Safety, Pharmacokinetics, and Food Effect of Tebipenem Pivoxil Hydrobromide after Single and Multiple Ascending Oral Doses in Healthy Adult Subjects

Tebipenem pivoxil hydrobromide (TBPM-PI-HBr, formerly SPR994) is an orally available prodrug of tebipenem, a carbapenem with activity versus multidrug-resistant (MDR) Gram-negative pathogens, including quinolone-resistant and extended-spectrum-β-lactamase-producing Enterobacteriaceae. The safety and pharmacokinetics (PK) of tebipenem were studied after administration of single and multiple ascending oral doses of TBPM-PI-HBr in fed and fasted states.

The PK profile of Orapenem at 300 mg during fasting was characterized by a T max of 0.5 h and half-life of 1.0 h, with C max exceeding that of the TBPM-PI-HBr IR formulations (Table 2 and Fig. 1). With Orapenem, a reduction in both AUC and C max but no change in T max was observed when administered in fed compared with fasted states (Table 3 and Fig. 2).
A summary of the effect of food on the relative bioavailability of tebipenem following administration of the IR and ER formulations of TBPM-PI-HBr and of Orapenem is presented in Table 4. Given that the 6-h and 12-h ER formulations were associated with decreased absorption, the fact that the relative bioavailability associated with the 2-h and 4-h ER formulations was not substantially better than that of the IR formulation, and the predictability of IR formulation PK characteristics over the range of doses studied, the IR formulation was utilized in the MAD phase of the study. Of note, food did not impact the AUC exposure observed following administration of 300 mg (IR) or 600 mg (IR) of TBPM-PI-HBr (Fig. 3).
(ii) MAD phase. Only the IR formulation of TBPM-PI-HBr (300 mg and 600 mg) was evaluated in the MAD phase of this study. C max was reached within 1.5 h of dose administration on both day 1 (single dose) and day 14 (steady state), with a median T max of less than 1 h (Table 5). Pharmacokinetic parameters of exposure increased more rapidly than dose, with AUC for the 600-mg dose being more than twice the AUC for the 300-mg dose on both day 1 (2.7-fold) and day 14 (2.5-fold). C max was dose proportional on day 1 and higher than dose proportional (2.7-fold) on day 14 for the 600-mg than for the 300-mg dose (Fig. 4). No accumulation occurred at a tebipenem doses of 300 mg and 600 mg every 8 h (q8h). The accumulation ratio of AUC from 0 to 8 h (AUC 0 -8 ) for day 14 versus day 1 was 1.01 for the 300-mg dose and 0.87 for the 600-mg dose, which was consistent with a short half-life (Ͻ1 h) for tebipenem.
Urine concentrations. In the SAD phase, the mean fraction of the administered dose excreted in urine as unchanged drug (tebipenem) with fasted administration of the IR and 2-h, 4-h, and 6-h ER formulations of TBPM-PI-HBr ranged from 35.0% to 59.2% and during fed administration from 45.1% to 61.8% (Table 6); the fractions excreted in urine were similar for the IR formulation and for Orapenem (59.2% fasted and 55.1% fed). For the 12-h ER formulation of TBPM-PI-HBr, the mean fractions of dose excreted in urine were 20.8% to 28.5% with fasted administration and 53.8% to 62.7% with fed administration. Renal clearance ranged from 12.8 to 22.7 liters/h and was not  affected by food. In the MAD phase, 57% and 66% of tebipenem for the 300-mg and 600-mg doses of TBPM-PI-HBr were excreted in urine on day 1. The fraction excreted (Fe; 0 to 8 h) was lower on day 14 (39.4% and 28.8%, respectively). Renal clearances were 15.2 to 16.7 liters/h on day 1 and 7.5 to 11.9 liters/h on day 14.
