Received 21 December 2012; returned 4 January 2013; revised 19 February 2013; accepted 23 February 2013

Transcription

1 J Antimicrob Chemother 013; 68: doi: /jac/dkt097 Advance Access publication 3 April 013 Safety, tolerability and pharmacokinetics of repeat dosing of the antibiotic GSK133, a peptide deformylase inhibitor: a randomized placebo-controlled study Odin J. aderer 1 *, Etienne Dumont, John Zhu 3, Milena Kurtinecz and Lori S. Jones 1 1 GlaxoSmithKline, 5 Moore Dr., Research Triangle Park, C 7709, USA; GlaxoSmithKline, 150 South Collegeville Rd, Upper Providence, PA, USA; 3 GlaxoSmithKline, 709 Swedeland Rd, King of Prussia, PA, USA *Corresponding author. Medicines Discovery and Development, GlaxoSmithKline, Research Triangle Park, C 7709, USA. Tel: ; Fax: ; odin.j.naderer@gsk.com Received 1 December 01; returned 4 January 013; revised 19 February 013; accepted 3 February 013 Objectives: GSK133 is a potent inhibitor of peptide deformylase, an essential bacterial enzyme required for protein maturation. In this two-part, double-blind, randomized, placebo-controlled, Phase 1 study (study identifier: PDF11668), the safety, tolerability and pharmacokinetics of single and repeat oral-dose GSK133 (500 ) in healthy adult and elderly volunteers were evaluated. Patients and methods: included GSK133 doses of 500, 750, 1000 and in healthy adults; evaluated of GSK133 in healthy elderly volunteers. Volunteers received a single morning dose of a powder-in-bottle formulation of GSK133 or placebo on day 1, no dosing on day and twice-daily dosing on days 3 1. Results: Of 5 enrolled volunteers, 40 and 1 volunteers were treated with GSK133 and placebo, respectively. Mean plasma GSK133 trough concentration increased with increasing dose and reached steadystate after days of repeat dosing. After single dosing of GSK133, maximum plasma concentration and exposure (AUC) were dose proportional from 500 to. However, after repeat dosing, AUC values at steady-state increased slightly more than proportionally, possibly because of a slightly longer terminal elimination t 1 after repeat dosing (compared with single-dose ) at higher doses (1000 and ). There t1 was no age effect or diurnal variation in the GSK133 pharmacokinetic profile. GSK133 was generally well tolerated all adverse events were mild to moderate in intensity. Conclusions: Repeat oral GSK133 (500 ) for 10 days was well tolerated. These data warrant further clinical investigation of GSK133. Keywords: pharmacokinetics, peptide deformylase inhibitors, steady-state, elderly, repeat dosing Introduction Bacterial resistance to antibiotics is on the rise and represents a critical unmet medical need. 1 3 In addition, there is a paucity of new antibiotics in the development pipeline, with the few agents under development often being improved derivatives of marketed products that are generally only partially effective against existing resistance mechanisms. Therefore, there is an urgent need to identify novel antibacterial targets and leads with new mechanisms of action. GSK133, the first in a new class of antibiotics, is a potent inhibitor of peptide deformylase (PDF) discovered by a combination of structure-based drug design and iterative medicinal chemistry (Figure 1). 4 PDF is an essential bacterial enzyme required for protein maturation. 5 Because PDF is not required by mammalian cells and is to date clinically unexploited, development of agents against this protein is an attractive proposition. GSK133 shows no target-based cross-resistance with currently used agents and is fully active against pathogens resistant to multiple classes of existing antibiotics. 6 GSK133 demonstrated potent in vitro and in vivo activity against multidrug-resistant respiratory and skin pathogens, including methicillin-resistant Staphylococcus aureus. 6 8 In vitro, GSK133 exhibits a potent sub-mic effect for most strains of S. aureus, inhibiting growth in vitro for 6 8 h at concentrations well below the MIC. 9,10 In addition, potent in vivo activity of GSK133 against rodent respiratory tract infection and skin and soft tissue infection models has also been demonstrated. 6,7 # The Author 013. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please journals.permissions@oup.com 1901

