The pharmacokinetics and safety of biapenem were studied in 36 healthy adult subjects in a randomized, placebo-controlled, double blind, sequential single- and multiple-ascending-dose study using doses from 250 to 1,250 mg administered three times a day using 3-h infusions. Maximum concentrations for biapenem were achieved at the end of the 3-h infusion.
KEYWORDS: biapenem, pharmacokinetics, phase 1
ABSTRACT
The pharmacokinetics and safety of biapenem were studied in 36 healthy adult subjects in a randomized, placebo-controlled, double blind, sequential single- and multiple-ascending-dose study using doses from 250 to 1,250 mg administered three times a day using 3-h infusions. Maximum concentrations for biapenem were achieved at the end of the 3-h infusion. Biapenem exposure (area under the curve [AUC]) increased in a slightly greater-than-dose-proportional manner after single and multiple doses with no evidence of accumulation with multiple doses. Plasma AUCs increased from 18 mg · h/liter at 250 mg to 150 mg · h/liter at 1,250 mg. Urinary recovery ranged from 14.2% at 250 mg to 42.3% at 1,250 mg. Biapenem was well tolerated up to 1,000 mg administered every 8 h by a 3-h infusion for 7 days; however, higher incidences of nausea, vomiting, and rash were reported at 1,250 mg. There were no serious adverse events (AEs) reported after either single or multiple doses of biapenem, and all AEs were mild or moderate in severity. (This study has been registered at ClinicalTrials.gov under registration no. NCT01702649.)
TEXT
Biapenem is a carbapenem antibiotic that has been marketed under the proprietary name Omegacin in Japan (Meiji Seika Pharma), since 2002, where it is indicated for the treatment of septicemia, pneumonia, lung abscess, secondary infection from chronic respiratory lesion, complicated urinary tract infections, pyelonephritis, peritonitis, and parametritis (1). Biapenem has broad-spectrum activity with in vitro potency similar to that of imipenem and meropenem (2). Biapenem has excellent activity against Enterobacterales, especially strains producing extended-spectrum beta-lactamases (3). Biapenem is similar to other carbapenems in that it has excellent activity against a wide range of anaerobic Gram-negative (e.g., Bacteroides spp.) and Gram-positive (e.g., Clostridia) organisms, including beta-lactamase-producing strains (4). Resistance rates to carbapenems (including biapenem) in Bacteroides spp. and other anaerobes are very low and have remained below 3% (5, 6). Biapenem offers several pharmacological advantages to approved carbapenems, including that it is not a substrate of bacterial efflux pumps in Pseudomonas aeruginosa or Acinetobacter baumannii infections (7, 8); has inherent stability against some beta-lactamases, which reduces bacterial resistance; has stability in the presence of the renal brush-border enzyme DHP-1, which negates the need for coadministration with a DHP-1 inhibitor, such as cilastatin (9); and has a low convulsive potential, which reduces the risk to patients (10, 11).
The pharmacokinetics of biapenem have been previously studied using single and twice-daily doses of up to 600 mg in 1-h intravenous infusions (12) and after a single 300-mg dose following a 3-h infusion (13). The pharmacodynamic targets for biapenem (as with other carbapenems) are time the free drug concentration stayed above the MIC (fT>MIC) of ∼50% for Enterobacterales and fT>MIC of ∼30% for P. aeruginosa and A. baumannii. With single and twice-daily biapenem dosage regimens of up to 600 mg, biapenem exposure is sufficient to have activity against strains with MICs of up to 0.5 mg/liter; however, these exposures are insufficient to cover some difficult-to-treat organisms, especially P. aeruginosa (14, 15). The purpose of this study was to explore the safety and pharmacokinetic profile of biapenem at doses of up to 1,500 mg administered three times daily by a 3-h infusion.
RESULTS
Demographics.
Subject baseline demographics are shown in Table 1. The subjects were an average of 37.9 years of age and predominantly white and Hispanic. Men and women were equally represented.
TABLE 1.
