Abstract
The pharmacokinetics, tolerability, and serum inhibitory and bactericidal titers of telavancin, a new rapidly bactericidal lipoglycopeptide with multiple mechanisms of action against gram-positive pathogens, were assessed in a two-part, randomized, double-blind, placebo-controlled, ascending-dose study with 54 healthy men. In part 1, single ascending intravenous doses of 0.25 to 15 mg/kg of body weight were studied. In part 2, multiple ascending doses (30-min infusions of 7.5 to 15 mg/kg/day) were studied over 7 days. Following the administration of multiple doses, steady state was achieved by days 3 to 4. At day 7 after the administration of telavancin at 7.5, 12.5, and 15 mg/kg/day, peak concentrations in plasma were 96.7, 151.3, and 202.5 μg/ml, respectively, and steady-state area-under-the-curve values were 700, 1,033, and 1,165 μg · h/ml, respectively. The elimination half-life ranged from 6.9 to 9.1 h following the administration of doses ≥5 mg/kg. Most adverse events were mild in severity. At 24 h postinfusion, serum from subjects given telavancin demonstrated potent bactericidal activity against methicillin-resistant Staphylococcus aureus and penicillin-resistant Streptococcus pneumoniae strains. The results suggest that telavancin may be an effective once-daily therapy for serious bacterial infections caused by these pathogens.
Telavancin (formerly TD-6424; Theravance Inc., South San Francisco, Calif.) is a new, rapidly bactericidal lipoglycopeptide with multiple mechanisms of action which is active against clinically relevant gram-positive pathogens, including important resistant strains (6; D. V. Debavov, J. Pace, M. Nodwell, S. Trapp, R. Campbell, D. Karr, T. Wu, K. Krause, D. Johnston, C. Lane, D. Schmidt, D. Higgins, B. Christensen, K. Judice, and K. Kaniga, Abstr. 43rd Intersci. Conf. Antimicrob. Agents Chemother., abstr. C1-1809, 2003; S. S. Hegde, N. Reyes, T. Wiens, R. Skinner, J. McCullough, N. Vanasse, and K. Judice, Abstr. 43rd Intersci. Conf. Antimicrob. Agents Chemother., abstr. F-2108, 2003). Data from in vitro and animal studies indicate that telavancin has superior activity to β-lactams, older glycopeptides (e.g., vancomycin), and the oxazolidinone linezolid (6). This antimicrobial agent is rapidly bactericidal against staphylococci, with >99.9% killing achieved within 4 h of exposure at concentrations achievable in vivo (8).
Unlike most glycopeptides, telavancin has multiple mechanisms of action. In addition to inhibiting peptidoglycan synthesis by blocking the transglycosylation step, telavancin also interacts with the bacterial membrane, dissipating the membrane potential and effecting changes in cell permeability. The multiple mechanisms of action may lead to a lower frequency of resistance (Debavov et al., 43rd ICAAC; K. Krause, D. Debabov, J. Pace, and K. Kaniga, Abstr. 43rd Intersci. Conf. Antimicrob. Agents Chemother., abstr. C1-1810, 2003). The rapid bactericidal activity of this agent may result in a reduction in the duration of therapy and improved clinical outcomes.
This paper reports the results of a two-part, randomized, double-blind, placebo-controlled study of sequentially ascending doses of telavancin with healthy adult male subjects. The study objectives were to assess the safety, pharmacokinetics, and pharmacodynamics (serum inhibitory and bactericidal titers) of intravenous (i.v.) telavancin.
(This work was presented in part at the 13th European Congress of Clinical Microbiology and Infectious Diseases, Glasgow, United Kingdom, 10 to 13 May 2003 [S. Barriere et al., Clin. Microbiol. Infect. 9(Suppl. 1):288, 2003].)
MATERIALS AND METHODS
Methodology.
This study was approved by the Independent Ethics Committee of Guy's Hospital, London, United Kingdom, and was performed in full compliance with the principles of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, Good Clinical Practice, and the Declaration of Helsinki. The trial was conducted at Guy's Drug Research Unit, Quintiles, Ltd., London, United Kingdom.
Study subjects.
Eligible male subjects (age, 18 to 50 years; weight, 50 to 100 kg) with no clinically relevant abnormal physical or laboratory findings and normal electrocardiograms (ECGs), blood pressure, and heart rate were included in the study. Subjects had to be able to comply with the study requirements and to provide written informed consent.