2 aderer et al. H O OH In a single-dose, pharmacokinetic (PK), first-time-in-human, Phase 1 study in healthy volunteers, GSK133 was administered as a powder-in-bottle formulation and demonstrated a favourable PK profile. 8 In this two-part, Phase 1 study, the objective of was to investigate the safety, tolerability and PK of GSK133 following single and repeat dosing with dose escalation from 500 to twice daily in healthy adult volunteers (18 65 years of age); the objective of was to assess the safety, tolerability and PK of GSK133 following single and repeat dosing of twice daily in healthy elderly volunteers (.65 years of age). Patients and methods Study design and population O H Figure 1. Chemical structure of GSK133. H This was a randomized, double-blind, placebo-controlled, single- and repeat-dose, dose-escalation, Phase 1 trial of healthy volunteers (GlaxoSmithKline Clinical Study Register; study identifier: PDF11668). Adult volunteers who were in generally good health with no clinically relevant abnormalities as determined by medical history, physical exam, laboratory tests and cardiac monitoring were eligible for the trial. Volunteers had a body mass index of kg/m, inclusive. Female volunteers were eligible to be enrolled if they were of nonchildbearing potential and were excluded if they were lactating or pregnant, as determined by positive human chorionic gonadotropin test at screening or prior to dosing. Volunteers were excluded from the study if they met one of the following conditions: a positive result for pre-study screening of alcohol and drugs of abuse, including amphetamines, barbiturates, cocaine, opiates, cannabinoids and benzodiazepines; a positive hepatitis B surface antigen or hepatitis C antibody result within 3 months of screening; a positive test result for HIV antibody; use of any investigational drug within 30 days, five half-lives or twice the duration of the biological effect of the investigational drug (whichever was longer) before the day of dosing; or exposure to more than four new chemical entities within 1 months before the day of dosing. All volunteers provided written informed consent. The study was approved by an institutional review board (Bellberry Human Research Ethics Committee, Dulwich, South Australia) and was conducted in accordance with Good Clinical Practice and the Declaration of Helsinki. Overall, five GSK133-treated cohorts were planned for this two-part study. was planned with four cohorts to study the single- and repeat-dose safety, tolerability and PK of GSK133 with dose escalation from 500 to (i.e. Cohorts A D) in adult volunteers aged years. The study was designed to administer GSK133 to eight volunteers and placebo to two volunteers at each dose level of 500, 750, 1000 and twice daily (i.e. Cohorts A, B, C and D, respectively). In addition, volunteers in one cohort (Cohort C) received midazolam (5 mg) as a metabolic probe F H O drug to understand the effect of GSK133 on cytochrome P450 3A activity. was planned with one cohort (Cohort E, twice daily) to study the safety, tolerability and PK of single- and repeat-dose GSK133 in elderly volunteers aged.65 years. This cohort was planned to comprise eight and four volunteers receiving GSK133 and placebo, respectively. Volunteers were admitted to the study unit the day before drug administration and discharged after all study procedures were completed on day 14. Volunteers were assigned to study treatment in accordance with the randomization schedule generated by Discovery Biometrics before the start of the study using validated internal software. Each volunteer scheduled to receive study drug received a treatment allocation number when randomized, which indicated whether the individual was to receive the scheduled dose of GSK133 or placebo. Volunteers received a single morning (AM) dose of GSK133 or placebo orally on day 1, no dosing on day and twice-daily dosing on days 3 1. The AM dose of GSK133 and placebo was administered following an overnight fast of 10 h. Volunteers were orally administered a powder-in-bottle formulation as a suspension of GSK133 