Baseline demographics
| Parameter | Pooled placebo (n = 9) | Biapenem dose (mg) |
|||||
|---|---|---|---|---|---|---|---|
| 250 (n = 3) | 500 (n = 6) | 750 (n = 6) | 1,000 (n = 6) | 1,250 (n = 6) | Combined (n = 27) | ||
| Sex (n [%]) | |||||||
| Male | 4 (44) | 2 (67) | 3 (50) | 3 (50) | 4 (67) | 3 (50) | 15 (56) |
| Female | 5 (56) | 1 (33) | 3 (50) | 3 (50) | 2 (33) | 3 (50) | 12 (44) |
| Age (yr) | |||||||
| Mean | 39.1 | 35.3 | 41.0 | 32.8 | 40.7 | 36.5 | 37.5 |
| Median | 37.0 | 32.0 | 41.0 | 35.5 | 44.0 | 35.5 | 38.0 |
| Range | 32–53 | 31–43 | 30–54 | 21–41 | 28–49 | 29–49 | 21–54 |
| Weight (kg, mean ± SD) | 81.2 ± 20.3 | 68.9 ± 5.4 | 70.9 ± 14.9 | 72.2 ± 12.1 | 71.4 ± 4.4 | ||
| Race (n [%]) | |||||||
| White | 9 (100) | 3 (100) | 6 (100) | 6 (100) | 6 (100) | 5 (83) | 26 (96) |
| Black | 0 | 0 | 0 | 0 | 0 | 1 (17) | 1 (4) |
| Ethnicity (n [%]) | |||||||
| Hispanic | 9 (100) | 2 (67) | 5 (83) | 6 (100) | 6 (100) | 4 (67) | 23 (85) |
| Not Hispanic | 0 | 1 (33) | 1 (17) | 0 | 0 | 2 (33) | 4 (15) |
Pharmacokinetics.
(i) Single-dose pharmacokinetics.
After single doses of biapenem ranging from 250 to 1,250 mg infused over 3 h, biapenem achieved maximum plasma concentrations (Fig. 1 and Table 2). Mean biapenem maximum concentration (Cmax) values ranged from 5.43 ± 0.55 mg/liter (250-mg dose) to 52.3 ± 18.2 mg/liter (1,250-mg dose), and the corresponding mean area under the curve from 0 h to infinity (AUC0–∞) values ranged from 18.0 ± 1.58 to 150 ± 35.9 mg · h/liter. The mean plasma elimination half-life (t1/2) ranged from 1.03 ± 0.03 h (750-mg dose) to 1.31 ± 0.31 h (1,250-mg dose). Biapenem t1/2 values did not change with the increase in biapenem dose. Mean plasma clearance (CL) values ranged from 8.73 ± 1.99 liters/h (1,000-mg dose) to 14.2 ± 1.22 liters/h (250-mg dose), and the mean volume of distribution at steady state (Vss) ranged from 15.3 ± 4.69 liters (1,000-mg dose) to 22.4 ± 8.55 liters (250-mg dose). Biapenem mean urinary recovery from 0 to 48 h (Ae0–48) after a single dose ranged from 35.3 ± 18.0 mg (250-mg dose) to 529 ± 104 mg (1,250-mg dose), which corresponds to urinary excretion (fe0-48) of 14.2 ± 7.24% to 42.3 ± 8.33% (Table 2). The exposure of biapenem (AUC) increased with increasing dose in a linear but slightly greater-than-dose-proportional manner (Fig. 2).
FIG 1.
Mean (± SD) biapenem plasma concentration-versus-time profiles after single 3-h intravenous infusions of 250 to 1,250 mg in healthy volunteers.
TABLE 2.