Exclusion criteria included a history of alcohol abuse or illicit drug use, investigational new drug use within 3 months of study admission, tobacco use within 2 years of admission, consumption of >6 cups of coffee (or caffeine equivalent) per day, vegetarian or vegan diet, and donation or loss of >400 ml of blood within 12 weeks of admission. Other exclusion criteria were a history of a relevant cardiovascular, pulmonary, hematologic, hepatic, renal, immunologic, endocrine, metabolic, rheumatic, neurologic, or psychiatric disorder; the presence of a recurrent or ongoing allergic condition requiring prescription medical treatment; any surgical or medical condition that might interfere with the absorption, distribution, metabolism, or excretion of the study drug; the need for any medication within 2 days of study admission or during the study; a serious adverse reaction or hypersensitivity to any drug; and any adverse reaction or hypersensitivity to glycopeptide antibiotics or i.v. infusion.
Dosing.
A summary of the study design is shown in Table 1. Part 1 of this study (with single ascending doses) was designed to include 16 subjects in an alternating panel design. Eight subjects were to participate in one of two panels (panels A and B) consisting of four treatment periods each at ascending dose levels. In each treatment period, six subjects were to receive telavancin and two were to receive placebo. Panel A treatment periods comprised 120-min infusions of telavancin at 0.25, 2.5, and 10 mg/kg and 60-min infusions of 12.5 mg/kg; panel B treatment periods comprised 120-min infusions of telavancin at 1, 5, and 12.5 mg/kg and 30-min infusions of 12.5 mg/kg. An additional panel (panel C) of eight subjects could be recruited, depending on the resultant safety and pharmacokinetic data for panels A and B, with dose levels and infusion rates to be determined. Each subject in panel C could participate in up to four treatment periods. Plasma samples were obtained over 24 h postdosing. A 1-week washout period followed each treatment period. No subject in part 1 was to receive placebo more than once.
TABLE 1.
Study design
| Study part and treatment period | Panel | Telavancin dose (mg/kg) | Infusion time (min) | No. of subjects receiving telavancin/no. of subjects receiving placebo |
|---|---|---|---|---|
| Part 1 | ||||
| 1 | A | 0.25 | 120 | 6/2 |
| 2 | B | 1.0 | 120 | 6/2 |
| 3 | A | 2.5 | 120 | 6/2 |
| 4 | B | 5.0 | 120 | 6/1 |
| 5 | A | 10.0 | 120 | 6/2 |
| 6 | B | 12.5 | 120 | 6/2 |
| 7 | A | 12.5 | 60 | 6/2 |
| 8 | B | 12.5 | 30 | 6/2 |
| 9 | C | 15.0 | 30 | 6/2 |
| Part 2 | ||||
| D | 7.5 | 30 | 6/2 | |
| E | 12.5 | 30 | 6/2 | |
| F | 15.0 | 30 | 6/2 |
Part 2 of this study (with multiple ascending doses) comprised three panels (panels D, E, and F) of eight subjects each (six randomized to telavancin and two randomized to receive placebo). The three dose levels of telavancin administered during the three panels were to be determined after review of the data from part 1. The highest dose administered in part 2 was not to be higher than a dose found to be safe and tolerable for the treated subjects in part 1, and the infusion rate was to be the shortest rate found to be safe and tolerable for the treated subjects in part 1. The study medication was administered once daily for 7 days. Plasma samples were obtained at regular intervals over 24 h after the initiation of infusion following administration of the first dose (day 1) and the last dose (day 7). No subject in part 2 was to receive placebo for more than 7 days.
Pharmacokinetics.
In part 1 of the study, for the 120-min infusions, plasma samples were collected predosing and at 15 and 40 min, 1 h 15 min, and 1 h 58 min after the initiation of infusion. They were also collected at 15 and 40 min; 1 h 15 min; and 2, 3, 4, 6, 10, and 24 h after the end of infusion. For the 60-min infusions, samples were collected predosing and at 10, 20, 40, and 58 min after the start of the infusion. They were also collected at 10, 20, and 40 min; 1 h 15 min; 2 h 15 min; and 4, 7, 11, and 24 h after the end of infusion. For the 30-min infusions, samples were collected predosing and at 5, 10, 20, and 28 min after the initiation of the infusion, as well as at 5, 10, and 30 min and 1, 2, 4, 7, 11, and 24 h after the end of infusion.
