Part 2, 67 all‐cause TEAEs were reported in 24/34 (70.6%) participants treated with multiple doses of ceftibuten + avibactam tomilopil or placebo + avibactam tomilopil q8h; all‐cause TEAEs are summarized in Table S7. In total, 47 TEAEs in 19 (55.9%) participants were treatment related (46 were mild and one was moderate).

Four of the 34 (11.8%) participants discontinued the study due to TEAEs, of whom two had treatment‐related TEAEs (moderate reflux gastritis in one participant [ceftibuten 400 mg + avibactam tomilopil 1350 mg q8h] and mild alanine aminotransferase [ALT] increased, abdominal discomfort, and abdominal distention in one participant [placebo + avibactam tomilopil 900 mg q8h]) and two had unrelated TEAEs (mild dermatitis acneiform in one participant and mild anxiety in one participant). There were no clinically significant findings in hematology or clinical chemistry, vital signs measurements, or electrocardiograms. Six participants had transient transaminase elevations (without associated bilirubin elevations), of which one event (mild ALT increased, as noted above) was reported as a treatment‐related TEAE. All reported transaminase elevations resolved without intervention.

Pharmacokinetics

Plasma Avibactam Tomilopil and Avibactam

Following single and multiple doses of avibactam tomilopil alone, or in combination with ceftibuten, avibactam tomilopil was rapidly converted to avibactam and hydroxypivalic acid, and most avibactam tomilopil plasma concentrations were below the limit of quantification (1.0 ng/mL). Plasma avibactam concentration–time profiles across each study/dosing scenario are shown in Figure 1a–d, and pharmacokinetic parameters are shown in Table 3 (single dose) and Table S8 (multiple dose). At all avibactam tomilopil doses across the three studies, there was rapid appearance of avibactam in the systemic circulation, starting at 15 min post dose for all participants, with time to C_max observed at 2–4 h and declining exponentially within 24 h. Avibactam plasma exposures across the avibactam tomilopil dose groups increased in a dose‐proportional manner. The power model analysis of dose linearity by analyte is shown in Table S9. For both analytes, drug exposure roughly increased proportionally with dose. In Study C4691003, plasma avibactam exposures were similar following single‐dose administration of ceftibuten‐avibactam tomilopil as a fixed‐dose combination tablet or as separate capsules in the fasted state; in the fed state, plasma avibactam exposure with a single‐dose ceftibuten‐avibactam tomilopil tablet was higher compared with the fasted state.

Figure 1.

Median plasma concentration–time profiles for avibactam (a–d) and cis‐ceftibuten (e–g): (a) single‐dose avibactam tomilopil (C4691002); (b) single‐dose ceftibuten + avibactam tomilopil (C4691001 Part 1); (c) multiple‐dose ceftibuten ± avibactam tomilopil in the fed condition (C4691001 Part 2, Day 6); (d) single‐dose ceftibuten‐avibactam tomilopil formulations (C4691003); (e) single‐dose ceftibuten ± avibactam tomilopil (C4691001 Part 1); (f) multiple‐dose ceftibuten ± avibactam tomilopil in the fed condition (C4691001 Part 2, Day 6); (g) single‐dose ceftibuten‐avibactam tomilopil formulations (C4691003). Insets show median plasma concentration of avibactam (a–d) and cis‑ceftibuten (e–g) on log scale. AVP, avibactam tomilopil; CTB, ceftibuten.

Table 3.

