A phase I, randomized, double-blind, placebo-controlled, ascending single- and multiple-dose study of the pharmacokinetics, safety, and tolerability of oral ceftibuten in healthy adult subjects

ABSTRACT This was a phase I, randomized, double-blind, placebo-controlled, ascending single- and multiple-dose study of oral ceftibuten to describe the pharmacokinetics (PK) of cis-ceftibuten (administered form) and trans-ceftibuten (metabolite), and to describe safety and tolerability at higher than licensed doses. Subjects received single 400, 600, or 800 mg doses of ceftibuten on Days 1 and 4, followed by 7 days of twice-daily dosing from Days 4 to 10. Non-compartmental methods were used to describe parent drug and metabolite PK in plasma and urine. Dose proportionality was examined using C max, AUC0–12, and AUC0–INF. Accumulation was calculated as the ratio of AUC0–12 on Days 4 and 10. Adverse events (AEs) were monitored throughout the study. Following single ascending doses, mean cis- and trans-ceftibuten C max were 17.6, 24.1, and 28.1 mg/L, and 1.1, 1.5, and 2.2 mg/L, respectively; cis-ceftibuten urinary recovery accounted for 64.3%–86.9% of the administered dose over 48 h. Following multiple ascending doses, mean cis- and trans-ceftibuten C max were 21.7, 28.1, and 38.8 mg/L, and 1.4, 1.9, and 2.8 mg/L, respectively; cis-ceftibuten urinary recovery accounted for 72.2%–96.4% of the administered dose at steady state. The exposure of cis- and trans-ceftibuten increased proportionally with increasing doses. Cis- and trans-ceftibuten accumulation factor was 1.14–1.19 and 1.28–1.32. The most common gastrointestinal treatment emergent AEs were mild and resolved without intervention. Ceftibuten was well tolerated. Dose proportionality and accumulation of cis- and trans-ceftibuten were observed. These results support the ongoing development of ceftibuten at doses up to 800 mg twice-daily. (The study was registered at ClinicalTrials.gov under the identifier NCT03939429.)

particularly members of the ESKAPE group of pathogens (1), has resulted in a crisis for the treatment of many hospital-acquired and community-acquired infections.In particular, the increase in Enterobacterales expressing extended-spectrum β-lactamases (ESBLs) and carbapenemases that are resistant to all oral beta-lactams and fluoroquino lones in the community have resulted in many patients requiring hospital admission just for intravenous antibiotics to treat their infections.The associated cost for the healthcare system is high (2).Thus, new oral therapeutic options are needed (3).
Ceftibuten is a cephalosporin antibiotic approved in the USA (4) for acute exacerba tions of chronic bronchitis, acute bacterial otitis media, and pharyngitis/tonsillitis at a dose of 400 mg once-daily for up to 10 days (5-7).The safety profile of ceftibuten is similar to other cephalosporin antibiotics with nausea (4%), headache (3%), diarrhea (3%), dyspepsia (2%) and dizziness, abdominal pain, and vomiting (all 1%) being the most common adverse reactions in the US Food and Drug Administration label (8).
Qpex Biopharma (San Diego, CA, USA) is developing a fixed combination antibiotic of ceftibuten (QPX2015) with a new β-lactamase inhibitor (xeruborbactam, formerly QPX7728).Xeruborbactam can be given both intravenously and orally (in prodrug form), and has inhibitory activity against ESBLs and carbapenemases, including both serine and metallo-β-lactamases (18,19).To maximize the efficacy of ceftibuten in more serious infections due to Gram-negative bacilli, higher doses of ceftibuten than those currently approved may be useful.
The aim of this study is to describe the PK, safety and tolerability of single and multiple oral doses of ceftibuten administered to healthy adult subjects at doses higher than the 400 mg once-daily approved in the USA.

RESULTS
In total, 40 subjects were included in the study; 32 subjects received ceftibuten and 8 received placebo.One subject withdrew prior study completion and did not provide data for Day 10 of the 800 mg dose (n = 15).The demographics for all subjects are summarized in Table 1.Overall, demographics were broadly consistent between the pooled ceftibuten and pooled placebo groups.As expected in these healthy volunteers, the mean baseline estimated glomerular filtration rate across all groups was 90 mL/min/ 1.73 m 2 with no difference between groups.