In part 2, plasma samples were collected predosing and at 5, 10, 20, and 28 min after the start of infusion, as well as at 5, 10, and 30 min and 1, 2, 4, 7, and 11 h after the end of infusion of the first and last doses. In addition, samples were collected predosing for the second through the sixth doses, as well as at 23.5 and 48 h after the end of the infusion of the last dose.
Plasma samples were analyzed for total telavancin concentrations by a validated bioanalytical method by reversed-phase, high-performance liquid chromatography-tandem mass spectrometry (Theravance Inc., internal report). This method was linear over the range of 0.25 to 200 μg/ml, and the validated limit of quantitation was 0.25 μg/ml, with an interassay coefficient of variation of 8.8%. The overall precision and accuracy of the quality controls and standards were better than 15% for all concentrations.
Pharmacokinetic parameters were estimated by noncompartmental analysis with WinNonlin software (version 3.2; Pharsight Corporation, Mountain View, Calif.). The parameters measured included the maximum concentration in plasma (Cmax), the area under the curve (AUC), plasma clearance (CL), and the steady-state volume of distribution (Vss). The AUC from the time of dosing to the time of the last measurable concentration (AUC0-t) was calculated by the linear trapezoidal rule and extrapolated to infinity (AUC0-∞). λz, the first-order rate constant associated with the terminal elimination phase, was estimated by linear regression of time versus log concentration. The half-life (t1/2) of the terminal elimination phase was estimated by use of the following equation: 0.693/λz. CL was calculated as dose/AUC0-∞, and Vss was calculated as CL × mean residence time. For the study with multiple ascending doses, on day 7, the pharmacokinetic parameters were evaluated as steady-state values; AUC0-t was determined as the steady-state AUC (AUCss), and CL was calculated as dose/AUC0-t.
Serum inhibitory and bactericidal titers.
Serum inhibitory and bactericidal titers were determined against a strain each of methicillin-resistant Staphylococcus aureus (MRSA), strain ATCC 33591, and penicillin-resistant Streptococcus pneumoniae (PRSP), strain SU-10. Serum samples were collected at regular intervals after the telavancin infusions.
In part 1, serum samples were collected predosing, at the end of infusion (peak), and 24 h after the start of infusion (trough). In part 2, samples were collected predosing, at the end of infusion (peak) on day 7, and 23.5 h after the start of infusion on day 7 (trough).
Serum inhibitory and bactericidal titers were determined at the R. M. Alden Research Laboratory, Santa Monica, Calif., according to the guidelines of the National Committee for Clinical Laboratory Standards (7). Positive control wells were included to check for bacterial growth, and negative control wells were included to check for contamination. The serum static titer was defined as the highest dilution of the serum that showed no visible growth of the organisms. To determine the bactericidal activity of telavancin in serum, 10 μl from each well with no visible growth was plated on tryptic soy agar medium, and the viable colonies were scored after incubation for 24 h. The serum bactericidal titer was defined as the highest dilution of the serum that showed a 99.9% reduction of bacterial viability.
Safety and tolerability.
Adverse events were monitored throughout the study. Hematology, serum chemistry, and coagulation parameters were recorded; and urinalysis was performed at the screening and the poststudy visits, as well as at admission and 24 h postinfusion during each treatment period in part 1. In part 2, hematology, serum chemistry, and coagulation parameters were recorded; and urinalysis was performed at screening; admission; prior to administration of the third, fifth, and seventh doses; 48 h following administration of the last dose; and at the poststudy visit.
Urinary proteins (retinol-binding protein for kidney function [4], albumin, and N-acetyl-β-d-glucosaminidase) were assessed in each treatment period at screening, admission, and 24 h after the infusion in part 1. In part 2, urinary proteins were assessed at screening; admission; prior to administration of the third, fifth, and seventh doses; and 48 h following administration of the last dose. Screening for drugs of abuse and alcohol was performed in parts 1 and 2 at screening and admission.