Plasma Pharmacokinetic Parameters for Avibactam Following Single Doses of Avibactam Tomilopil or Ceftibuten + Avibactam Tomilopil

	Single‐Dose AVP Study (C4691002) a			Single‐Dose CTB + AVP Study (C4691001 Part 1) b			Relative Bioavailability Single‐Dose Crossover Study (C4691003) c
Parameter	AVP 300 mg (n = 8)	AVP 900 mg (n = 8)	AVP 1350 mg (n = 8)	CTB 400 mg + AVP 900 mg (n = 6)	CTB 800 mg + AVP 1350 mg (n = 6)	CTB 1200 mg + AVP 1350 mg (n = 6)	CTB 400 mg + AVP 1125 mg Capsule Fasted (n = 12)	CTB 402 mg + AVP 1200 mg Tablet Fasted (n = 13)	CTB 402 mg + AVP 1200 mg Tablet Fed (n = 13)
N2, N3	–	–	–	6, 6	6, 6	6, 6	12, 12	13, 13	13, 13
AUCinf (ng h/mL)	8250 (36)	34,557 (19)	44,320 (29)	22,050 (34)	38,060 (13)	38,090 (19)	29,680 (14)	32,330 (9)	49,150 (20)
CL/F (L/h)	28.7 (50)	18.3 (25)	21.9 (26)	36.10 (33)	40.91 (13)	41.67 (19)	39.41 (15)	38.66 (9)	61.03 (20)
Cmax (ng/mL)	2740 (45)	8363 (16)	10,260 (23)	3856 (44)	5955 (13)	6714 (26)	4834 (34)	4217 (19)	9472 (29)
t1/2 (h)	1.50 (17)	2.69 (15)	2.33 (8)	4.0 ± 1.1	5.3 ± 1.5	3.6 ± 0.86	5.7 ± 1.8	5.7 ± 2.8	2.3 ± 0.11
Tmax (h)	1.79 (1.0–3.0)	2.75 (1.5–4.0)	2.25 (0.5–3.0)	4.01 (2.08–6.00)	3.50 (1.50–6.00)	4.50 (2.50–6.02)	3.00 (1.00–6.00)	2.50 (1.05–6.02)	3.98 (2.50–6.02)
Vz/F (L)	58.8 (35)	69.3 (14)	73.5 (25)	154.6 (27)	175.0 (33)	121.5 (33)	199.0 (32)	186.2 (47)	54.42 (20)

AUC_inf, area under the plasma drug concentration–time curve from time 0 to infinity; AVP, avibactam tomilopil; CL/F, oral clearance; C_max, maximum observed concentration; CTB, ceftibuten; t_1/2, terminal half‐life; T_max, time to C_max; Vz/F, apparent volume of distribution.

^a AVP was administered as an oral suspension under fed (regular meal) conditions.

^b CTB and AVP were administered as separate capsules under fed (regular meal) conditions.

^c CTB (400 mg) and AVP (1125 mg) were administered as separate capsules under fasted conditions and as a fixed‐dose combination tablet of CTB 402 mg + AVP 1200 mg under fasted and fed (high‐fat meal) conditions.

N = total number of participants in the indicated population.

N2 = number of participants contributing to the summary statistics.

N3 = number of participants contributing to the summary statistics for AUC_inf, AUC_inf(dn), CL/F, t_1/2, and Vz/F.

Values are geometric mean (geometric %coefficient of variation) for all except median (range) for T_max, and for C4691001 and C4691002 arithmetic mean ± standard deviation for t_1/2.

Plasma Cis‐Ceftibuten

Plasma cis‐ceftibuten concentration–time profiles following single and multiple doses of ceftibuten alone or in combination with avibactam tomilopil are shown in Figure 1e–g), and pharmacokinetic parameters are shown in Table 4 (single dose) and Table S10 (multiple dose). Following single doses of ceftibuten alone or in combination with avibactam tomilopil (C4691001 Part 1), the increase in systemic exposure of cis‐ceftibuten following administration was less than dose proportional for ceftibuten doses of 800 mg and higher. Plasma exposure of cis‐ceftibuten was similar following single doses of ceftibuten 800 mg + avibactam tomilopil 1350 mg or ceftibuten 800 mg alone (Table 4). In Study C4691003, plasma cis‐ceftibuten exposures were similar when ceftibuten + avibactam tomilopil was administered in fasted and fed conditions, and following administration as a fixed‐dose combination tablet or as separate capsule formulations. Following multiple doses of ceftibuten + avibactam tomilopil q8h (C4691001 Part 2), plasma cis‐ceftibuten exposures were generally similar within each dosage group under fed (Day 6) and fasted (Day 7) conditions (Table S10).

