https://orcid.org/0000-0002-6036-3263
Abstract
Tebipenem pivoxil hydrobromide is an orally bioavailable carbapenem prodrug of the active agent tebipenem with broad-spectrum activity against drug-resistant Enterobacterales. This study aimed to evaluate the relative bioavailability of crushed tebipenem tablets administered via nasogastric tube (NGT) with or without concomitant enteral feeds.
This Phase 1, open label study randomized 12 healthy subjects to receive a crushed tebipenem tablet via NGT (n = 6) or via NGT with concomitant Osmolite® enteral feeds (n = 6) on Study Day 1, followed by oral administration of tebipenem whole tablet (reference formulation) on Study Day 2. Tebipenem plasma concentrations were measured by LC with mass spectrometry. Bioequivalence was determined using pharmacokinetic parameters derived through non-compartmental analyses.
Mean ± SD tebipenem pharmacokinetic parameters in plasma for subjects who received a crushed tablet via NGT (relative to whole tablet) and a crushed tablet with enteral feeds (relative to whole tablet) were as follows: maximum total plasma concentration (Cmax), 11.1 ± 3.9 (12 ± 3.4) and 10.2 ± 1.9 (10 ± 4) mg/L; area under the curve (AUC0–8), 17.5 ± 3.5 (17.9 ± 2.3) and 15 ± 4.3 (13.4 ± 5.3) mg•h/L. Using the 90% CI criteria, Cmaxand AUC0–8 values for tebipenem were found to be bioequivalent following alternative methods of administration compared with oral dosing of the whole tablet. The three methods of administration were well tolerated.
Results demonstrate that tebipenem maintained bioequivalence when crushed and administered via NGT with and without accompanying enteral feeds in healthy subjects, relative to whole tablet oral administration. Data therefore support alternative methods of tebipenem administration depending on patient condition.
Introduction
Tebipenem is the active agent of the prodrug tebipenem pivoxil hydrobromide and has extended in vitro activity against facultative anaerobic, Gram-positive and -negative pathogens, including quinolone-resistant and ESBLs.1–3 The advent of parenteral novel β-lactam/β-lactamase inhibitor antibiotics has been tremendous in affording clinicians safe and efficacious options to treat infected patients.4 However, the availability of tebipenem pivoxil hydrobromide as an oral carbapenem would expand therapeutic options for ESBL-harbouring Enterobacterales and provide an opportunity to step-down intravenous agents to an oral agent.
Enteral feeding tubes are regularly used for food and medication administration in patients who find it difficult to swallow safely, or patients who are critically ill.5,6 In these cases, several factors need to be considered including tube size, distal site placement and drug formulation to ensure the tubes are not clogged and drug is appropriately delivered.6 Because tebipenem pivoxil hydrobromide is formulated as an immediate-release oral tablet, this study aimed to evaluate whether the tablet can be crushed and administered as a suspension via a nasogastric tube (NGT) with and without ongoing enteral feeds, as well as to determine the relative bioavailability and safety profile of crushed tebipenem relative to oral administration of the whole tablet.
Methods
Ethics
This study was conducted in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki. Study protocol was approved by the Hartford Healthcare Institutional Review board (HHC-2021-0354).
Study design and participants
The present study was an open label, randomized, one-way crossover pharmacokinetic study (NCT05296382) in 12 healthy volunteers housed in the Clinical Research Center at Hartford Hospital (Table S1, available as Supplementary data at JAC online). Subjects were randomized to receive tebipenem as a crushed suspension via NGT (crushed-NGT) or crushed suspension via NGT with concomitant enteral feeds (crushed-NGT-enteral feed) on Study Day 1, followed by oral administration of tebipenem whole tablet (reference formulation) on Study Day 2 after a wash-out period. Predefined enteral feeds (Osmolite® 1.2 cal; Abbott Nutrition) were administered through NGT via a feeding pump (Kangaroo™ ePump; Covidien). Enteral feeds were run at a rate of 40 mL/h over a 6 h period (2 h predose to 4 h postdose).