Single dose plasma PK of cis-and trans-ceftibuten
Cisand trans-ceftibuten plasma PK profiles on Days 1 and 4 after single oral doses of 400, 600, and 800 mg are shown in Fig. 1.
Both cisand trans-ceftibuten exhibited a dose-dependent increase in their respective mean maximum observed plasma concentration (C max ) values.The time of maximum observed plasma concentration (T max ) ranged from 2.6 to 3 h for cis-ceftibuten and from 4.4 to 4.8 h for trans-ceftibuten.Additionally, both cisand trans-ceftibuten showed a dose-related rise in the mean area under the plasma concentration-time curve from 0 to 12 h (AUC 0-12 ) and from 0 extrapolated to time infinity (AUC 0-INF ).The mean terminal half-life (t 1/2 ) remained consistent across the studied dose range, with values ranging   from 2.3 to 2.7 h for cis-ceftibuten and 3.1-3.2h for trans-ceftibuten.Cis-ceftibuten mean apparent volume of distribution (Vz/F) ranged from 15.8 to 18.9 L, and mean apparent clearance (CL/F) ranged from 4.4 to 4.9 L/h.Cisand trans-ceftibuten plasma PK parameters on Day 4 were similar to those on Day 1 (Table 2).

Single dose urine PK of cis-, trans-, and total ceftibuten
Cis-ceftibuten mean amount of drug excreted in the urine (Ae) over 48 h ranged from 332.6 mg for the 400 mg dose to 521.1 mg for the 600 mg dose.The mean fraction of the administered dose excreted in the urine (fe) varied from 64.3% to 86.9%.Mean renal clearance (CL R ) ranged from 3.1 to 4.2 L/h (Table 2).
Trans-ceftibuten mean Ae over 48 h ranged from 43.8 mg for the 400 mg dose to 92.7 mg for the 800 mg dose.The mean fe varied from 10.9% to 12.5%.Mean CL R ranged from 4.8 to 6.3 L/h (Table 2).
Total ceftibuten mean Ae over 48 h ranged from 376.4 mg for the 400 mg dose to 607.4 mg for the 800 mg dose.The mean fe varied from 75.9% to 99.3%.Mean CL R ranged from 3.2 to 4.4 L/h (Table 2).In general, renal excretion is a significant pathway of ceftibuten elimination.

Multiple dose plasma PK of cis-and trans-ceftibuten
Cisand trans-ceftibuten plasma PK profiles after 7 days (Day 10) of ceftibuten adminis tered twice-daily at doses of 400, 600, and 800 mg are shown in Fig. 2.
Both cisand trans-ceftibuten exhibited a dose-dependent increase in their respective C max values.T max ranged from 2.3 to 2.4 h for cis-ceftibuten and from 3.3 to 3.5 h for trans-ceftibuten.Additionally, both cisand trans-ceftibuten showed a dose-related rise in AUC 0-12 and AUC 0-INF (washout) values.The mean t 1/2 remained consistent across the studied dose range, with values ranging from 2.7 to 3.1 h for cis-ceftibuten and 3.0-3.5 h for trans-ceftibuten.Cis-ceftibuten mean apparent volume of distribution (Vz/F) ranged from 16.8 to 18.0 L, and mean apparent clearance (CL/F) ranged from 3.9 to 4.3 L/h (Table 3).

Multiple dose urine PK of cis-, trans-, and total ceftibuten
Cis-ceftibuten mean Ae at steady state (Ae 0-12 ) ranged from 322.8 mg for the 400 mg dose to 578.1 mg for the 600 mg dose.The mean fe at steady state (fe 0-12 ) varied from 72.2% to 96.4%.Mean CL R ranged from 3.0 to 4.2 L/h (Table 3).
Trans-ceftibuten mean Ae 0-12 ranged from 48.2 mg for the 400 mg dose to 98.3 mg for the 800 mg dose.The mean fe 0-12 varied from 12.1% to 14.4%.Mean CL R ranged from 4.9 to 6.3 L/h (Table 3).Total ceftibuten mean Ae 0-12 ranged from 371.0 mg for the 400 mg dose to 676.2 mg for the 800 mg dose.The mean fe 0-12 varied from 84.5% to 110.8%.Mean CL R ranged from 3.2 to 4.4 L/h (Table 3).

Dose proportionality
The exposure (AUC 0-12 ) of cis-ceftibuten increased with increasing doses.Linear regression analysis of the data from Day 1 (y = 0.1718x + 19.83; r = 0.9986), Day 4 (y = 0.1966x + 11.01; r = 0.9726), and Day 10 (y = 0.2201x + 17.20; r = 0.9844) showed that increases were dose proportional.The analysis of variance (ANOVA) confirmed the dose proportionality of cis-ceftibuten since no statistical differences were found for AUC 0-12 and AUC 0-INF on Days 1, 4, and 10 (P > 0.05).Dose proportionality was also assessed using C max after multiple doses (Day 10) and for a single dose (Day 4).However, a statistically significant difference was seen only between the 400 and 800 mg mean C max on Day 1 for a single dose (P = 0.024; Tukey-Kramer post hoc test).
The AUC 0-12 of trans-ceftibuten also increased with increasing doses.Linear regression analysis of the data from Day 1 (y = 0.019x − 0.3; r = 0.9679), Day 4 (y = 0.0202x − 0.6267; r = 0.9805), and Day 10 (y = 0.0254x − 0.3967; r = 0.9866) showed that increases were dose proportional.The ANOVA confirmed the dose proportionality of trans-ceftibuten since no statistically significant differences were found between the mean values of C max , AUC 0-12 , and AUC 0-INF on the three sampling days (P > 0.05).

Safety and tolerability
There were no serious adverse events (AEs), deaths, or other significant AEs reported in the study.
In the single ascending dose (SAD) period of the study, 18 (56.3%) of 32 subjects receiving ceftibuten reported a treatment emergent adverse event (TEAE), and 4 (50%) of 8 subjects reported five events in the pooled placebo group.Overall, the most frequently reported TEAEs in the 32 subjects in the total ceftibuten group were: headache, 9 events reported in 7 (21.9%)subjects; dysgeusia, 4 events reported in 3 (9.4%)subjects; and nausea, 4 events reported in 4 (12.5%)subjects.All TEAEs were mild or moderate in severity.No subjects discontinued from the study during the SAD period of the study.
In the multiple ascending dose (MAD) period of the study, 22 (68.8%) of 32 subjects that received ceftibuten reported 65 TEAEs compared to 3 (37.5%) of 8 subjects that reported 9 events in the pooled placebo group.Overall, the most frequently reported TEAEs in the 32 subjects that received ceftibuten were: headache, 14 events reported in 8 (25%) subjects; nausea, abdominal pain and diarrhea, each with 4 events reported in 4 (12.5%)subjects; and upper abdominal pain and dysgeusia, each with 3 events reported in 3 (9.4%)subjects (Table 4).The majority of TEAEs reported during the MAD period of the study were assessed as mild in severity, transient, and resolved while subjects were still receiving study drug.The incidence, but not severity, of gastrointestinal TEAEs increased with increasing dose.One subject in the ceftibuten treatment group (800 mg) discontinued from the study due to persistent nausea.
Alanine aminotransferase (ALT) elevations were all mild in severity, asymptomatic, not associated with bilirubin elevations, and resolved following cessation of treatment and were observed in 1 (12.5%) of 8 subjects in the 400 mg ceftibuten group, 3 (37.5%) of 8 subjects in the 600 mg group, and 6 (37.5%) of 16 subjects in the 800 mg ceftibuten group.
No clinically significant trends were observed in other chemistry data, hematology, coagulation, urinalysis, vital signs, or electrocardiograms.

DISCUSSION
The data described in this study after single and multiple twice-daily oral ceftibuten administered to healthy adult subjects at doses of 400 mg is consistent with previously published data for C max , T max , t 1/2 , total body clearance, urinary recovery, and CL R of both cisand trans-ceftibuten (12,14,15).However, in this study, the mean cis-ceftibuten AUC 0-12 values were higher than those previously reported [89.6 vs 83.8 and 79.2 mg × h/L after a single 400 mg dose (12,15) and 109.8 vs 97.1 mg × h/L after multiple twice-daily 400 mg doses (12)].Furthermore, following the administration of a single oral dose of 800 mg of ceftibuten, the mean cisand trans-ceftibuten C max (28.1 and 2.2 mg/L, respectively) and AUC 0-12 (158.3 and 15.5 mg × h/L) were also higher than the values reported by Lin et al. (15) (C max of 23.3 and 1.6 mg/L, and AUC 0-12 of 118.0 and 10.4 mg × h/L for cisand trans-ceftibuten, respectively).Differences between the Bressolle et al. (12), Lin et al. (15), and the present study could be attributed to the age demographics of the participants in the respective studies.Subjects were generally younger in the Bressolle et al. (12) (n = 12, age range 18-26, mean age ± SD = 23.7 ± 1.9 years) and the Lin et al. (15) (n = 4, age range 19-38, mean age not provided) studies compared to those in our study (n = 8, age range 18-55, mean age ± SD = 34.3± 9.5 years).
To the best of our knowledge, this is the first study to report cisand trans-ceftibuten plasma and urine PK following a single oral dose of 600 mg and multiple twice-daily oral doses of 600 and 800 mg.Our findings revealed measurable cisand trans-cefti buten concentrations in urine, and we observed dose proportional plasma PK.Previous studies of oral ceftibuten in humans demonstrated that plasma exposures of ceftibuten increased in proportion to the administered dose for doses ranging from 25 to 200 mg (9).However, only Lin et al. (15) evaluated dose proportionality at higher doses of 200, 400, and 800 mg using similar statistical approaches to those used in this study.The authors concluded that after the administration of 200 and 400 mg of ceftibuten, plasma exposures increased in proportion to the administered dose, whereas following the 800 mg dose, exposures were lower than expected and not concluded to be dose proportional.In the present study, dose proportionality in plasma for 400, 600, and 800 mg was observed.Interestingly, although the C max after a single dose on Day 1 was not dose proportional between 400 and 800 mg, dose proportionality was seen after a single dose on Day 4 and after multiple doses (Day 10).
In our study, we observed a higher ceftibuten exposure than reported by Lin et al. ( 15) with a single 800 mg dose.The values we measured meant that we could conclude the presence of dose proportionality, a conclusion that Lin et al. ( 15) did not reach.There are notable differences between the two studies.Lin et al. (15) assessed dose proportionality after single doses of 200, 400, and 800 mg, whereas in our study, dose proportionality was assessed more comprehensively using doses of 400, 600, and 800 mg on Days 1, 4, and 10.Additionally, Lin et al. (15) evaluated dose proportionality based on a 200 mg dose, which is lower than the 400 mg dosage employed in our study.Furthermore, the formulation of the materials used by Lin et al. (15) is unknown.In contrast, we utilized commercially available 200 mg ceftibuten capsules, and all subjects were dosed in a fasting state.These differences may have contributed to the varying results observed.
The accumulation ratios of cisand trans-ceftibuten following multiple doses of 400, 600, and 800 mg twice-daily of 1.14-1.19and 1.28-1.32,are similar to those previously reported for 400 mg twice-daily of 1.24 (12) and 1.17 (12), respectively; the cis-ceftibuten accumulation is also in line with the ratio of 1.13 reported following multiple daily oral ceftibuten doses of 400 mg ( 14), and 1.2 after multiple twice-daily 200 mg doses (13).These data provide reassurance of the consistency of cisand trans-ceftibuten PK in healthy adult volunteers.
The present study found that ceftibuten was well tolerated when administered in all studied single and multiple doses.There were no serious, severe, life-threatening TEAEs, or TEAEs resulting in death reported throughout the study (SAD and MAD periods).
In the SAD period of the study, at ceftibuten doses up to 800 mg, the majority of TEAEs were mild in severity and there was no evidence of increasing incidence or severity of TEAEs with increasing dose.In the MAD period of the study, at ceftibuten doses up to 800 mg twice-daily for 7 days, the frequency of TEAEs was similar among all dose levels; however, the number of subjects reporting TEAEs in the total ceftibuten group was approximately twice that of the pooled placebo group.Mild ALT increases occurred in all cohorts with an increase in the incidence with increasing doses of ceftibuten.Approxi mately 30% of subjects in the 600 and 800 mg cohorts had an increase in their ALT, all of which were less than three times the upper limit of normal of 51 IU/L.ALT increases were initially observed 4-5 days after initiation of dosing and were maximal 3 days after the completion of dosing.All increases were asymptomatic, resolved spontaneously over  the follow-up period and were not associated with bilirubin or alkaline phosphatase increases.No subjects discontinued dosing due to ALT increases.Oral cephalosporins have been linked to slight elevations in ALT and alkaline phosphatase levels, which are typically mild, temporary, and not accompanied by any symptoms or progression to more severe liver injury.The reported frequency of these elevations can reach up to 11%, although this rate varies based on factors such as the frequency of monitoring, duration of treatment, and nature and severity of the underlying disease (20).
Overall, the most commonly reported TEAEs were headache, nausea, diarrhea, and abdominal pain, the majority of which were mild in severity.The TEAEs observed in this study are similar to those reported with ceftibuten (8,20).However, the incidence of headache and gastrointestinal TEAEs was higher than previously reported in the ceftibuten 800 mg twice-daily group.These SAD and MAD data are reassuring about the tolerability profile of ceftibuten at therapeutic doses, although future larger studies may provide further specific data.
Based on recent publications, the pharmacodynamic target for ceftibuten is free ceftibuten concentrations above the minimum inhibitory concentration (MIC) for 60%-67% of the dosing interval (21,22).Based on this PK/PD target, 400 mg twice-daily should adequately cover MICs up to 1 mg/L and for 800 mg twice-daily, MICs up to 4 mg/L.

Conclusion
The plasma and urine PK of cis-ceftibuten and its trans metabolite were investigated in healthy adult subjects following single and multiple oral doses higher than the 400 mg once-daily approved in the USA.CL R was the significant pathway for the total CL of ceftibuten, which was mainly recovered as cis-ceftibuten.Dose proportionality was seen following single and multiple doses of 400, 600, and 800 mg.There is little drug accumulation of cisand trans-ceftibuten during multiple dosing.Overall, the safety and PK data from this study supports the ongoing development of ceftibuten for single and multiple doses up to and including 800 mg twice-daily.

MATERIALS AND METHODS
The ceftibuten used in the trial was sourced from Shionogi & Co, Ltd (Osaka, Japan); each capsule contained 200 mg of ceftibuten.
This research adhered to the ethical standards outlined in the Declaration of Helsinki (Ethical Principles for Medical Research Involving Human Subjects) and the National Health and Medical Research Council (NHMRC) (23) (updated 2018) (23).The protocol was approved on 5 April 2019 by the Bellberry Human Research Ethics Committee (HREC).The study was registered on ClinicalTrials.govunder the identifier: NCT03939429.

Study design
This was a double-blind, randomized, placebo-controlled, and sequential ascending single-and multiple-dose study of oral ceftibuten.
Three doses were studied.The 400 and 600 mg dosing groups consisted of 10 subjects (8 active drug and 2 placebo), while the 800 mg group consisted of 20 subjects (16 active drug and 4 placebo).Within each group, subjects received a single oral dose on Days 1 and 4 (SAD); then, after the first dose on Day 4, 12-hourly doses were administered for 7 days (Days 4-10) (MAD).

Blinding
Breaking of the blind prior to study completion was expressly forbidden except in the event of a medical emergency where the identity of the drug had to be known to properly treat the subject or to assess the stopping rules.

Sample analysis
The plasma and urine concentrations of cisand trans-ceftibuten were assayed using a validated high-performance liquid chromatography method coupled with ultraviolet detection (HPLC-UV) (Microconstants, San Diego, CA, USA) (24).The HPLC column used was a Restek Ultra Biphenyl, 5 µm, 150 × 3.0 mm.UV detection was set at 254 nm.Cisand trans-ceftibuten retention times were 4.5 and 5.4 min, respectively.The internal standard was cefdinir.
Acetonitrile (500 µL) was added to the plasma samples (500 µL), vortex-mixed for 10 s and centrifuged at 3,000 × g for 10 min.Afterward, 800 µL of the supernatant was obtained and added to 5 mL of dichloromethane, vortex-mixed for 10 s, and centrifuged again.The aqueous solution was separated, and 50 µL was injected into the chromato graphic system.For the plasma assay, the mobile phase consisted of ammonium acetate (3.85 g/L in water and 2 mL of triethylamine, adjusted to pH four with formic acid)/ acetonitrile (95.5/4.5) at a flow rate of 1.75 mL/min.
Urine samples were diluted (1/10-1/40) with purified water.A volume of 50 µL was injected into the chromatographic system.For the urine assay, the mobile phase consisted of Na 2 HPO 4 (17.9 g/L in water, adjusted to pH 7 with H 3 PO 4 10%)/acetonitrile (97.5/2.5) at a flow rate of 1 mL/min.

Pharmacokinetics
PK parameters were calculated from the individual plasma concentrations, and urine concentrations and volumes, by non-compartmental analysis using Phoenix WinNonlin version 8.2.0.4383 (Certara, Princeton, NJ, USA).Summary statistics (N, mean, and SD) were tabulated by dosing group and day for each of the PK parameters.Plasma PK parameters C max , T max , AUC 0-12 , AUC 0-INF , t 1/2 , Vz/F, and CL/F were obtained for cisand trans-ceftibuten.Urine PK parameters Ae, fe, and CL R were obtained for cis-, trans-, and total ceftibuten to characterize its elimination.
All concentration values below the quantification limit were treated as missing.A terminal phase could not be defined for some concentration-time curves, and conse quently no value for AUC 0-INF , t 1/2 , Vz/F, CL/F, and CL R were calculated.

Dose proportionality
Dose proportionality for increasing oral dose and plasma pharmacokinetic parameters was examined graphically for cisand trans-ceftibuten using AUC 0-12 values on Days 1, 4, and 10 using linear regression.The equation for linear regression model fit was AUC = β × dose + μ where β represents the slope of the regression model and µ is the intercept.If the slope for each day is greater than 0, then some evidence of proportionality is assumed.
Dose proportionality was also assessed statistically using the exposure parameters of Cmax, AUC 0-12 and AUC 0-INF .Each subjects' parameter values from the three sampling days were normalized to 400 mg and an ANOVA was performed.If the ANOVA achieved statistically significant results (P ˂ 0.05), post hoc tests were performed: Tukey Kramer for normally distributed data and Kruskall-Wallis for non-normally distributed data.Normality was assessed with the Shapiro-Wilk test.

Accumulation in plasma exposure
Accumulation of cisand trans-ceftibuten going from a single dose to steady state with repeated administrations was calculated as the ratio of Day 10 AUC 0-12 /Day 4 AUC 0-12 .

Safety and tolerability
AE monitoring was conducted daily during the trial.An AE was defined as any unfav orable and unintended sign, symptom, or disease temporally associated with use of ceftibuten.Each AE was assessed for its relationship to drug treatment (not related, unlikely, possible, and probable) with signs or symptoms graded on a 5-point severity scale (mild, moderate, severe, life-threatening, and death).Serious AE monitoring was conducted as part of the AE monitoring.

FIG 1
FIG 1Cisand trans-ceftibuten plasma concentrations (mean ± SD) on Days 1 and 4 after single oral administration in healthy adult subjects.

FIG 2
FIG 2 Washout cisand trans-ceftibuten plasma concentrations (mean ± SD) on Day 10 after 7 days of twice-daily oral administration in healthy adult subjects.

TABLE 4 N
Treatment emergent adverse events observed in three or more subjects receiving ceftibuten during the multiple ascending dose period of the study a

TABLE 1
Demographics of the study population a

TABLE 2
Cisand trans-ceftibuten plasma and urine pharmacokinetic parameters (mean ± SD) by dosing group after single oral doses on Days 1 and 4 a a N, number of subjects; C max , maximum observed plasma concentration; T max , time of maximum observed plasma concentration; AUC 0-12 , area under the plasma concentration-time curve from 0 to 12 h; AUC 0-INF , area under the plasma concentration-time curve from 0 extrapolated to time infinity; t 1/2 , terminal half-life; Vz/F, apparent volume of distribution; CL/F, apparent clearance; Ae, amount of drug excreted in the urine (over 48 h on Day 1 and 12 h on Day 4); fe, fraction of the administered dose excreted in the urine (over 48 h on Day 1 and 12 h on Day 4); CL R , renal clearance (Ae 0-48 /AUC 0-INF ).b "-" no data available.

TABLE 3
Cisand trans-ceftibuten plasma and urine pharmacokinetic parameters (mean ± SD) by dosing group after multiple doses on Day 10 a a N, number of subjects; C max , maximum observed plasma concentration; T max , time of maximum observed plasma concentration; AUC 0-12 , area under the plasma concentration-time curve from 0 to 12 h; AUC 0-INF , area under the plasma concentration-time curve from 0 extrapolated to time infinity; t 1/2 , terminal half-life; Vz/F, apparent volume of distribution; CL/F, apparent clearance; Ae 0-12 , amount of drug excreted in the urine at steady state; fe 0-12 , fraction of the administered dose excreted in the urine at steady state; CL R , renal clearance (Ae 0-12 /AUC 0-12 ).
N, number of subjects; E, number of events; BID, twice-daily; TEAE, treatment emergent adverse event. a