Table 4.

Plasma Pharmacokinetic Parameters for Cis‐Ceftibuten Following Single Doses of Ceftibuten or Ceftibuten + Avibactam Tomilopil

	Single‐Dose CTB ± AVP Study (C4691001 Part 1) a					Relative Bioavailability Single‐Dose Crossover Study (C4691003) b
Parameter	CTB 400 mg + AVP 900 mg (n = 6)	CTB 800 mg + AVP 1350 mg (n = 6)	CTB 800 mg (n = 6)	CTB 1200 mg + AVP 1350 mg (n = 6)	CTB 1600 mg (n = 6)	CTB 400 mg + AVP 1125 mg Capsule Fasted (n = 12)	CTB 402 mg + AVP 1200 mg Tablet Fasted (n = 13)	CTB 402 mg + AVP 1200 mg Tablet Fed (n = 13)
N2, N3	6, 6	6, 6	6, 6	6, 6	6, 6	12, 12	13, 13	13, 13
AUCinf (ng h/mL)	94,730 (18)	155,800 (13)	173,200 (14)	184,900 (15)	321,900 (24)	77,020 (16)	73,640 (25)	76,300 (22)
CL/F (L/h)	4.221 (18)	5.136 (13)	4.620 (14)	6.492 (15)	4.973 (24)	5.192 (16)	5.460 (25)	5.268 (22)
Cmax (ng/mL)	18,170 (24)	25,470 (18)	30,510 (16)	27,120 (12)	44,990 (25)	15,370 (21)	13,120 (29)	12,440 (29)
t1/2 (h)	3.073 ± 0.543	2.708 ± 0.570	2.908 ± 0.539	3.138 ± 0.276	3.180 ± 0.2882	2.783 ± 0.473	2.780 ± 0.491	2.903 ± 0.483
Tmax (h)	3.21 (2.12–4.05)	4.03 (3.03–4.15)	3.50 (1.50–4.02)	5.05 (4.03–6.05)	4.01 (2.02–4.10)	2.54 (1.03–4.12)	2.50 (1.05–6.00)	3.00 (2.00–6.00)
Vz/F (L)	18.44 (20)	19.70 (14)	19.10 (16)	29.28 (14)	22.72 (30)	20.58 (23)	21.61 (35)	21.77 (29)

AUC_inf, area under the plasma drug concentration–time curve from time 0 to infinity; AVP, avibactam tomilopil; CL/F, oral clearance; C_max, maximum observed concentration; CTB, ceftibuten; t_1/2, terminal half‐life; T_max, time to C_max; Vz/F, apparent volume of distribution.

^a CTB and AVP were administered as separate capsules under fed (regular meal) conditions.

^b CTB (400 mg) and AVP (1125 mg) were administered as separate capsules under fasted conditions and as a fixed‐dose combination tablet of CTB 402 mg + AVP 1200 mg under fasted and fed (high‐fat meal) conditions.

N = total number of participants in the indicated population.

N2 = number of participants contributing to the summary statistics.

N3 = number of participants contributing to the summary statistics for AUCinf, AUCinf(dn), CL/F, t_1/2, and Vz/F.

Values are geometric mean (geometric %coefficient of variation) for all except median (range) for Tmax, and arithmetic mean ± standard deviation for t1/2.

Urine Pharmacokinetic Results

In the C4691002 study, the total amounts of avibactam and hydroxypivalic acid recovered in urine increased with increasing single doses of avibactam tomilopil. The fraction of total converted drug that was excreted/recovered in urine was consistent across doses; mean dose fractions ranged from 45.1% to 56.1% for avibactam, and from 7.0% to 9.5% for hydroxypivalic acid (Table S11). Following multiple doses of ceftibuten 400 mg + avibactam tomilopil 1350 mg q8h (C4691001 study; Part 2, Day 6), mean total converted drug excreted/recovered in urine over 8 h was 32.7% for avibactam, 5.4% for hydroxypivalic acid, and 45.4% for cis‑ceftibuten (Table S11).