Healthy adult male and female subjects aged ≥18 years with a body mass index ≥18.5 and <35 kg/m2 were eligible for enrolment. All subjects were considered healthy on the basis of physical examination, medical/surgical history, chemistry profile, blood count and urinalysis all assessed in screening evaluations within 38 days of drug administration. Within 24 h before the dosing, subjects underwent another physical and medical examination as well as clinical laboratory testing to confirm that no clinically relevant changes from the screening baseline had occurred.
Nasogastric tube placement and tebipenem administration
A lubricated 14-Fr (diameter), 122-cm (length) enteral feeding tube (Salem Sump; Covidien), was inserted through a nostril into the nasal passageway and then swallowed, as directed by the medical team, at least 2 h before dose or enteral feed administration. Topical lidocaine jelly (2%) was applied in the nasal passageway to reduce discomfort approximately 15 minutes before the procedure. Appropriate positioning of the NGT tip in the stomach was determined by an abdominal X-ray per Hartford Hospital's standard operating procedure.
Tebipenem pivoxil hydrobromide tablets were provided by Spero Therapeutics (Boston, MA, USA). Subjects were randomized to one of two intervention groups for dose 1: six subjects received crushed tebipenem tablets (600 mg dose delivered as two 300 mg tablets) suspended in 50 mL of water and administered by syringe through the NGT. Immediately afterwards, an additional 50 mL of water was used to rinse out any remaining drug and flush the tube for each subject. The other six subjects received the same dose regimen and route as intervention group 1 in addition to continuous enteral feeding for 6 hours (beginning 2 h predose). To minimize drug loss typically associated with a mortar and pestle, each subject’s dose was crushed in a pouch with a Silent Knight Pill Crusher®. The next day (23 h wash-out period), all 12 subjects were administered whole tablet tebipenem 600 mg dose (two 300 mg tablets) orally. On both study days, subjects were fasting for a minimum of 10 h before each dose (and up to 4 h postdose) or enteral feed.
Sample collection and protein binding studies
Whole-blood samples were collected at 0 (immediately prior to drug dose), 0.25, 0.5, 1, 2, 3, 4, 5, 6 and 8 hours after dosing. Within 1 h, samples were centrifuged at 1600 × g for 10 minutes at 4°C and separated plasma was stored at −80°C until analysis. Protein binding was performed for each subject on each study day using additional plasma from the 1 h blood sampling time point. An aliquot of plasma was retained at each corresponding time point for total drug concentration determination in the plasma (Cplasma). The amount of protein binding was calculated using the following equation: % protein binding = 100−(100×Cultrafiltrate/Cplasma).
Pharmacokinetic analysis and statistical analysis
Tebipenem concentrations were determined using LC with tandem mass spectrometry (Keystone Bioanalytical, Inc., PA, USA). Intra-batch and inter-batch precision [percentage coefficient of variation (% CV)] for all standards and samples was ±20%. The assay lower limit of quantitation was 2 ng/mL. Total tebipenem in plasma for each participant was analysed using non-compartmental analysis in Phoenix WinNonlin (v.6.3, Certara, Princeton, NJ, USA) as previously described.7
AUC0–8 and Cmax for the two interventions, crushed-NGT and crushed-NGT-enteral feed were compared with the reference formulation (whole tablet) using the log-transformed pharmacokinetic values. Dosing groups were considered bioequivalent if the 90% CIs of the log-transformed AUC0–8 and Cmax values were within the 80%–125% range.
Safety assessment
Participants were monitored for any sign or symptom of adverse events throughout the course of the study. All adverse events were assessed by the study physician and recorded. An end of study evaluation was conducted including a full physical examination, vital sign measurement and clinical laboratory tests.
Results
Plasma pharmacokinetics
The mean tebipenem concentration–time profiles for the alternative methods (crushed-NGT and crushed-NGT-enteral feeds) relative to oral administration of the whole tablet are shown in Figure 1. Plasma pharmacokinetic parameters are reported in Table 1. Overall, tebipenem was rapidly absorbed irrespective of the dosing formulation or administration route. No drug was detected on Study Day 2 predose, demonstrating appropriateness of the wash-out period. Relative to whole tablets, the crushed tablets (with and without enteral feeds) met the bioequivalence criteria regarding Cmax and AUC0–8.