Events of diarrhea were assessed in detail (6 TBPM-PI-HBr-treated subjects and 1 placebo-treated subject). There was no trend in diarrhea TEAEs with respect to TBPM-PI-HBr dosage or fed versus fasting status. The 6 diarrhea TEAEs in the TBPM-PI-HBrtreated subjects occurred in 6 different dosage cohorts (ranging from 100 mg to 900 mg), and the events occurred under either the fed (3/7 events) or fasting (4/7 events) condition. All events of diarrhea were deemed mild in severity by the principal investigator. The time to onset of all diarrhea TEAEs was Ͻ1 day from dosing, with the exception of an unknown time to onset in the 100-mg 12-h subject, and most events resolved within 1 day. There were no cases of Clostridium difficile infection. In addition, gastrointestinal events of nausea and vomiting were not observed in any subject in  the SAD phase, and no TBPM-PI-HBr-treated subject had ALT or AST elevation over 3ϫ the ULN.
In the MAD phase, a total of 34 TEAEs were reported for 16 of 16 (100%) subjects (12 TBPM-PI-HBr-treated subjects and 4 placebo-treated subjects). All TEAEs were mild in severity, except for 1 moderately severe TEAE (1 event of ALT increased [Ͼ3ϫ to 5ϫ the ULN] in a subject treated with TBPM-PI-HBr at 300 mg q8h). No subject in the MAD phase experienced a severe TEAE, TEAE that led to premature discontinuation of study drug or study withdrawal, or a serious AE. The moderate ALT increase in the subject treated with TBPM-PI-HBr at 300 mg q8h was deemed probably related to study treatment. This TEAE commenced 6 days following first dose administration and resolved 12 days later. This subject had 2 doses temporarily held (dose 3 on day 8 and  dose 1 on day 9), due to the AEs of ALT and AST increases. Follow-up unscheduled serum aminotransferase values on day 8 and day 9 were trending down from peak levels; therefore, a decision was made to restart TBPM-PI-HBr. The subject completed the remainder of TBPM-PI-HBr doses, with an overall treatment compliance of 95% (38/40 doses). Of note, the aminotransferase levels did not worsen after rechallenge with TBPM-PI-HBr. The most common type of TEAE by system organ class in both treatment groups was gastrointestinal disorders (11 [69%] TBPM-PI-HBr-treated subjects and 2 [50%] placebo-treated subjects), consisting primarily of diarrhea (2 subjects treated with TBPM-PI-HBr at 300 mg q8h, 5 subjects treated with TBPM-PI-HBr at 600 mg q8h, and 1 placebo-treated subject). Other commonly occurring TEAEs in the TBPM-PI-HBr cohorts, i.e., TEAEs reported for at least 2 (Ն10%) of TBPM-PI-HBr-treated subjects, included headache (2 subjects), abdominal pain (2 subjects), and ALT increase (3 subjects).
Adverse events determined to be possibly or probably related to study drug were reported for 13 (92%) TBPM-PI-HBr-treated subjects and 4 (100%) placebo-treated subjects. All study drug-related AEs in the MAD phase were of mild severity, except for the single case of moderate ALT increase in the subject treated with TBPM-PI-HBr at 300 mg q8h described above. All gastrointestinal TEAEs (9 TBPM-PI-HBr-treated subjects and 2 placebo-treated subjects) and aminotransferase elevation TEAEs (3 TBPM-PI-HBrtreated subjects) in the MAD phase were deemed possibly or probably related to study drug.
Although limited by the small numbers of subjects per cohort (6 subjects per TBPM-PI-HBr cohort), more TEAEs of diarrhea occurred in the higher-dose cohort (600 mg q8h) than in the 300-mg q8h group or placebo group. However, all events of diarrhea were deemed mild in severity by the principal investigator. The time to onset of all diarrhea TEAEs was Ͻ1 day from dosing, and most events resolved within 1 day (2 of the 8 diarrhea TEAEs resolved in approximately 2 days). There were no cases of C. difficile infection. Vomiting was not observed in any subject in the MAD phase; however, 1 subject treated with TBPM-PI-HBr at 600 mg q8h and 1 placebo-treated subject experienced nausea (both cases mild and possibly related to study drug). Finally, with the exception of the single moderate TEAE of ALT increase described above, no subject in the MAD phase had ALT elevations Ͼ3ϫ the ULN.
No clinically significant findings were observed for physical examinations, vital signs, clinical laboratory testing, or electrocardiogram (ECG) testing in either the SAD or MAD phase.

DISCUSSION
TBPM-PI-HBr is being developed as an oral carbapenem for the treatment of serious infections caused by MDR Gram-negative pathogens, with the potential opportunity for avoidance of hospitalization and/or to transition patients home more quickly after initiating therapy with i.v. antibiotics in the hospital. Unlike other carbapenems used to treat MDR infections in adults, TBPM-PI-HBr is an orally administered tablet formulation that provides high tebipenem bioavailability (50% to 60%). Thus, oral administration may allow physicians to avoid or limit the duration of i.v. antibiotics, provide an oral carbapenem option as step-down therapy from i.v. carbapenem therapy, or allow for a reduction in costs associated with avoiding hospitalization.
Results from this study demonstrate that the PK profile of tebipenem generally was dose proportional and linear after single doses of 100 to 900 mg with the IR formulation. Results from the MAD phase indicate dose proportionality and approximately linear PK with 300 and 600 mg q8h, with no accumulation over 14 days. While C max was lower with the 300-mg dose of the IR formulation during the fed state, exposure (AUC from 0 h to infinity [AUC 0-∞ ]) was proportional for both the 300-mg IR and 600-mg IR doses between fed and fasted states, supporting administration of TBPM-PI-HBr without respect to meals. More variability in the PK profile of the ER formulations was observed across doses. While this study examined the various ER formulations to determine PK properties and their potential for extending the dosage interval, based on results during the SAD phase, the IR formulation will be used in future studies. Studies of PK in patients with serious infections are needed to confirm these results.
In this SAD/MAD study, TBPM-PI-HBr was well tolerated. Gastrointestinal events were the most common types of TEAEs in both the SAD and MAD parts of the study (whether in TBPM-PI-HBr-treated subjects or control groups), predominantly consisting of transient, mild events of loose stools that occurred on the first day of dosing and resolved spontaneously within 24 h. In the MAD study, these events resolved within 1 to 2 days despite ongoing study drug dosing q8h for the full 14-day course. There were no cases of Clostridium difficile infection. Gastrointestinal events such as diarrhea are common, well-described effects of the ␤-lactam antibiotic class.
Of note, plasma concentrations of tebipenem at day 1 with the 300-and 600-mg doses of TBPM-PI-HBr exceeded the MIC 90 for Klebsiella pneumoniae (0.06 ng/ml) and Escherichia coli (0.03 ng/ml) for 4 h, which is 50% of the q8h dosing interval. Urine concentrations of tebipenem were 50-to 100-fold greater than free plasma tebipenem concentrations. Thus, urine concentrations exceeded the MIC 90 of 0.03 ng/ml for 24 h with single oral doses of 300 or 600 mg of TBPM-PI-HBr. Consequently, TBPM-PI-HBr should prove valuable as an oral agent for treating patients with complicated urinary tract infection and acute pyelonephritis.
Carbapenems have emerged as the standard of care for multiple types of MDR Gram-negative bacterial infections, but carbapenems currently are available only as i.v. formulations, highlighting the unmet need for an oral formulation of carbapenems to treat serious infections due to MDR pathogens. Results from in vitro studies demonstrated that tebipenem has potent antibacterial activity against MDR strains, including ESBL-producing Enterobacteriaceae (6)(7)(8). Combined with the promising PK and tolerability of its orally available TBPM-PI-HBr formulation, tebipenem is well positioned to address this unmet need.
An unmet medical need exists for safe and effective oral treatment options directed against serious infections caused by MDR Gram-negative pathogens, such as ESBLproducing or quinolone-resistant Enterobacteriaceae. The data described here provide evidence in support of the safe administration of TBPM-PI-HBr orally q8h for up to 14 days in healthy adults. Thus, oral TBPM-PI-HBr dosed at 600 mg q8h provides a highly bioavailable oral carbapenem to support the treatment of serious infections caused by cephalosporin-and fluoroquinolone-resistant Enterobacteriaceae, such as complicated urinary tract infection and acute pyelonephritis, and has the potential to decrease the need for i.v. antibiotic therapy in the hospital or outpatient setting.