Population Pharmacokinetic Analysis and Simulations

Final Population Pharmacokinetic Model

Plasma pharmacokinetic data from 71 healthy adults (57 males, 14 females) treated with ceftibuten and/or avibactam tomilopil in the three Phase 1 studies were included in the population pharmacokinetic analysis. Excluding samples with concentrations below the limit of quantification, there were 1467 plasma cis‐ceftibuten observations and 1707 plasma avibactam observations.

A one‐compartment model including a depot compartment and five transit compartments linked with a Ktr was determined to be the most appropriate structural model for cis‐ceftibuten. The IIV on CL/F, Vc/F, and Ktr were included in the model. Correlations between η(s) for CL/F and Vc/F were incorporated into the model. A two‐compartment model including a depot compartment and three transit compartments linked with Ktr adequately described the plasma avibactam concentration–time data. The IIV on CL/F, Vc/F, and Ktr were included in the model. Correlations between η(s) for CL/F and Vc/F were incorporated into the model.

For both AVI‐PO and CTB‐PO models, the effects of a high‑fat meal on Ktr and rBA were significant, whereas effects of tablet formulation on Ktr and rBA were not significant based on decrease in objective function value. The regular meal was administered in the C4691001 study; however, owing to confounding from accumulation, results were not definitive. Based on the final models, a simultaneous fit analysis for plasma cis‐ceftibuten and avibactam was conducted. Parameter estimates of the final models were estimated with acceptable precision (Table S12). Overall, ceftibuten rBA for monotherapy was 34% higher than that for ceftibuten/avibactam tomilopil combination therapy, whereas avibactam CL/F for avibactam tomilopil monotherapy was 27% higher than that for combination therapy (Table S12). However, interpretation of these differences was limited due to the small number of subjects and, for avibactam, the inability to separate the effects of monotherapy and formulation (suspension). Plasma cis‐ceftibuten concentration–time profiles were comparable between tablet and capsule formulations. Formulation (tablet or capsule) was not a covariate in model. Prediction‑corrected visual predictive check plots from the final simultaneous ceftibuten/avibactam tomilopil‐PO model for plasma avibactam (Figure S2) and plasma cis‐ceftibuten (Figure S3) were consistent with the observed profiles across the time bins following oral administration of ceftibuten and/or avibactam tomilopil regardless of formulation (capsule vs tablet) or food condition (fed vs fasted). Forest plots for the final and simulation models are presented in Figure S4.

Simulations to Select the Ceftibuten‐Avibactam Tomilopil Dose for Phase 3 Evaluation

The ceftibuten/avibactam tomilopil‐PO joint pharmacokinetic model was modified for jPTA simulations to include relationships between CrCL and CL/F for ceftibuten and avibactam in participants with decreased renal function, and only included covariate effects that were clinically relevant/plausible. The differences between covariate model and simulation model are listed in Table S13. The relationship between interindividual and residual variability for ceftibuten and avibactam in the simulation model is presented in Table S14. Since linear relations between CL/F and CrCL for ceftibuten, and between clearance and CrCL for (intravenous) avibactam were reported in participants with renal impairment, ³³ , ³⁵ in the simulation model the effect of nCrCL on CL/F was replaced with a linear effect of CrCL on CL/F. Parameter estimates for this simulation model are presented in Table S15.