or microcrystalline cellulose for placebo. Volunteers in Cohort C were also administered a single dose of 5 mg of midazolam on the day before study drug administration, and 5 mg of midazolam was coadministered with the morning dose of GSK133 or placebo on days 1 and 1. Volunteers in all cohorts returned for follow-up visits at 7 10 and 8 days after their last dose of study medication. PK assessments Blood samples to measure plasma GSK133 concentrations were collected pre-dose (within 15 min before dosing) and for a 48 h period (i.e. at 0.5, 0.5, 1, 1.5,, 4, 6, 8, 1, 18, 4, 36 and 48 h) after dosing on day 1. On days 5, 6, 10 and 11, blood samples were collected pre-dose (within 15 min before AM dosing). On days 7 and 1, for AM dosing, blood samples were collected pre-dose (within 15 min before AM dosing) and for a 1 h period (i.e. at 0.5, 0.5, 1, 1.5,, 4, 6, 8 and 1 h) post-dose. On day 1, for evening (PM) dosing, blood samples were collected for a 7 h period (i.e. at 0.5, 0.5, 1, 1.5,, 4, 6, 8, 1, 18, 4, 36, 48 and 7 h) after the PM dose. Volunteers emptied their bladder 0 min before dosing and 0 ml urine samples were collected at baseline on day 1 (0 h) for reference. On day 1, urine was collected over the following intervals: 0 1 h after the AM dose and 0 1 h after the PM dose. Plasma and urine GSK133 concentrations were determined by Worldwide Bioanalysis (GlaxoSmithKline, King of Prussia, PA, USA) using HPLC with tandem mass spectrometry with a validated range of ng/ml GSK133 concentration in human plasma. The assay for GSK133 concentration in human urine was validated over a range of 0.5 /L. PK analyses of plasma GSK133 concentration time data were conducted using non-compartmental Model 00 (for extravascular administration) of Winonlin w, version 5. (Pharsight Corporation, St Louis, MO, USA). The plasma PK parameters assessed included the AUC, C max, T max and terminal elimination t 1. The accumulation ratio (Ro) was calculated as the ratio of the AUC from time 0 1 h after AM dosing [AUC 0 1 (AM)] on days 7 and 1 to the AUC from time 0 1 h (AUC 0 1 ) on day 1 for each volunteer. The time invariance ratio (Rs) was calculated as the ratio of the AUC over two dosing intervals (AUC 0 4 ) on day 1 to two times the AUC 0 1 on day 1 for each volunteer. For urine PK analysis, the total amount of GSK133 excreted (Ae) and CL R were assessed. From the GSK133 urine data, the Ae was determined after repeat dosing at steady-state on day 1 and was calculated as the product of the concentration in urine and the urine weight (assuming a urine density of 1 g/ml). The CL R was calculated as follows: CL R ¼Ae 0 4 /AUC 0 4 [where Ae 0 4 ¼Ae 0 1 (AM)+Ae 0 1 (PM) and AUC 0 4 ¼AUC 0 1 (AM)+AUC 0 1 (PM)]. 190

3 Repeat-dose safety and pharmacokinetics of GSK133 JAC Safety assessments Safety was assessed by the evaluation of reported and observed adverse events (AEs), vital sign measurements, electrocardiograms (ECGs) and clinical laboratory tests (i.e. chemistry, haematology and urinalysis). Twelve-lead ECGs were obtained as three measurements taken pre-dose on day 1. The ECGs were centrally read by Quintiles Cardiac Safety Services (Mumbai, India). Holter monitoring was performed for 4 h at screening. Statistical analyses Baseline and demographic characteristics, safety data and PK parameters were summarized using descriptive statistics. All PK parameters were log e transformed with the exception of T max. The dose proportionality of GSK133 PK parameters for single-dose (AUC 0 1 and C max ) and repeat-dose [AUC over two dosing intervals (AUC 0 4 ), C max (AM) and C max (PM)] administration was assessed using the power model: y¼a.dose b (where y denotes the PK parameter being analysed, a depends on the random error and the exponent b was estimated by regressing the log e -transformed PK parameter on the log e -transformed dose). Dose proportionality required b to be at unity for dose-dependent parameters, whilst the corresponding 90% CI was used to quantify the degree of proportionality or non-proportionality. For steady-state assessment, the plasma GSK133 pre-morning dose concentration values obtained between days 5 and 1 of the repeat-dose phase