In part 1, vital signs and 12-lead ECGs were obtained at the screening and the poststudy visits, as well as at admission, predosing, postinfusion, and 24 h after the infusion in each treatment period. Lead-II ECG monitoring was performed in each treatment period of part 1, commencing predosing and continuing until 2 h postinfusion. In part 2, vital signs and 12-lead ECGs were obtained at screening, admission, prior to the administration of each dose, at the end of each infusion, 48 h following administration of the last dose, and at the poststudy visit. A physical examination was performed at the screening and the poststudy visits in parts 1 and 2.
Statistical methods.
SAS versions 6.12 and 8 (SAS Institute Inc., Cary, N.C.) were used to perform all statistical analyses.
RESULTS
Subjects.
A total of 54 male subjects were enrolled in this study. The demographics of the subjects are listed in Table 2. In part 1, 27 subjects were randomized, including 3 replacement participants. All subjects in panels A and B participated in four treatment periods, with the exception of the three participants who terminated early and their replacements. Panel C comprised eight subjects who received a single 30-min infusion of telavancin at 15 mg/kg (n = 6) or placebo (n = 2). Of the three subjects from panels A and B who prematurely terminated the study, two left possibly due to drug-related causes: one withdrew because of moderate presyncope that began immediately after the start of infusion in treatment period 3, and the other terminated due to tinnitus, which began after administration of the first dose and which had resolved by the poststudy visit. The third subject left the study after administration of the first dose due to glycosuria, which had been present at the screening visit.
TABLE 2.
Demographic characteristics of study subjects
| Characteristic | Part 1 (n = 27) | Part 2 (n = 27) | Total (n = 54) |
|---|---|---|---|
| Age (yr) | |||
| Mean (SDa) | 24.4 (4.6) | 26.1 (4.7) | 25.3 (4.7) |
| Range | 18-37 | 19-37 | 18-37 |
| Wt (kg) | |||
| Mean (SD) | 79.4 (9.2) | 81.6 (10.9) | 80.5 (10.0) |
| Range | 60.0-96.6 | 59.0-97.3 | 59.0-97.3 |
| Ht (cm) | |||
| Mean (SD) | 181.5 (6.0) | 180.0 (9.6) | 181.0 (7.9) |
| Range | 168-192 | 161-203 | 161-203 |
SD, standard deviation.
In part 2, 27 subjects were randomized, including 3 replacement participants. All subjects in panels D, E, and F received a 30-min infusion of telavancin of 7.5, 15, and 12.5 mg/kg/day, respectively, or placebo for 7 days. Of the five subjects who terminated the study prematurely, four experienced adverse events: one developed mild tinnitus prior to dosing on day 3, which resolved in 2 days; one subject withdrew shortly after the beginning of infusion on day 1 due to mild urticaria, which resolved in about 20 h; one participant withdrew due to mild pruritus after infusion on day 1, which resolved within 19 h; and one subject developed a moderate morbilliform rash after administration of the second dose, which remained at the poststudy visit. The fifth subject withdrew consent after dosing on day 3 due to excessive cannulation.
Linearity and dose proportionality. (i) Part 1: single ascending doses.
At the end of infusion, the plasma telavancin concentrations were quantifiable in all subjects at all dose levels. Following single-dose administration, plasma telavancin concentrations declined in a monoexponential manner, with a short distribution phase immediately after the end of infusion (Fig. 1) and with t1/2 increasing with dose from 2.9 to 9.1 h. The mean values of the pharmacokinetic parameters for telavancin are listed in Table 3. For the 0.25-mg/kg dose, the last measurable concentrations in plasma were at 8 h postdosing. Therefore, the AUC and half-life may be underestimated and CL values may be overestimated.
FIG. 1.
Mean (standard deviation) concentrations in plasma following a 120-min i.v. administration of telavancin at 0.25 to 12.5 mg/kg.
TABLE 3.