The jPTA simulations using the final population pharmacokinetic model focused on ceftibuten 400 mg + avibactam tomilopil 800 mg to 1350 mg q8h in patients with cUTI under fed and fasted conditions. In the fed condition, jPTA for ceftibuten 400 mg + avibactam tomilopil 800 mg q8h was >90% for MIC ≤2 mg/L. However, in the sensitivity analysis when IIVs were inflated, jPTA for ceftibuten 400 mg + avibactam tomilopil 800 mg q8h did not reach 90% for any MIC. In the fasted condition, jPTA at each MIC was lower than in the fed condition for corresponding ceftibuten‐avibactam tomilopil doses, and ceftibuten 400 mg + avibactam tomilopil 800 mg q8h did not achieve 90% jPTA at any MIC. With inflated IIVs of 50%, jPTA was further reduced, and the lowest dose required for jPTA >90% at MIC = 1 mg/L was ceftibuten 400 mg + avibactam tomilopil 1200 mg q8h (Figure 2, Table S16).

Figure 2.

jPTA and isolates at each ceftibuten MIC. jPTA at the selected Phase 3 dose in red. ^aThe joint probability of target attainment was simulated under fed conditions (CTB/AVP 400 mg/1200 mg TID). The joint probability of target attainment for MIC 0.06 mg/L or lower was extrapolated from that for MIC 0.12 mg/L. The distribution represents the frequency of ESBL phenotype Enterobacterales isolates from cUTI at each CTB‐AVI MIC. ²⁹ AVI, avibactam; AVP, avibactam tomilopil; CTB, ceftibuten; cUTI, complicated urinary tract infection; ESBL, extended‑spectrum β‐lactamase; jPTA, joint probability of target attainment; MIC, minimum inhibitory concentration, TID, three times a day.

Discussion

The Phase 1 studies reported here evaluated avibactam tomilopil doses of 900 to 1350 mg and ceftibuten doses of 400 to 1600 mg. Across these studies, all ceftibuten and avibactam tomilopil doses (alone or in combination), including the highest doses tested, were safe and generally well tolerated. The most frequent all‐cause TEAEs and treatment‐related TEAEs were gastrointestinal disorders (primarily diarrhea and abdominal pain), which are common adverse reactions associated with ceftibuten. ¹⁶ These results are consistent with the previously documented safety profiles of oral ceftibuten and intravenous avibactam. ¹⁶

Oral avibactam tomilopil was rapidly metabolized to active avibactam and inactive hydroxypivalic acid. Plasma avibactam and cis‐ceftibuten pharmacokinetic profiles were in line with previous observations ²² , ²³ ; dose proportionality was observed for avibactam and for cis‐ceftibuten up to 800 mg. Both avibactam and cis‐ceftibuten had similar plasma half‐lives and were predominantly renally excreted; fractions of total converted drug excreted unchanged in urine were consistent across doses. When dosed with food, the tablet formulation (a fixed‐dose combination of ceftibuten‐avibactam tomilopil) showed no appreciable change in the exposures of cis‐ceftibuten, whereas the exposures of avibactam increased. Such increases in avibactam exposure are within the range of previous evaluations of higher doses of (intravenous) avibactam and, as such, deemed safe. ⁴³ In C4691003, the terminal half‐life for avibactam following administration of ceftibuten‐avibactam tomilopil as a fixed‐dose tablet under high‐fat meal condition (arithmetic mean 2.3 h) was comparable with that of avibactam following intravenous administration (approximately 2 h), ⁴⁴ suggesting the elimination might be affected by absorption of oral avibactam tomilopil. However, a flip‐flop model was not explored in the population modeling exercise due to limited data for parameter estimation.

In the population pharmacokinetic analysis, which used participant pharmacokinetic data from the three Phase 1 studies, jPTA simulations applied covariates for patients with cUTIs, including weight and CrCL, for cis‐ceftibuten and avibactam exposures. This reflected the relationship between CrCL and CL/F and enabled a more accurate prediction of exposure across a spectrum of renal impairment. The simulations utilized free plasma exposures and a joint pharmacokinetic/pharmacodynamic target derived from a murine neutropenic thigh infection study which was expected to correlate with clinical efficacy (data on file). Separate simulations were done for fed and fasted conditions to quantify the impact on jPTA of the effect of food on avibactam bioavailability; sensitivity analyses explored the impact of inflated patient covariate IIVs. The results of the jPTA simulations indicate that ceftibuten 400 mg + avibactam tomilopil 1200 mg q8h is associated with >90% jPTA for achievement of the prespecified plasma exposure targets for both cis‐ceftibuten and avibactam tomilopil. Therefore, this suggests that this dosage regimen could attain clinical efficacy against Enterobacterales strains with ceftibuten‐avibactam tomilopil MICs up to 1 mg/L in adult patients with cUTIs. Based on contemporary surveillance data from patients with UTIs, this would be sufficient to cover >97% of ESBL, >90% of MDR, and >70% of CRE Enterobacterales isolates. ²⁷ , ²⁹