were plotted and summarized. A mixed-effects model with individual as a random effect was performed by dose on the log e -transformed C t. Day was treated as a continuous variable in the model. The 90% CI of the slope of the linear regression was calculated for each dose group. For the assessment of Ro and Rs, analyses of variance with terms for volunteer as a random effect and day as a fixed effect were performed on the log e -transformed AUC with day treated as a categorical variable. Reference points were AUC 0 1 on day 1 for Ro and two times the AUC 0 1 on day 1 for Rs. The potential effect of age on the single-dose and steady-state PK of GSK133 at was determined by comparing the AUC and C max obtained from elderly healthy volunteers with those from healthy adult volunteers. Following log e transformation, AUC 0 1 on day 1 and AUC 0 4 over two dosing intervals on day 1 were separately analysed using analysis of variance with age as a fixed effect. Results A total of 5 volunteers enrolled in the study between May and September 009: 40 in and 1 in (Figure ). Of the 40 volunteers included in, 8 volunteers in each of four treatment cohorts were randomized to receive 500, 750, 1000 or of GSK133 and 8 volunteers were randomized to placebo. Three volunteers in (one each in Cohorts A, B and C) of the study withdrew because of AEs. Of the 1 elderly volunteers included in, 4 received placebo and 8 received of GSK133. All volunteers in completed the study as planned. The majority of volunteers were white (85%) and male (87%; Table 1). In Parts A and B, the age of the volunteers ranged from 0 to 53 and from 65 to 74 years, respectively. PK Following single-dose administration (day 1) of 500 of GSK133 to volunteers, the drug was readily absorbed with a median T max of 0.5 h and was eliminated with mean t 1 values ranging from 5.3 to 6.8 h across doses in both Parts A and B of the study (Table and Figure 3). With repeat dosing (days 7 and 1) of 500 of GSK133, the median T max was h after morning and evening doses across all cohorts in both Parts A and B of the study. After PM dosing on day 1, GSK133 was eliminated with a mean t 1 of 5 6 h at low doses (500 and ) and a slightly longer mean t 1 ( 8 9 h) at higher doses (1000 and ). The mean C max and AUC values increased with increasing dose. The AUC, C max and T max values were similar between the morning and evening dosings of GSK133, indicating no diurnal variation in GSK133 PK. In addition, although the mean plasma GSK133 trough concentrations (C t ) increased with increasing dose following multiple dosing, the mean C t values remained generally constant, with clustering between 0.07 and 0.5 mg/l from day 5 to day 13 that indicated that steady-state was achieved within days of repeat dosing (i.e. on day 5; Figure 4). The slope estimates of C t values versus time were generally close to zero, confirming the achievement of steady-state by day 5 (Table 3). The results of the dose-proportionality assessment indicated that after a single oral dose of GSK133, the point estimates of the slopes for AUC 0 1 and C max were around unity (i.e. 1.0), suggesting that the PK parameters of GSK133 were approximately dose proportional from 500 to (Table 4). After repeat dosing, AUC 0 4 values over two dosing intervals at steady-state on day 1 were slightly greater than dose proportional (slope of 1.9). This may be due to the slightly longer t 1 (i.e. 8 9 h) with repeat dosing as compared with the single-dose t 1 (i.e. 5 7 h) at higher doses (1000 and ). Dose proportionality assessment results for C max at steady-state differed slightly between morning and evening doses. C max (AM) values were proportional to the GSK133 dose; however, C max (PM) values were slightly more than proportional to dose. At low doses (i.e. 500 and ), GSK133 followed linear PK after repeat dosing, as the point estimates of Rs were close to 1 and the 90% CI contained 1 (Table 5). The Ro was minimal (i.e. 10% 1%), which is consistent with its t 1 of 5 6 h and the dosing frequency. However, at higher doses (i.e and ) a small degree of time-dependent nonlinearity was observed, with Rs.1 and Ro being slightly higher (i.e. 13% 