MATERIALS AND METHODS
This study was conducted according to the principles of the Declaration of Helsinki and Guidance on Good Clinical Practice. The study protocol, amendments, and informed consent forms were reviewed and approved by an Institutional Review Board. All subjects provided written informed consent prior to participating in any study activities. This study was registered at Clinicaltrials.gov under registration number NCT03395249.
Investigational products. For this study, TBPM-PI-HBr was formulated as IR and ER oral tablets containing TBPM-PI at 100, 300, or 600 mg. Multiple TBPM-PI-HBr formulations of various release times, including IR, 2-h release, 4-h release, 6-h release, and 12-h release, were tested. Placebo tablets (100, 300, and 600 mg) were pressed from a single placebo blend consisting of the same inactive ingredients as TBPM-PI-HBr; the active pharmaceutical ingredient was replaced by mannitol 200SD. Orapenem fine granules (containing 65 mg of TBPM-PI, equivalent to 50 mg of TBPM per sachet) were manufactured by Meiji Seika Pharma Co., Tokyo, Japan. Study design. This was a double-blind, placebo-controlled, ascending-dose, multicohort study. The study was conducted in two parts: a SAD phase, followed by a MAD phase. Each phase of the study consisted of a screening period, a treatment period, and a follow-up period. The sponsor, the principal investigator, clinical study personnel participating in the study, and subjects were blinded to treatment assignment.
In sequential SAD cohorts, 8 subjects were randomized per cohort in a 3:1 ratio to receive TBPM-PI-HBr at 100, 300, 600, or 900 mg in various IR and ER tablet formulations or placebo (TBPM-PI-HBr dosages indicate amounts of TBPM-PI; each 300-mg dose of TBPM-PI contains 231 mg of active TBPM) ( Table 8). Subjects in cohorts 1 and 7 to 14 received a single dose of TBPM-PI-HBr or placebo in a fasted state (at least a 10-h fast) and a second dose after a 5-day washout following a standardized high-fat meal (approximately 930 kcal) to investigate the food effect on the PK of tebipenem (Table 8). Subjects in cohorts 3, 6, 16, and 17 received a single dose of TBPM-PI-HBr in the fasted state only. Subjects in cohort 2 (TBPM-PI-HBr at 600 mg in a 12-h ER formulation) initially received a single dose of TBPM-PI-HBr or placebo in a fasted state, and 5 of these subjects received a second dose of TBPM-PI-HBr or placebo following a standardized meal. A second cohort of subjects (cohort 7) also received this dose and formulation in the fasted and fed state to ensure adequate PK data for analysis (Table 8).
To compare the PK of TBPM-PI-HBr to those of the commercial preparation of TBPM-PI pediatric fine granules (Orapenem), which is approved for the treatment of respiratory infections in Japan, an additional open-label control cohort was included in which all 8 subjects received a single 300-mg oral dose of Orapenem (equivalent to 389.1 mg of TBPM-PI granules) following a 10-h fast and a second dose on day 7 in the fed state following a minimum 5-day washout period (Table 8).
Blinded safety data were reviewed by a safety monitoring group prior to each dose escalation. The decision to escalate to the next dose was governed by predefined criteria.
The MAD cohorts were enrolled following confirmation that the 300-and 600-mg dose levels were safe and well tolerated in SAD and that these doses produced plasma concentration-time profiles likely under fasting-only and fasting/fed conditions, respectively. A protocol amendment allowed subjects in cohort 2 to return to the unit for repeated dosing in fed condition after a 5-day washout, in order to maximize the number of subjects with fed-condition dosing at this dose. Five of the 8 subjects in cohort 2 returned for this fed-condition dosing. These cohorts were combined for the fasted/fed PK analysis of the 600-mg 12-h ER dosing group. c Orapenem dosage refers to 300 mg of active TBPM, or 389.1 mg of TBPM-PI granules. The Orapenem granule cohort was open label, not placebo controlled.
PK parameters were back-transformed to present the geometric ratio of least-squares means and 90% confidence limits. All statistical analyses were performed using SAS version 9.3.