Values of pharmacokinetic parameters in plasma following single-dose infusion of telavancin i.v.
| Parameter | Valuea at the following time postinfusion (min)a:
|
||||||||
|---|---|---|---|---|---|---|---|---|---|
| 120 | 60 | 30 | 30 | ||||||
| Dose (mg/kg) | 0.25 | 1 | 2.5 | 5 | 10 | 12.5 | 12.5 | 12.5 | 15 |
| No. of subjects | 6 | 6 | 5b | 6 | 5c | 6 | 5d | 6 | 6 |
| Cmax (μg/ml) | 1.98 (0.25) | 9.97 (0.91) | 23.6 (4.8) | 44.9 (3.2) | 87.5 (6.0) | 112 (18) | 114 (5) | 154 (26) | 179 (10) |
| AUC0-t (μg · h/ml) | 7.60 (0.91) | 59.1 (8.8) | 182 (30) | 386 (38) | 762 (81) | 996 (150) | 815 (77) | 1,006 (202) | 1,210 (138) |
| AUC0-∞ (μg · h/ml) | 8.92e (1.33) | 63.2 (6.4) | 193 (31) | 426 (49) | 858 (109) | 1,143 (195) | 913 (95) | 1,136 (241) | 1,430 (202) |
| t1/2 (h) | 2.9e (0.2) | 4.6 (0.5) | 5.7 (0.6) | 6.9 (0.6) | 7.5 (0.6) | 7.9 (0.9) | 7.6 (0.3) | 7.8 (0.6) | 9.1 (1.0) |
| CL (mL/h/kg) | 28.5e (4.2) | 15.9 (1.6) | 13.2 (2.0) | 11.9 (1.5) | 11.8 (1.4) | 11.3 (2.3) | 13.8 (1.4) | 11.4 (2.5) | 10.7 (1.6) |
| Vss (ml/kg) | 104e (18) | 93.5 (4.8) | 99.8 (19.3) | 106 (5) | 115 (6) | 116 (13) | 135 (9) | 115 (18) | 124 (8) |
| Cmax/dose | 7.91 (1.01) | 9.97 (0.91) | 9.45 (1.94) | 8.97 (0.65) | 8.75 (0.60) | 8.93 (1.46) | 9.12 (0.39) | 12.3 (2.1) | 11.9 (0.6) |
| AUC/dose | 35.7 (5.3) | 63.2 (6.3) | 77.3 (12.4) | 85.2 (9.8) | 85.8 (10.9) | 91.4 (15.6) | 73.0 (7.6) | 90.9 (19.3) | 95.3 (13.5) |
Values are means (standard deviations).
The data for one subject, for whom most concentrations in plasma were below the limit of quantitation, was excluded from calculations of the mean.
For one subject the time to Cmax was 4 h, and data were not included in calculations of the mean.
One subject had no quantifiable concentration in plasma at the end of infusion, and data were not included in calculations of the mean.
n = 4; for two subjects >20% of the AUC values were extrapolated and were excluded from the calculations of the mean.
Telavancin exhibited linear pharmacokinetics at doses from 1 to 12.5 mg/kg, based on Cmax and AUC values (Fig. 2). The values of the pharmacokinetic parameters for the 0.25-mg/kg dose group were excluded from dose-proportionality analysis due to lower AUC values and limited measurable concentrations in plasma. Dose-proportional increases in Cmax of 2.4-, 4.5-, 8.8-, and 11-fold were observed for the 2.5-, 5-, 10-, and 12.5-mg/kg dose groups, respectively. On the basis of the dose-normalized AUC0-∞ (normalized to 1 mg/kg), however, the values for doses of 2.5, 5, 10, and 12.5 mg/kg were 22, 35, 36, and 45%, respectively, more than predicted from a dose-proportional increase. From dose levels of 1 to 12.5 mg/kg, the CL values decreased approximately 30%, and a 24% increase was observed for Vss.
FIG. 2.
Dose linearity analysis for Cmax (A) and AUC (B) for 120-min infusions of telavancin at 1 to 12.5 mg/kg.
For the 12.5-mg/kg dose, the infusion duration was varied from 2 h to 30 min. This was done to explore the tolerability of a more rapid infusion. Analysis of the effect of the infusion rate on telavancin pharmacokinetics revealed that the mean AUC0-∞ was lower for the 60-min infusion (912.6 ± 95.4 μg · h/ml) than for the 30- and 120-min infusions (1,136 ± 241 and 1,143 ± 195 μg · h/ml, respectively). As expected, however, the mean Cmax for a 30-min infusion (153.8 ± 26.3 μg/ml) was higher than those for 60- and 120-min infusions (114.0 ± 4.9 and 111.7 ± 18.3 μg/ml, respectively). There was no apparent correlation between adverse effects and infusion duration.
(ii) Part 2: multiple ascending doses.