In the final model, power functions for BSA‐nCrCL were included for ceftibuten and avibactam CL/F. In the simulation model, these functions were replaced with linear relationships based on absolute CrCL as reported in the published literature. ³³ , ³⁵ The published studies included subjects with mild, moderate, and severe renal impairment as well as reference populations. This modification was not intended as a sensitivity analysis, but rather as the primary simulation approach to ensure the model is applicable to the cUTI population, whose renal function distribution extends beyond that of the healthy dataset used for model development. In contrast, the final model using BSA‐nCRCL was retained to support robust parameter estimation and to separate body size and renal function in the narrow and correlated covariates of the analysis dataset. Further data are required to better characterize the relationships between renal function and CL/F for ceftibuten and avibactam in patients with cUTI, and identify potential covariates impacting on the pharmacokinetics. The joint pharmacokinetic model will be updated, once ceftibuten/avibactam tomilopil pharmacokinetics data from patients with cUTI are available.

Limitations of the current analyses include the relatively small participant sample size from the Phase 1 studies, which resulted in a narrow range of available covariate information, including a relatively narrow CrCL distribution, this limitation was overcome by resampling covariate information (body weight and CrCL) in patients with cUTIs from a previous aztreonam‐avibactam dataset, ⁴² and linear CrCL–CL/F relationships from published literature. ³³ There were design limitations of the studies presented in the manuscript. Notably, in C4691001 and C4691002, participants received a regular meal under fed administration, whereas those in C4691003 received a high‐fat meal for fed administration. Coupled with formulation differences, the results are not directly comparable across all three studies. Another point to consider is that the C4691001 study evaluated fasted state on Day 7 whereas Day 1 and Day 6 pharmacokinetic evaluations were after drug administration in regular meal fed state. It is thus advisable to use caution when comparing results from different studies.

Conclusions

Across three Phase 1 studies, the primary objectives were to evaluate the safety, tolerability, pharmacokinetics, and dose‑selection rationale for oral avibactam tomilopil administered alone or in combination with ceftibuten. Coadministration of avibactam tomilopil with ceftibuten is expected to restore and enhance the activity of ceftibuten against Gram‐negative bacterial strains that are otherwise resistant due to β‐lactamase production. Across these studies, single and multiple doses of oral avibactam tomilopil up to 1350 mg q8h (alone or in combination with ceftibuten), single doses of ceftibuten up to 1600 mg, and multiple doses of ceftibuten 400 mg q8h were safe and generally well tolerated in healthy adults, consistent with the safety profiles of oral ceftibuten and intravenous avibactam. Avibactam tomilopil was rapidly metabolized to active avibactam and hydroxypivalic acid. The pharmacokinetic profiles of avibactam and cis‐ceftibuten were consistent with previous findings. Based on jPTA simulations using a simultaneous ceftibuten/avibactam tomilopil‐PO population pharmacokinetic model, ceftibuten 400 mg + avibactam tomilopil 1200 mg administered q8h without regard to food was associated with >90% jPTA for achievement of the prespecified plasma exposure targets for both cis‐ceftibuten and avibactam tomilopil. Therefore, it is expected to demonstrate clinical efficacy against Enterobacterales strains with ceftibuten‐avibactam tomilopil MICs up to 1 mg/L in adult patients with cUTI. Based on jPTA simulations using a simultaneous oral ceftibuten‐avibactam tomilopil population pharmacokinetic model, a tablet formulation of ceftibuten 400 mg + avibactam tomilopil 1200 mg dosed q8h without regard to food is recommended to be evaluated in the Phase 3 study in adult patients with cUTI.