Logarithmic plot of mean (±SD) plasma concentration versus time for 600-mg dose of tebipenem administered as crushed or whole tablets. (a) Crushed-NGT versus whole tablet and (b) crushed-NGT-Enteral feeds versus whole tablet. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.
Comparison of tebipenem pharmacokinetic parameters when administered as whole tablet orally or crushed tablet formulation with or without enteral feeds via NGT
| Pharmacokinetic parameter | Mean (SD) | Crushed-NGT/ Whole tablet ratio (%, 90% CI) | Mean (SD) | Crushed-NGT with Enteral feeds/Whole tablet ratio (%, 90%CI) | ||
|---|---|---|---|---|---|---|
| Crushed-NGT | Whole tableta | Crushed-NGT with Enteral feeds | Whole tableta | |||
| AUC0–8(mg•h/L) | 17.5 (3.5) | 17.9 (2.6) | 98.5 (95, 102) | 14.97 (4.3) | 13.4 (5.3) | 106.2 (100, 113) |
| Cmax (mg/L) | 11.1 (3.9) | 12 (3.4) | 96.3 (91, 102) | 10.2 (1.9) | 10 (4) | 105.7 (97, 114) |
| Tmax(h) | 1.3 (0.5) | 1.25 (0.6) | — | 0.66 (0.2) | 0.92 (0.18) | — |
| T1/2(h) | 0.92 (0.06) | 0.99 (0.1) | — | 0.9 (0.07) | 0.94 (0.06) | — |
| Pharmacokinetic parameter | Mean (SD) | Crushed-NGT/ Whole tablet ratio (%, 90% CI) | Mean (SD) | Crushed-NGT with Enteral feeds/Whole tablet ratio (%, 90%CI) | ||
|---|---|---|---|---|---|---|
| Crushed-NGT | Whole tableta | Crushed-NGT with Enteral feeds | Whole tableta | |||
| AUC0–8(mg•h/L) | 17.5 (3.5) | 17.9 (2.6) | 98.5 (95, 102) | 14.97 (4.3) | 13.4 (5.3) | 106.2 (100, 113) |
| Cmax (mg/L) | 11.1 (3.9) | 12 (3.4) | 96.3 (91, 102) | 10.2 (1.9) | 10 (4) | 105.7 (97, 114) |
| Tmax(h) | 1.3 (0.5) | 1.25 (0.6) | — | 0.66 (0.2) | 0.92 (0.18) | — |
| T1/2(h) | 0.92 (0.06) | 0.99 (0.1) | — | 0.9 (0.07) | 0.94 (0.06) | — |
Reference formulation.
Comparison of tebipenem pharmacokinetic parameters when administered as whole tablet orally or crushed tablet formulation with or without enteral feeds via NGT
| Pharmacokinetic parameter | Mean (SD) | Crushed-NGT/ Whole tablet ratio (%, 90% CI) | Mean (SD) | Crushed-NGT with Enteral feeds/Whole tablet ratio (%, 90%CI) | ||
|---|---|---|---|---|---|---|
| Crushed-NGT | Whole tableta | Crushed-NGT with Enteral feeds | Whole tableta | |||
| AUC0–8(mg•h/L) | 17.5 (3.5) | 17.9 (2.6) | 98.5 (95, 102) | 14.97 (4.3) | 13.4 (5.3) | 106.2 (100, 113) |
| Cmax (mg/L) | 11.1 (3.9) | 12 (3.4) | 96.3 (91, 102) | 10.2 (1.9) | 10 (4) | 105.7 (97, 114) |
| Tmax(h) | 1.3 (0.5) | 1.25 (0.6) | — | 0.66 (0.2) | 0.92 (0.18) | — |
| T1/2(h) | 0.92 (0.06) | 0.99 (0.1) | — | 0.9 (0.07) | 0.94 (0.06) | — |
| Pharmacokinetic parameter | Mean (SD) | Crushed-NGT/ Whole tablet ratio (%, 90% CI) | Mean (SD) | Crushed-NGT with Enteral feeds/Whole tablet ratio (%, 90%CI) | ||
|---|---|---|---|---|---|---|
| Crushed-NGT | Whole tableta | Crushed-NGT with Enteral feeds | Whole tableta | |||
| AUC0–8(mg•h/L) | 17.5 (3.5) | 17.9 (2.6) | 98.5 (95, 102) | 14.97 (4.3) | 13.4 (5.3) | 106.2 (100, 113) |
| Cmax (mg/L) | 11.1 (3.9) | 12 (3.4) | 96.3 (91, 102) | 10.2 (1.9) | 10 (4) | 105.7 (97, 114) |
| Tmax(h) | 1.3 (0.5) | 1.25 (0.6) | — | 0.66 (0.2) | 0.92 (0.18) | — |
| T1/2(h) | 0.92 (0.06) | 0.99 (0.1) | — | 0.9 (0.07) | 0.94 (0.06) | — |
Reference formulation.