The pharmacokinetics of i.v. telavancin in healthy subjects was independent of dose following the administration of seven daily doses of 7.5, 12.5, and 15 mg/kg. The plasma telavancin concentrations after the first i.v. infusion reached quantifiable levels in all participants at all dose levels. Thereafter, plasma telavancin concentrations exhibited a short distribution phase after the end of the infusion and then declined in a monoexponential manner, regardless of the day on which they were recorded.
The mean Cmax, AUC0-∞, and t1/2 of telavancin on day 1 were not significantly different from those on day 7 for all dose levels. The mean t1/2 was close to 8 h on day 1 for all dose levels and was not significantly different from the values observed on day 7 (approximately 9 h) (Table 4). Trough plasma telavancin concentrations, determined every 24 h between days 1 and 7, indicated that steady state was attained on days 3 to 4; and the concentrations in plasma did not increase further after that point.
TABLE 4.
Pharmacokinetic parameters for telavancin following i.v. infusion for 7 consecutive days
| Parameter | Value for the following dose (mg/kg/day)a:
|
|||||
|---|---|---|---|---|---|---|
| 7.5
|
12.5
|
15
|
||||
| Day 1 | Day 7 | Day 1 | Day 7 | Day 1 | Day 7 | |
| No. of subjects | 7 | 6 | 6 | 6 | 7 | 4 |
| Cmax (μg/ml) | 90.3 (10.7) | 96.7 (19.8) | 155 (24) | 151 (17) | 181 (35) | 203 (29) |
| AUC0-∞ or AUCss (μg · h/mL) | 668 (137) | 700 (114) | 1,013 (118) | 1,033 (91) | 1,239 (144) | 1,165 (232) |
| t1/2 (h) | 7.86 (0.90) | 8.83 (1.71) | 7.26 (1.22) | 9.11 (2.33) | 7.33 (0.97) | 8.78 (1.46) |
| CL (ml/h/kg) | 11.6 (2.3) | 10.9 (1.6) | 12.5 (1.5) | 12.2 (1.1) | 12.3 (1.6) | 13.3 (2.6) |
| Vss (ml/kg) | 113 (14) | 105 (20) | 121 (14) | 119 (18) | 117 (18) | 126 (15) |
| Ratio of AUC on day 1/AUC on day 7 | 1.05 (0.19) | 1.02 (0.04) | 1.01 (0.22) | |||
Values are means (standard deviations).
The ratios of the AUCss at day 7 to AUC0-∞ at day 1 for telavancin at 7.5, 12.5, and 15 mg/kg were 1.05, 1.02, and 1.01, respectively, less than the predicted accumulation indices of 1.12 to 1.15. A comparison of the mean plasma concentration-time curves for telavancin at 7.5, 12.5, and 15 mg/kg/day on days 1 and 7 is shown in Fig. 3.
FIG. 3.
Comparison of mean (standard deviation) concentration-time course of telavancin in plasma on days 1 and 7 at 7.5 mg/kg/day (A), 12.5 mg/kg/day (B), and 15 mg/kg/day (C).
Microbiology.
High and prolonged serum static titers and serum bactericidal titers were demonstrated against one strain each of MRSA and PRSP. In part 1, telavancin demonstrated excellent bactericidal activity against MRSA strain ATCC 33591 and PRSP strain SU-10, even 24 h after the initiation of infusion. In part 2, there were no detectable differences in the serum inhibitory or bactericidal concentrations of telavancin compared with those seen in part 1. The results were also consistent with the pharmacokinetic data, indicating that telavancin did not accumulate in the subjects. Table 5 shows the median peak and trough bactericidal titers obtained against MRSA 33591 and PRSP SU-10 during the 24 h following the administration of doses of 7.5 to 15 mg/kg.
TABLE 5.
Serum bactericidal activity following i.v. infusion of telavancin once daily for 7 days
| Dosage (mg/kg) | Median bactericidal titera:
|
|||
|---|---|---|---|---|
| MRSA ATCC 33591
|
PRSP SU-10
|
|||
| Peak | Trough | Peak | Trough | |
| 7.5 | 256 | 16 | ≥512 | 128 |
| 12.5 | ≥512 | 24 | ≥512 | 256 |
| 15 | ≥512 | 32 | ≥512 | ≥512 |
On day 7.
Safety.