51%) than expected, which was probably due to the longer t 1 observed with repeat dosing (i.e. 8 9 h) compared with that of the single dose (i.e. 5 7 h) at these dose levels. There was no effect of midazolam on the single-dose or repeat-dose GSK133 PK profile in Cohort C volunteers ( of GSK133). The effect of GSK133 on the plasma midazolam PK profile is beyond the scope of this article and therefore will be reported elsewhere. In brief, there was a significant interaction between single and repeat doses of GSK133 and inhibition of cytochrome P450 3A4/5, resulting in reduced midazolam clearance. The effect of age on the GSK133 PK profile was assessed by comparing the AUC, C max and T max values for dosing of GSK133 at in elderly volunteers (.65 years of age; Cohort E) versus adult volunteers (18 65 years of age; Cohort C). When comparing the AUC [i.e. AUC 0 4 (over two dosing intervals on day 1) and AUC 0 1 (single dose)] and C max of GSK133 between these two cohorts, the point estimates were close to 1 and the 90% CI included 1, indicating that age had no effect on the systemic exposure of GSK133 (Table 6). 1903

4 aderer et al. Assessed for eligibility ( = 5) Randomized to treatment (n = 40) Randomized to treatment (n =1) Allocated to intervention Placebo (n =8) GSK133 (n =8) (n =8) (n =8) (n =8) Allocated to intervention Placebo (n =4) GSK133 (n =8) Reasons for withdrawal AEs (n =3) Completed and analysed Placebo (n =8) GSK133 (n =7) (n =7) (n =7) (n =8) Completed and analysed Placebo (n =4) GSK133 (n =8) Figure. Participant flow. Table 1. Volunteer demographics placebo placebo (n¼4) Total (n¼5) Age (years), mean (SD) 5.4 (3.3) 30.6 (7.5) 33.0 (13.8) 31.0 (8.3) 4.6 (1.6) 70.0 (3.7) 69.6 (.7) 38.3 (18.9) Male, n (%) 8 (100) 8 (100) 7 (88) 7 (88) 8 (100) (50) 5 (63) 45 (87) BMI (kg/m ), mean (SD) 3.4 (1.6) 5.1 (.5) 4.5 (3.5) 4.4 (.9) 4.8 (.1) 6.5 (.0) 5.1 (3.6) 4.7 (.7) Race, n (%) white 8 (100) 8 (100) 7 (88) 8 (100) 4 (50) 3 (75) 6 (75) 44 (85) Asian (50) 1 (5) 0 5 (10) mixed race (13) (5) 3 (6) BMI, body mass index. Most of these PK parameters exhibited moderate within-volunteer variability, with the exception of C max (AM), which tended to have a higher variation than the other parameters. The amount of GSK133 excreted in the urine over two dosing intervals at steady-state (Ae 0 4 ) increased as the dose increased (Table 7). On the basis of the mean Ae 0 4, the fraction 1904

5 Repeat-dose safety and pharmacokinetics of GSK133 JAC Table. Plasma PK parameters of single and repeat dosing of GSK133 Parameter AUC 0 1 (AM), mg.h/l day (16) 19.8 (31) 7.6 (17) 37.6 (36) 6.4 (41) day (8) 3.9 (5) 31.1 (4) 51.4 (9) 9.9 (43) day (1) 1. (6) 41.8 (18) 47.4 (31) 35.7 (35) AUC 0 1 (PM), mg.h/l day (1) 1.4 () 37.6 (13) 49. (8) 38.1 (30) AUC 0 4,mg.h/L day (11) 4.8 () 80.9 (14) 97.4 (5) 74.4 (9) AUC 0 1,mg.h/L day (16) 0.8 (9) 9. (17) 40. (31) 8.4 (37) C max (AM), mg/l day (19) 7.86 (48) 9.5 (4) 18.7 (50) 10.8 (81) day (18) 1.5 (4) 10.4 (43) 19.4 (6) 10.7 (6) day (1) 7.51 (39) 11.7 (6) 18.1 (5) 13.9 (51) C max (PM), mg/l day (9) 8.0 (36) 1.3 (0) 19.9 (4) 13.9 (33) t 1,h day (38) 5.4 (34) 6.8 (0) 5.3 (9) 6.6 (4) day (64) 6.0 (36) 8.9 (3) 8.3 (33) 7.8 (1) T max (AM), h a day ( ) 0.5 ( ) 0.5 (0. 1.5) 0.5 ( ) 0.5 (0.5.0) day ( ) 0.5 ( ) 1.0 ( ) 0.5 ( ) 0.5 (0.5.0) day ( ) 0.5 ( ) 1.0 (0..0) 0.5 ( ) 0.5 (0.5.0) T max (PM), h a day ( ) 1.0 ( ) 0.5 ( ) 0.5 ( ) 1.0 (0.5.0) AUC 0 1 (AM), AUC during 1 h after AM dosing; AUC 0 1 (PM), AUC during 1 h after PM dosing; CVb, between-volunteer coefficient of variation; t 1, terminal elimination half-life; T max (AM), T max after AM dosing; T max (PM), T max after PM dosing. The results are presented as mean (CVb, %), unless otherwise stated. a Median (range). of intact GSK133 recovered in the urine in 4 h ranged from % to 5% of the total administered daily dose. The mean CL R of GSK133 at steady-state was generally consistent across all regimens, including that for Cohort E (elderly volunteers), and ranged from 6 to 9 L/h. Safety GSK133 doses of 500, given over 10 days of continuous dosing, were generally well tolerated in this study. The most frequently reported AEs in the study (both Parts A and B) included