Safety and tolerability
Tebipenem was found to be well tolerated, with no serious adverse events reported. Six healthy subjects experienced minor adverse effects which required no interventions and did not affect their participation in the study. Two participants experienced contact dermatitis secondary to adhesive tape at the intravenous catheter insertion site. Headache (n = 3), nausea (n = 1), hyponatraemia (n = 1), hyperbilirubinaemia (n = 1) and back-pain (n = 1, unrelated to drug) were observed during the study window.
Discussion
Tebipenem pivoxil hydrobromide is an immediate-release oral tablet that is highly water soluble and readily permeable across the gastrointestinal tract. Given the potential of this oral antibiotic to be used in a variety of healthcare settings, it is important to evaluate the pharmacokinetics of alternate methods of administration.8 This current study demonstrated that the systemic exposure of tebipenem following administration of the crushed tablet with and without enteral feeds was not significantly altered compared with plasma exposures after administration of the whole tablet as defined by bioequivalence 90% CIs cutoffs of 80% and 125%.
The observed concentration–time profiles in this study are similar to those reported from previous Phase 1 pharmacokinetic studies. In a study by Eckburg and colleagues, the mean fasted and fed AUC values after a single tebipenem 600 mg oral dose were 12.7 and 14.2 mg.h/L, respectively and the authors observed no clinically relevant food effect.9 Similarly, no meaningful food effect was observed in this current study between subjects that received enteral feeds compared with fasted subjects.
Variability in oral bioavailability can occur due to several factors including various drug physiochemical properties such as particle size and pH as well as metabolism by the gastrointestinal tract and liver.10,11 Within this context, the placement of the NGT is worth considering. Nasogastric feeding tubes are common and easy to place with the distal end of the tube positioned in the stomach, however, other distal locations or tube routes such as ileostomy tube are also used.6,12 A previous study involving nasogastric and nasoduodenal tube administration of ciprofloxacin demonstrated that drug absorption was higher when administered via the nasoduodenal tube.13 Importantly, because tebipenem pivoxil hydrobromide is a prodrug that undergoes conversion to tebipenem by carboxylesterases localized in jejunum and ileum enterocytes, it is crucial that the prodrug be delivered proximal to this segment as was done in this current study.14,15
Overall, this study demonstrated that crushing tebipenem tablets is a viable formulation and retains equivalent bioequivalence to the whole tablet formulation when administered with and without concomitant enteral feeds. Administration of either the whole or crushed tablet via a NGT was also safe and well tolerated. This study outlines several alternative methods for administering tebipenem pivoxil hydrobromide depending on clinical conditions and in patients who are unable to swallow the oral dose formulation.
Acknowledgements
We thank the staff of the Center for Anti-Infective Research and Development and Hartford Hospital including a special gratitude to Lee Steere, Elizabeth Anne Cyr, Angela Berry, Andrew Fratoni, Yasmeen Abouelhassan, Ashley Gonzales and Jessica O’Connor for their assistance in the conduct of this study
Funding
This study was funded by an investigator-initiated grant from Spero Therapeutics.
Transparency declarations
DPN has served as a consultant, speaker’s bureau member or has received research funding from Abbvie, Cepheid, Merck, Paratek, Pfizer, Wockhardt, Shionogi and Tetraphase. TEA has received funding from Venatorx Pharmaceuticals and the U.S. Food and Drug Administration. All other authors have no conflicts of interest to disclose.
Supplementary data
Table S1 is available as Supplementary data at JAC online.