At i.v. doses up to 15 mg/kg/day over 30 min for 7 days, the observed adverse events were mild in severity, and none were judged to be serious. The most commonly reported treatment-emergent adverse events were transient, mild taste disturbance and headache. Taste disturbance was reported in 75% of the subjects receiving telavancin, whereas it was reported in 14% of the subjects receiving placebo. No interventions regarding these cases of taste disturbance were made, and all except one of the cases resolved within 24 h of onset; the one case that was the exception resolved after 31 h. Headache was reported in 40% of the subjects receiving telavancin, whereas it was reported in 29% of the subjects receiving placebo. Other commonly reported adverse events in the subjects receiving telavancin included dizziness (35% versus 0% for the subjects receiving placebo), procedural site reaction (25% versus 14% for the subjects receiving placebo), and nausea (20% versus 14% for the subjects receiving placebo). Two subjects who received telavancin (both in the 15-mg/kg group) developed infusion-associated reactions (pruritis, flushing, urticaria, nausea, and headache) following administration of the first dose, which led to study discontinuation. These were judged to be mild in severity and resolved quickly.
All mean hematology, serum chemistry, coagulation, urine microprotein, and urinalysis values for subjects receiving telavancin were normal. In part 2, some mean serum chemistry values were slightly below the normal range, but they were not considered clinically relevant. Transiently elevated levels for coagulation parameters in one subject were unexplained. The test results for this subject were above normal on study days 3 and 7, when blood samples were obtained postdosing, compared with the values prior to infusion of the study drug; however, the clinical relevance of these findings is unknown. All out-of-range values returned to normal when this subject was tested on the following day.
There were no detectable trends regarding vital signs before and after infusion. One subject who received telavancin at 12.5 mg/kg developed a mild macular rash on the upper body on day 7 that resolved spontaneously in <7 days. Another subject (described above) withdrew from the study on day 2 due to a mild morbilliform rash.
DISCUSSION
The management of infections due to S. aureus has long been a therapeutic challenge. The ongoing emergence of resistant organisms underscores the importance of the availability of effective, well-tolerated, and convenient alternative antimicrobial agents. Vancomycin has long been the mainstay of antimicrobial therapy for infections caused by resistant strains. This situation has begun to change, however, since the first report in 2002 of an S. aureus isolate that was completely resistant to vancomycin (9). In addition, it has long been recognized that vancomycin exerts a slow bactericidal effect, and numerous reports of the slow resolution of infection or frank treatment failures have been reported for patients with S. aureus infections (3, 5).
The results of the present study support the potential role of telavancin as an effective antimicrobial treatment for serious infections caused by clinically significant gram-positive bacteria such as S. aureus and S. pneumoniae, including important resistant organisms. The pharmacokinetic disposition of telavancin was found to be approximately linear and predictable and, thus, supportive of a once-daily i.v. dosing regimen. The t1/2s ranged from approximately 5 to 9 h following the administration of doses of 1 to 15 mg/kg and were generally similar to those observed for vancomycin in humans (3 to 9 h) (2). Slightly longer t1/2s were observed for doses ≥5 mg/kg (7 to 9 h). The predicted accumulation indices for telavancin based on the first dose were 1.12 to 1.15, suggesting that daily dosing would lead to minimal accumulation. The observed ratios of the AUCss at day 7 to the AUC0-∞ at day 1 for telavancin at the 7.5-, 12.5-, and 15-mg/kg dose levels were 1.05, 1.02, and 1.01, respectively, which are less than the predicted accumulation indices. These data confirm that there was minimal accumulation of telavancin in plasma following the administration of seven daily doses of 7.5, 12.5, and 15 mg/kg in this study.
Statistical analysis showed that after dosing on day 7, mean values of Cmax, AUC, and t1/2 were not significantly different from the corresponding values on day 1 for all telavancin dose levels except for Cmax in the 15-mg/kg dose group. However, telavancin at 15 mg/kg was evaluated in only four subjects, and the percent increase in Cmax was minimal (6%).
The pharmacokinetic profile of telavancin at 12.5 mg/kg/day was similar among all three infusion rates (120, 60, and 30 min), and no infusion duration-related adverse events were observed. However, AUC was somewhat lower following a 60-min infusion. The mean Cmax, however, was significantly higher with the 30-min infusion, as would be expected. Overall, these results provided further support for the linear kinetics of telavancin in healthy men.