Biapenem pharmacokinetic parameters after single dose or the final dose after 7 days of multiple doses
| Parameter | Biapenem dose (mg, mean ± SD)a |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| 250 |
500 |
750 |
1,000 |
1,250 |
||||||
| SD (n = 3) | MD (n = 3) | SD (n = 6) | MD (n = 6) | SD (n = 6) | MD (n = 5) | SD (n = 6) | MD (n = 6) | SD (n = 6) | MD (n = 5) | |
| Cmax (mg/liter) | 5.43 ± 0.55 | 5.71 ± 0.89 | 16.3 ± 2.70 | 16.6 ± 4.20 | 22.6 ± 3.09 | 20.8 ± 3.85 | 39.8 ± 13.1 | 38.2 ± 9.56 | 52.3 ± 18.2 | 44.8 ± 9.08 |
| AUC0–τ (mg · h/liter) | 17.5 ± 1.45 | 18.4 ± 1.99 | 52.4 ± 9.52 | 49.4 ± 8.42 | 68.3 ± 10.8 | 70.0 ± 12.0 | 123 ± 36.2 | 115 ± 23.2 | 148 ± 36.3 | 146 ± 21.4 |
| AUC0–∞ (mg · h/liter) | 18.0 ± 1.58 | 53.5 ± 9.62 | 69.3 ± 11.0 | 124 ± 35.9 | 150 ± 35.9 | |||||
| t1/2 (h) | 1.10 ± 0.45 | 1.06 ± 0.07 | 1.30 ± 0.11 | 1.13 ± 0.24 | 1.03 ± 0.04 | 1.20 ± 0.30 | 1.21 ± 0.21 | 1.42 ± 0.26 | 1.31 ± 0.31 | 1.63 ± 0.16 |
| CL (liters/h) | 14.2 ± 1.22 | 13.7 ± 1.47 | 9.81 ± 1.78 | 10.4 ± 2.06 | 11.2 ± 1.75 | 11.0 ± 1.86 | 8.73 ± 1.99 | 8.99 ± 1.79 | 9.02 ± 2.16 | 8.71 ± 1.35 |
| Vss (liters) | 22.4 ± 8.55 | 21.1 ± 3.43 | 18.5 ± 4.35 | 17.0 ± 4.73 | 16.7 ± 2.36 | 18.5 ± 3.16 | 15.3 ± 4.69 | 18.6 ± 5.98 | 16.4 ± 2.64 | 20.5 ± 4.33 |
| Ae0–48 (mg) | 35.3 ± 18.0 | 19.8 ± 15.6 | 91.5 ± 16.6 | 73.2 ± 34.7 | 226 ± 112 | 241 ± 59.4 | 384 ± 103 | 446 ± 137 | 529 ± 104 | 468 ± 73.6 |
| fe0–48 (%) | 14.2 ± 7.24 | 7.70 ± 6.11 | 18.3 ± 3.34 | 14.7 ± 6.97 | 34.1 ± 14.9 | 32.2 ± 7.93 | 38.4 ± 10.3 | 44.6 ± 13.7 | 42.3 ± 8.33 | 37.5 ± 5.89 |
SD, single dose; MD, following final dose after 7 days of multiple doses.
FIG 2.
Linear regression of biapenem plasma exposure as a function of dose.
(ii) Multidose pharmacokinetics.
After 7 days of biapenem dosing every 8 h by a 3-h infusion (q8h) at doses ranging from 250 to 1,250 mg, mean biapenem Cmax values ranged from 5.71 ± 0.89 mg/liter (250-mg dose) to 44.8 ± 9.08 mg/liter (1,250-mg dose), and the corresponding mean AUC0–τ values ranged from 18.4 ± 1.86 to 151 ± 22.4 mg · h/liter (Table 2). The mean plasma elimination t1/2 ranged from 1.06 ± 0.07 h (250-mg dose) to 1.63 ± 0.16 h (1,250-mg dose). The mean plasma CL after multiple doses ranged from 8.71 ± 1.35 liters/h (1,250-mg dose) to 13.7 ± 1.47 liters/h (250-mg dose), and mean Vss ranged from 17.0 ± 4.73 liters (500-mg dose) to 21.1 ± 3.43 liters (250-mg dose). Consistent with a short t1/2, there was no accumulation of biapenem after repeated dosing. The plasma exposures of biapenem (AUC) after multiple ascending doses increased with increasing dose in a linear but slightly greater-than-dose-proportional manner (Fig. 2). After multiple doses, mean Ae0–48 values ranged from 19.2 ± 15.2 mg (250-mg dose) to 468 ± 73.6 mg (1,000-mg dose), which corresponds to urinary excretion of 7.70 ± 6.11% to 37.5 ± 5.89%. Biapenem excretion after 7 days of q8h dosing was approximately equal to that after a single dose (Table 2).
Safety and tolerability.
Overall, biapenem was well tolerated at doses up to 1,000 mg q8h for 7 days. The highest dose planned was 1,500 mg; however, due to the high incidence of nausea, vomiting, and rash at 1,250 mg q8h, 1,500-mg doses were not tested.