Author Contributions

Term	CRediT (contributor roles taxonomy) definition	Author initials
Conceptualization	Ideas; formulation or evolution of overarching research goals and aims	SAS, SS, ASJ, BKA, ST
Data curation	Management activities to annotate (produce metadata), scrub data and maintain research data (including software code, where it is necessary for interpreting the data itself) for initial use and later reuse
Formal analysis	Application of statistical, mathematical, computational, or other formal techniques to analyze or synthesize study data	SAS, SS, ASJ, BJM, ASD
Funding acquisition	Acquisition of the financial support for the project leading to this publication
Investigation	Conducting a research and investigation process, specifically performing the experiments, or data/evidence collection	CK, JKM
Methodology	Development or design of methodology; creation of models	SS, ST
Project administration	Management and coordination responsibility for the research activity planning and execution	BKA, CK, JKM
Resources	Provision of study materials, reagents, materials, patients, laboratory samples, animals, instrumentation, computing resources, or other analysis tools	CK, JKM
Software	Programming, software development; designing computer programs; implementation of the computer code and supporting algorithms; testing of existing code components	SS, BJM, ASD
Supervision	Oversight and leadership responsibility for the research activity planning and execution, including mentorship external to the core team	OS, AB, NNA, RSPS
Validation	Verification, whether as a part of the activity or separate, of the overall replication/reproducibility of results/experiments and other research outputs	SS, BJM, ASD
Visualization	Preparation, creation and/or presentation of the published work, specifically visualization/data presentation	SS
Writing – original draft	Preparation, creation and/or presentation of the published work, specifically writing the initial draft (including substantive translation)
Writing – review and editing	Preparation, creation and/or presentation of the published work by those from the original research group, specifically critical review, commentary, or revision – including pre‐or post‐publication stages	All

Conflicts of Interest

Siddhee A. Sahasrabudhe and Negar Niki Alami are former employees of Pfizer. Satoshi Shoji, Abhijeet S. Jakate, Bisrat K. Abraham, Sima S. Toussi, Benjamin J. Maligalig, Amanda S. Darekar, Sakambari Tripathy, Constantino Kantaridis, Josue K. Mfopou, Oxana Selivanova, Arthur Bergman, and Ravi Shankar P. Singh, are employees of Pfizer. Amanda S. Darekar, Oxana Selivanova, Constantino Kantaridis, Sima S. Toussi, Arthur Bergman, Ravi Shankar P. Singh and Abhijeet S. Jakate own stock or stock options in Pfizer. Satoshi Shoji is an employer of Pfizer Inc., Pfizer R&D Japan and owns stock or stock options in Pfizer.

Funding

These studies and the population pharmacokinetic/pharmacodynamic analyses were sponsored by Pfizer, other than Study C4691002 (which was sponsored by Arixa Pharmaceuticals prior to its acquisition by Pfizer).

Supporting information

Supplemental Information

Data Availability Statement

Upon request, and subject to certain criteria, conditions, and exceptions (see https://www.pfizer.com/science/clinical‐trials/trial‐data‐and‐results for more information), Pfizer will provide access to individual de‐identified participant data from Pfizer‐sponsored global interventional clinical studies conducted for medicines, vaccines, and medical devices (1) for indications that have been approved in the United States and/or European Union or (2) in programs that have been terminated (i.e., development for all indications has been discontinued). Pfizer will also consider requests for the protocol, data dictionary, and statistical analysis plan. Data may be requested from Pfizer trials 24 months after study completion. The de‐identified participant data will be made available to researchers whose proposals meet the research criteria and other conditions, and for which an exception does not apply, via a secure portal. To gain access, data requestors must enter into a data access agreement with Pfizer.