Telavancin has a high level of protein binding (∼93% in human plasma), whereas that of vancomycin is ∼50% and that of daptomycin is ∼92%. However, the presence of human serum has a minimal impact on the activity of telavancin against staphylococci (including MRSA) and streptococci (including PRSP) (K. Kaniga, D. Johnson, T. Wu, D. Debabov, K. Krause, J. Pace, D. Higgins, B. Christensen, and K. Judice, Abstr. 43rd Intersci. Conf. Antimicrob. Agents Chemother., abstr. C1-1632, 2003). The serum of subjects dosed with telavancin produced significant bactericidal effects against the PRSP and MRSA test strains in this study. Serum bactericidal activity against these strains persisted for 24 h following the administration of doses as low as 2.5 and 5 mg/kg, respectively.
In the present study, the most common treatment-emergent adverse events caused by telavancin were a mild, transient taste disturbance and headache. All taste disturbances occurred at doses of 10 mg/kg or higher but had no apparent correlation with the Cmax or AUC values. However, headaches occurred in subjects across all doses from 0.25 to 12.5 mg/kg.
In healthy subjects, the principal adverse effects of vancomycin are infusion-associated anaphylactoid reactions, such as urticaria, pruritis, headache, wheezing, and flushing of the head and trunk (red man syndrome). It has been demonstrated that ∼90% of subjects will develop one or more of these reactions if they are given i.v. infusions of 1,000 mg of vancomycin (∼15 mg/kg) over 1 h (2). Additionally, infusion site reactions such as pain, erythema, swelling, and thrombophlebitis also commonly occur. In contrast, only two subjects who received telavancin (both in the 15-mg/kg group) developed such reactions, both following administration of the first dose, and these led to study discontinuation. One subject reported headache, urticaria, and nausea. The other subject reported facial flushing and pruritis. These events were mild and resolved spontaneously. Mild infusion site reactions (tingling and pain) also occurred in some telavancin-treated subjects at incidences that appeared to be independent of the dose.
Increases in the QTc interval in subjects receiving telavancin at ≥10 mg/kg were observed to be greater than those in subjects receiving placebo. However, the study was not designed to detect changes in the QTc interval. There were substantial amounts of inter- and intrasubject variability and group variability. No subjects had clinically significant changes in their ECGs, and none had abnormally prolonged QTc intervals. A subsequent definitive study of the QTc interval (with positive and negative controls) demonstrated that telavancin produced a mean increase of <5 ms in the QTc interval; furthermore, the changes in the QTc interval observed with telavancin were significantly less than those observed with moxifloxacin (1).
Although transient elevated levels for coagulation parameters (i.e., prothrombin time, activated partial thromboplastin time, and international normalized ratio) were observed in one subject in the present study, there was no evidence of bleeding in this or any previous study of telavancin. In a subsequent study of telavancin, high concentrations of the drug were found to interfere with the prothrombin time and the activated partial thromboplastin time; but no significant abnormalities in activated clotting time, bleeding time, or whole blood clotting time were noted (S. Barriere, J. P. Shaw, J. Seroogy, E. Spencer, and M. Kitt, Abstr. 43rd Intersci. Conf. Antimicrob. Agents Chemother., abstr. A-20, 2003). The elevated values of the coagulation parameters in the aforementioned subject, therefore, were likely an artifact of the testing methods. Furthermore, all out-of-range values returned to normal when this subject was tested on the next day.
In conclusion, the present study demonstrated that the overall pharmacokinetic profile of telavancin is linear and predictable and, thus, supportive of once-daily i.v. dosing. Telavancin exhibited a safety and tolerability profile supportive of further investigation for the treatment of serious infections. In addition, this new antimicrobial agent demonstrated excellent bactericidal activities against the test strains of MRSA and PRSP at both peak and trough levels. The pharmacokinetics, microbiological activity, and tolerability reported in this study support the continued development of telavancin as a once-daily i.v. treatment at doses of 7.5 mg/kg or higher for serious bacterial infections caused by these pathogens.
Acknowledgments
This work was supported by Theravance, Inc.
We thank Ellie J. C. Goldstein, Diane M. Citron, and Kerin L. Tyrrell from the R. M. Alden Research Laboratory, Santa Monica, Calif., for assistance.
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