There were no deaths, serious adverse events (AEs), or laboratory AEs reported after either single or multiple doses of biapenem. The most frequent AEs reported by subjects treated with biapenem were infusion-site phlebitis (n = 14; 52%), nausea (n = 8; 30%), injection-site edema and injection-site pain (n = 7 each; 26%), headache (n = 6; 22%), feeling hot (n = 5; 19%), hypersensitivity (rash) and dizziness (n = 5 each; 19%), decreased appetite and vomiting (n = 4 each; 15%), and fatigue and infusion-site hemorrhage (n = 3 each;11%). Infusion-site phlebitis was reported with similar frequency across all dose groups, including the placebo group (n = 5; 56%). Infusion-site edema and pain were reported in most dose groups; whereas nausea, vomiting, hypersensitivity (rash), fatigue, and decreased appetite were only reported after biapenem administration and were more commonly seen in the 1,250-mg cohort. All of the AEs reported were mild or moderate in severity; 15 (56%) of 27 biapenem subjects reported ≥1 AE of moderate severity. The most frequently reported moderately severe events were infusion-site phlebitis (7 [26%] of 27 biapenem subjects and 2 [22%] of 9 placebo subjects), hypersensitivity (rash) (5 biapenem subjects; 15%), infusion-site pain (3 biapenem subjects; 11%), and nausea, vomiting, headache, and fatigue (2 biapenem subjects each; 7%). With the exception of two episodes of infusion-site pain, all of the frequently reported moderate AEs were considered by the principal investigator to possibly or probably be related to the study drug.
The number of AEs reported by biapenem subjects in the 1,250-mg dose cohort (60 AEs) was approximately double that reported by the biapenem 500-, 750-, and 1,000-mg dose cohorts (19, 33, and 24 AEs, respectively) (Table 3). This was also true for the number of treatment-related adverse events (52 versus 11, 20, and 19, respectively). There were no clinically significant changes in clinical laboratory parameters, vital signs, or electrocardiograms.
TABLE 3.
Treatment-emergent adverse events with >5% incidence in biapenem groups, single and multiple dose combined
| Adverse event | Incidence of adverse event (n [%]) in: |
|||||
|---|---|---|---|---|---|---|
| Placebo group (n = 9) | Biapenem group, by dose (mg) |
|||||
| 250 (n = 3) | 500 (n = 6) | 750 (n = 6) | 1,000 (n = 6) | 1,250 (n = 6) | ||
| No. (%) of subjects with ≥1 AE | 6 (67) | 2 (67) | 6 (100) | 6 (100) | 6 (100) | 6 (100) |
| Total AEs | 31 | 6 | 19 | 33 | 24 | 60 |
| General disorder and administration site condition | 6 (67) | 2 (67) | 5 (83) | 6 (100) | 5 (83) | 5 (83) |
| Infusion-site phlebitis | 5 (56) | 2 (67) | 3 (50) | 4 (67) | 2 (33) | 3 (50) |
| Infusion-site edema | 1 (11) | 0 | 0 | 2 (33) | 1 (17) | 4 (67) |
| Infusion-site pain | 0 | 0 | 2 (33) | 2 (33) | 0 | 3 (50) |
| Feeling hot | 0 | 0 | 1 (17) | 2 (33) | 1 (17) | 1 (17) |
| Fatigue | 0 | 0 | 0 | 0 | 0 | 3 (50) |
| Infusion-site hemorrhage | 1 (11) | 0 | 1 (17) | 2 (33) | 0 | 0 |
| Vessel puncture-site pain | 2 (22) | 1 (33) | 0 | 2 (33) | 0 | 0 |
| Vessel puncture-site swelling | 2 (22) | 0 | 0 | 1 (17) | 1 (17) | 1 (17) |
| Catheter-site pain | 0 | 0 | 0 | 1 (17) | 0 | 1 (17) |
| Pyrexia | 0 | 0 | 0 | 0 | 1 (17) | 1 (17) |
| Gastrointestinal disorder | 1 (11) | 0 | 2 (33) | 0 | 4 (67) | 6 (100) |
| Nausea | 1 (11) | 0 | 1 (17) | 0 | 3 (50) | 4 (67) |
| Vomiting | 0 | 0 | 0 | 0 | 0 | 4 (67) |
| Abdominal distention | 0 | 0 | 0 | 0 | 2 (33) | 0 |
| Abdominal pain | 0 | 0 | 0 | 0 | 1 (17) | 1 (17) |
| Constipation | 0 | 0 | 1 (17) | 0 | 1 (17) | 0 |
| Dyspepsia | 1 (11) | 0 | 1 (17) | 0 | 0 | 1 (17) |
| Nervous system disorder | 2 (22) | 0 | 1 (17) | 4 (67) | 3 (50) | 4 (67) |