headache, somnolence, upper respiratory tract infection, musculoskeletal pain, dyspepsia and nausea (Table 8). All AEs were mild to moderate in intensity. o trends in AEs related to dose were observed. Somnolence, a known side effect of midazolam, was only reported when midazolam was given alone or concomitantly with GSK133 (Cohort C). o non-fatal or fatal serious AEs were reported in this study; however, three volunteers withdrew from the study because of AEs. One volunteer receiving of GSK133 (Cohort B) withdrew on day 11 because of diffuse maculopapular rash that developed after the day 10 PM dose. This rash was considered by the investigator to be related to the study drug and resolved in 6 days. Two volunteers had mildly elevated liver enzymes that met protocol-defined volunteer stopping criteria (i.e. at least three times the upper limit of normal), one receiving of GSK133 (Cohort A) and the other receiving of GSK133 (Cohort C). These AEs were also considered by the investigator to be related to the study drug. The volunteer in Cohort A had a maximal elevated alanine aminotransferase (ALT) value of 90 IU/L (i.e. three times the upper limit of normal) on day 11 that resolved in 11 days. Similarly, the volunteer in Cohort C had an ALT value of 163 IU/L on day 13 that resolved in 18 days. However, these ALT changes were not associated with clinical symptoms or changes in bilirubin. 1905

6 aderer et al. Plasma concentration (ng/ml) Plasma concentration (ng/ml) (a) Time (h) 10 1 (b) (elderly) (elderly) Time (h) Figure 3. (a) Linear and (b) semi-log mean plasma GSK133 concentration time profile after a single oral dose of 500 of GSK133. Table 3. Steady-state assessment of plasma GSK133 trough concentrations a Parameter Table 4. Dose proportionality assessment of GSK133 PK parameters a C t, mean slope % CI 0.04, , , , , 0.06 C t, plasma trough concentration. a From day 5 to day 1. Parameter Mean slope+sem 90% CI AUC 0 4,mg.h/L day , 1.47 AUC 0 1,mg.h/L day , 1.30 C max (AM), mg/l day , 1. day , 1.17 C max (PM), mg/l day , 1.4 AUC 0 4, AUC from time 0 to 4 h over two dosing intervals; C max (AM), C max after AM dosing; C max (PM), C max after PM dosing. a GSK133 doses of 500. Trough plasma concentration (ng/ml) (elderly) Time (days) Figure 4. Mean plasma trough concentration time profile of GSK133 after repeat oral dosing of 500 of GSK133. o significant trends or changes from baseline in vital signs, chemistry and haematology data were observed. Apart from the two volunteers on GSK133 that had elevated ALT that met protocol-defined subject stopping criteria and withdrew from the study, two more volunteers on active treatment and one volunteer on placebo had elevations in ALT. o significant trends or changes from baseline in ECG data were observed. Although no volunteers had QT duration corrected for heart rate by Bazett s formula (QTcB) values that were.480 ms, eight volunteers had QTcB values of potential clinical importance (i.e. values.450 ms or representing a change from baseline of.60 ms; six adults and one elderly volunteer on GSK133, and one adult on placebo). Discussion This two-part, Phase 1 study evaluated the safety, tolerability and PK of GSK133 at doses of 500 in healthy adult (aged years) and elderly (aged.65 years) volunteers following single and multiple oral dosing. GSK133 at doses of 500, given over 10 days of continuous dosing, was generally well tolerated, with no serious AEs occurring during the study. Three volunteers in withdrew from the study because of AEs; one volunteer had a diffuse maculopapular rash and two volunteers had elevated liver enzymes. 1906