| Headache | 2 (22) | 0 | 0 | 3 (50) | 2 (33) | 1 (17) |
| Dizziness | 0 | 0 | 1 (17) | 1 (17) | 1 (17) | 2 (33) |
| Presyncope | 0 | 0 | 0 | 2 (33) | 0 | 0 |
| Skin and subcutaneous tissue disorder | 1 (11) | 0 | 1 (17) | 2 (33) | 1 (17) | 2 (33) |
| Dermatitis contact | 1 (11) | 0 | 0 | 1 (17) | 0 | 1 (17) |
| Pruritus | 0 | 0 | 1 (17) | 0 | 0 | 1 (17) |
| Immune system disorder: hypersensitivity (rash) | 0 | 0 | 0 | 1 (17) | 1 (17) | 3 (50) |
| Metabolism and nutrition disorder: decreased appetite | 0 | 0 | 0 | 0 | 2 (33) | 2 (33) |
| Eye disorder: blurred vision | 0 | 0 | 0 | 0 | 0 | 2 (33) |
DISCUSSION
The safety, tolerability, and pharmacokinetics of biapenem were investigated in healthy adult subjects after single and multiple doses ranging from 250 to 1,250 mg administered by a 3-h infusion. Biapenem was well tolerated at doses of up to 1,000 mg, with reduced tolerability at 1,250 mg when administered q8h for 7 days. Biapenem plasma exposure (AUC) increased with increasing doses in a slightly greater-than-dose-proportional manner. The terminal t1/2 approximated 1 h at all doses. The volume of distribution at steady state and plasma clearance were independent of dose. Clearance and volume of distribution for biapenem did not change with repeated dosing, and there was no evidence of accumulation of biapenem in plasma after 7 days of repeated q8h dosing. In this study, urinary recovery of intact biapenem was low at 8% to 42% compared with ∼60% recovery reported by Nakashima et al. (12). The reason for the lower biapenem urinary recovery in this study is not known but may be related to sample handling and processing because the urine samples contained large amounts of hydrolyzed biapenem (open-lactam ring). Of note, the lower doses had a higher percentage of hydrolyzed biapenem in the urine than the higher doses, which might explain the greater urinary recovery observed at the higher doses. The plasma clearance of biapenem in this study was consistent with the clearance reported by Nakashima et al. (12), despite using longer infusions (3 versus 1 h) and higher doses (up to 1,250 versus up to 600 mg).
The currently approved dosage regimens for biapenem in Japan and China are up to 600 mg twice daily by a 0.5- to 1-h infusion (1). Recent reports have emphasized that these dosage regimens do not provide sufficient biapenem exposure and that more frequent dosing using extended infusions of biapenem are necessary to improve target attainment against respiratory pathogens, especially P. aeruginosa (14, 15). Because biapenem is only 7% protein bound (16), the data from this study suggest that 750 to 1,000 mg q8h may produce free biapenem concentrations of >8 mg/liter for at least 50% of the dosage interval. Because the pharmacokinetic-pharmacodynamic target for carbapenems is 30% to 50% of the fT>MIC in 24 h, these higher doses administered q8h should substantially improve target attainment of biapenem for treatment of serious bacterial infections caused by organisms with these high MICs.
MATERIALS AND METHODS
Study design.
The plasma and urine pharmacokinetics of biapenem were investigated in healthy volunteers after single or multiple increasing intravenous doses of biapenem (ClinicalTrials.gov registration no. NCT01702649). A total of 36 subjects allocated to 5 dose cohorts were enrolled in the study. In cohort 1, 3 subjects were randomized to receive biapenem and 1 subject received placebo. In each of cohorts 2 through 5, 6 subjects were randomized to receive biapenem and 2 subjects received placebo. Subjects were randomized to receive doses of biapenem as a 3-h infusion first as a single dose on day 1 and subsequently q8h for 7 days at 250, 500, 750, 1,000, and 1,250 mg from days 4 to 10.
The main inclusion criteria for the study were that subjects be of nonchildbearing potential, nonsmokers for the previous 6 months, and aged 18 to 55 years and have a body mass index within the range 18.5 to 29.9 kg/m2 and no significant illness. Subjects were excluded if they had a history of being HIV, HBsAg, or hepatitis C virus positive; were excessive drinkers (>3 drinks/day or >21 drinks/week); were taking any medications other than oral contraceptives, pregnant, lactating; had creatinine clearance of <80 ml/min; or had a QT corrected by Fridericia’s formula of >450 ms at screening. Additionally, all subjects were required to sign an informed consent approved by a local ethics committee before undergoing any screening or study activities. After informed consent was obtained, a medical history, physical examination, and electrocardiography were conducted. Blood was drawn to test for abnormalities and alcohol abuse, and vital signs and concomitant medications were recorded. Subjects were required to complete the screening procedures within 28 days of entering the study. If subjects passed the screening procedures and were found to be eligible for the study, they were randomized. Randomization occurred via a computerized randomization scheme created by an unblinded statistician. The randomization scheme was available to only the clinic pharmacy staff who prepared the study drug. It was not available to the sponsor, study subjects, or members of the staff responsible for monitoring and evaluating safety assessments.
Safety.
Safety was assessed throughout the study via medical history, physical examination, monitoring of vital signs, electrocardiograms (ECGs), and clinical safety labs before and through 72 h after dosing. Additionally, safety was monitored by subject self-reports of AEs and specific inquiries to subjects regarding symptoms. Subjects with >1 episode of the same AE were recorded only once in the per-subject analysis. Following each cohort and between the single- and multiple-dose phases within each cohort, the principal investigator and the sponsor reviewed all pertinent blinded safety data (e.g., physical examinations, vital signs, ECGs, clinical laboratory tests, and AEs, including those from previous cohorts) and determined to (i) continue with the study/cohorts as planned, (ii) continue with the study and add additional safety evaluations, (iii) continue with the study by repeating the dose and adjusting to a dose between the current dose and the next planned dose or adjust to a dose between the current dose and the previous lower dose, or (iv) stop dose escalation of the study. All cohorts proceeded as planned with dose escalations.
Pharmacokinetic samples.
Blood samples were taken after the first dose and after the last dose following 7 days of dosing at predose (time zero) and 1.5, 3, 3.17, 3.33, 3.5, 3.75, 4, 5, 6, 7, 8, 12, and 24 h after the start of infusion to determine biapenem concentrations. Urine samples were collected during the following intervals: 0 to 4, 4 to 8, 8 to 12, 12 to 24, and 24 to 48 h after start of infusion. All blood samples (∼2 ml) were obtained via an indwelling cannula, collected into EDTA tubes, and immediately placed on ice and centrifuged at 3,000 × g for 15 min. All plasma samples were diluted 1:1 with morpholinepropanesulfonic acid (MOPS) buffer (to stabilize biapenem), thoroughly mixed, and frozen at −20°C. Urine sample volumes were recorded for each collection period, and an aliquot was removed and diluted 1:1 with MOPS buffer, mixed, and frozen at −20°C.
Bioanalytical analyses.
Concentrations of biapenem in plasma and urine were measured by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) at Microconstants, Inc. (San Diego, CA, USA). Plasma and urine samples were mixed with their internal standard (meropenem) and precipitated with a 50:50 mixture of methanol:acetonitrile. The calibration ranges of the plasma and urine assays for biapenem were linear (r2, 0.999), from 0.2 to 100 μg/ml for both matrices. A total of 1,237 unique plasma samples were analyzed in 20 analytical runs, and a total of 381 unique urine samples were analyzed in 11 analytical runs, which all met acceptance criteria for standard curve and quality control (QC) samples. The accuracy of the method was determined by comparing the mean measured concentrations with theoretical concentrations of each analyte in the QC samples.
Pharmacokinetic analyses.
Analyses of the plasma and urine were performed using noncompartmental methods (WinNonlin Professional 6.1.1; Pharsight Corp., Mountain View, CA, USA). The pharmacokinetic parameters that were determined included peak (Cmax), time to maximum concentration (Tmax), AUC, t1/2, CL, and V.
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