7 Repeat-dose safety and pharmacokinetics of GSK133 JAC Table 5. Accumulation ratio and time invariance assessment of GSK133 plasma PK parameters Parameter, measurement Ro point estimate day 7:day (1.01, 1.18) 1.1 (1.08, 1.36) 1.13 (1.0, 1.5) 1.37 (1.15, 1.6) 1.13 (1.0, 1.6) day 1:day (1.08, 1.7) 1.11 (0.98, 1.5) 1.51 (1.37, 1.68) 1.6 (1.06, 1.50) 1.35 (1., 1.50) CVw, % Rs point estimate day 1:day (0.95, 1.18) 1.06 (0.97, 1.16) 1.41 (1.33, 1.49) 1.1 (1.08, 1.36) 1.31 (1.15, 1.49) CVw, % CVw, within-volunteer coefficient of variation; Ro, accumulation ratio; Rs, time invariance ratio. Table 6. Age assessment of GSK133 plasma PK parameters for Cohort C a versus Cohort E b Parameter Point estimate 90% CI CVw, % AUC 0 4,mg.h/L day , AUC 0 1,mg.h/L day , C max (AM), mg/l day , day , 1.67 C max (PM), mg/l day , T max (AM), h day 1 0 c 0.5, 0.5 day 1 0 c 0.5, 0.3 AUC 0 4, AUC from time 0 to 4 h over two dosing intervals; C max (AM), C max after AM dosing; C max (PM), C max after PM dosing; CVw, withinvolunteer coefficient of variation; T max (AM), T max after AM dosing. a Adult volunteers (aged years) receiving GSK133 at a dose of. b Elderly volunteers (aged.65 years) receiving GSK133 at a dose of. c Estimated median difference. These AEs resolved after study drug discontinuation and were considered by the investigator to be mild and related to the study drug. GSK133 dose selection in this study was based on animal models simulating the human serum concentrations necessary for potent antibacterial activity 11 and PK results from the firsttime-in-human, single-dose study. 8 The single- and repeat-dose PK of GSK133 evaluated in the current study were, in general, consistent with those observed in the first-time-in-human study that used the same powder-in-bottle formulation for GSK133. After a single dose, GSK133 C max and AUC 0 1 were dose proportional from 500 to. However, after repeat doses, AUC at steady-state was slightly more than dose proportional, perhaps because of slightly higher than expected accumulations of GSK133 (as a result of the somewhat longer t 1 with repeat dosing compared with that of single dosing) at higher doses (i.e and ). Physiological changes in the elderly often alter the PK of drugs, necessitating dose adjustments for the therapeutics used to treat this population. 1 However, the PK and tolerability of GSK133 after single or repeat dosing with elderly volunteers were similar to those observed with younger volunteers in this study. Therefore, GSK133 may be used to treat elderly patients without the need for any dose adjustments. GSK133 administered over 10 days of continuous dosing was generally well tolerated. All AEs were mild or moderate in intensity in this study and no trends in AEs related to dose were observed. The most frequently reported AEs in this study were headache, somnolence, upper respiratory tract infection and musculoskeletal pain. It is noteworthy that somnolence was only reported when midazolam was given alone or when coadministered with GSK133. GSK133 was well tolerated from a gastrointestinal perspective as gastrointestinalrelated AEs were uncommon in this study and did not prevent volunteers from completing a 10 day course of twice-daily dosing. Overall, 10% (4 of 40) and 1% (1 of 8) of volunteers on GSK133 and placebo, respectively, had elevations in ALT in this study. All elevations in ALT associated with the study drug occurred within 5 7 days of repeat dosing and were asymptomatic and fully reversible upon cessation of drug treatment. Results from this and other Phase 1 PK studies show favourable PK and safety profiles of GSK133. However, the trial described herein was conducted with a small number of healthy volunteers per dose group, thus limiting the generalizability of these results and prompting the need for further evaluation of GSK133 in clinical studies. With the novel mechanism of action of GSK133 providing targeted antibacterial activity against multidrug-resistant community respiratory and skin pathogens and the promising PK and safety data observed to date, 1907

8 aderer et al. Table 7. GSK133 urine PK parameters Parameter Ae 0 1 (AM), mg (344) (8) (17) (7) (0) Ae 0 1 (PM), mg (1) (18) 1574 (11) (4) 158 (7) Ae 0 4, mg (3) () (1) (7) (17) CL R, L/h 8.79 (35) 8.41 (19) 5.91 (19) 7.71 (14) 6.6 (9) Ae 0 1 (AM), total amount of GSK133 excreted during 1 h after AM dosing; Ae 0 1 (PM), total amount of GSK133 excreted during 1 h after PM dosing; Ae 0 4, total amount of GSK133 excreted from time 0 to 4 h over two dosing intervals; CVb, between-volunteer coefficient of variation. The results are presented as mean (CVb, %). Table 8. Most commonly reported AEs a AE placebo placebo (n¼4) Any AE 7 (88) 7 (88) 7 (88) 8 (100) 7 (88) 3 (75) 7 (88) headache 4 (50) (5) 7 (88) 5 (63) 7 (88) (50) 3 (38) somnolence 1 (13) (100) upper respiratory tract 1 (13) 3 (38) (5) 1 (13) 1 (13) 0 0 infection musculoskeletal pain 1 (13) (5) 0 1 (13) 0 (50) 1 (13) dyspepsia (5) 1 (13) (5) 0 nausea (5) 0 (5) The results are presented as n (%). a Occurring in at least four volunteers overall. GSK133 has the potential to become the first-in-class PDF inhibitor for clinical use. Funding Funding was provided by GlaxoSmithKline for the conduct of the study and for editorial support in development of this manuscript. Transparency declarations All authors are employees of GlaxoSmithKline and own GlaxoSmithKline stock. Editorial support in the form of developing the manuscript outline and first draft, suggesting editorial revisions to drafts, assembling tables, collating author comments, copy-editing, fact checking and referencing was provided by Pratibha Hebbar and Chris Lawrence at MedThink SciCom. Author contributions Study design: all authors. Full access to study data: all authors. Data analysis: O. J.., E. D., J. Z. and L. S. J. Statistical analysis: M. K. Guarantor of study data: O. J.. Manuscript development and review: all authors. Manuscript approval: all authors. References 1 Schmieder R, Edwards R. Insights into antibiotic resistance through metagenomic approaches. Future Microbiol 01; 7: Donadio S, Maffioli S, Monciardini P et al. Sources of novel antibiotics aside the common roads. Appl Microbiol Biotechnol 010; 88: Davies J, Davies D. Origins and evolution of antibiotic resistance. Microbiol Mol Biol Rev 010; 74: Aubart K, Benowitz A, Campobasso et al. Hydrazinopyrimidines as a new class of peptide deformylase inhibitors. In: Abstracts of the Fiftieth Interscience Conference on Antimicrobial Agents and Chemotherapy, Boston, MA, 010. Abstract F American Society for Microbiology, Washington, DC, USA. 5 Jain R, Chen D, White RJ et al. Bacterial peptide deformylase inhibitors: a new class of antibacterial agents. Curr Med Chem 005; 1: Lewandowski T, DeMarsh P, Peters T et al. Potent activity of GSK133, a novel peptide deformylase inhibitor, after oral dosing in a murine multi-drug resistant Staphylococcus aureus infection. In: Abstracts of the Fiftieth Interscience Conference on Antimicrobial Agents and Chemotherapy, Boston, MA, 010. Abstract F American Society for Microbiology, Washington, DC, USA. 7 Lewandowski T, Peters T, Simon et al. Potent activity of GSK133, a novel peptide deformylase inhibitor, in a Haemophilus influenzae and 1908

9 Repeat-dose safety and pharmacokinetics of GSK133 JAC Streptococcus pneumoniae respiratory tract infection model. In: Abstracts of the Fiftieth Interscience Conference on Antimicrobial Agents and Chemotherapy, Boston, MA, 010. Abstract F American Society for Microbiology, Washington, DC, USA. 8 aderer OJ, Jones LS, Zhu J et al. A novel antibacterial peptide deformylase inhibitor (GSK133): first time in human safety and pharmacokinetics. In: Slides presented at the Fiftieth Interscience Conference on Antimicrobial Agents and Chemotherapy, Boston, MA, 010. Abstract F American Society for Microbiology, Washington, DC, USA. 9 Butler D, Chen D, O Dwyer K et al. Two methodologies confirm the unique potent sub-mic effect of peptide deformylase inhibitors on the growth of Staphylococcus aureus. In: Abstracts of the Fiftieth Interscience Conference on Antimicrobial Agents and Chemotherapy, Boston, MA, 010. Abstract A1-00. American Society for Microbiology, Washington, DC, USA. 10 Ross JE, Scangarella-Oman E, Miller LA et al. Determination of disk diffusion and MIC quality control ranges for GSK133, a novel peptide deformylase inhibitor. J Clin Microbiol 011; 49: Singley C, Hoover J, DeMarsh P et al. Efficacy of PDF inhibitor GSK133 against abscess infections caused by MRSA using a computer-controlled infusion system to recreate human PK profiles in rats. In: Abstracts of the Fiftieth Interscience Conference on Antimicrobial Agents and Chemotherapy, Boston, MA, 010. Abstract F American Society for Microbiology, Washington, DC, USA. 1 Turnheim K. When drug therapy gets old: pharmacokinetics and pharmacodynamics in the elderly. Exp Gerontol 003; 38: