John Zhu

Single-Dose Safety, Tolerability, and Pharmacokinetics of the Antibiotic GSK1322322, a Novel Peptide Deformylase Inhibitor

ABSTRACT GSK1322322 is a potent inhibitor of peptide deformylase, an essential bacterial enzyme required for protein maturation. GSK1322322 is active against community-acquired skin and respiratory tract pathogens, including methicillin-resistant Staphylococcus aureus, multidrug-resistant Streptococcus pneumoniae, and atypical pathogens. This phase I, randomized, double-blind, placebo-controlled, 2-part, single-dose, dose escalation study (first time in humans) evaluated the safety, tolerability, and pharmacokinetics of GSK1322322 (powder-in-bottle formulation) in healthy volunteers. In part A, dose escalation included GSK1322322 doses of 100, 200, 400, 800, and 1,500 mg under fasting conditions and 800 mg administered with a high-fat meal. In part B, higher doses of GSK1322322 (2,000, 3,000, and 4,000 mg) were evaluated under fasting conditions. Of the 39 volunteers enrolled in the study, 29 and 10 volunteers were treated with GSK1322322 and placebo, respectively. Upon single-dose administration, GSK1322322 was absorbed rapidly, with median times to maximum plasma concentration (Tmax) ranging from 0.5 to 1.0 h. The maximum observed plasma concentration (Cmax) and exposure (area under the concentration-time curve [AUC]) of GSK1322322 were greater than dose proportional between 100 and 1,500 mg and less than dose proportional between 1,500 and 4,000 mg. Administration of the drug with a high-fat meal reduced the rate of absorption (reduced Cmax and delayed Tmax) without affecting the extent of absorption (no effect on AUC). GSK1322322 was generally well tolerated, with all adverse events being mild to moderate in intensity during both parts of the study. The most frequently reported adverse event was headache. Data from this study support further evaluation of GSK1322322.

Safety, Tolerability, and Efficacy of GSK1322322 in the Treatment of Acute Bacterial Skin and Skin Structure Infections

ABSTRACT GSK1322322 represents a new class of antibiotics that targets an essential bacterial enzyme required for protein maturation, peptide deformylase. This multicenter, randomized, phase IIa study compared the safety, tolerability, and efficacy of GSK1322322 at 1,500 mg twice daily (b.i.d.) with that of linezolid at 600 mg b.i.d. in patients suspected of having Gram-positive acute bacterial skin and skin structure infections (ABSSSIs). The primary endpoint was assessment of the safety of GSK1322322, and a key secondary endpoint was the number of subjects with a ≥20% decrease in lesion area from the baseline at 48 and 72 h after treatment initiation. GSK1322322 administration was associated with mild-to-moderate drug-related adverse events, most commonly, nausea, vomiting, diarrhea, and headache. Adverse events (86% versus 74%) and withdrawals (28% versus 11%) were more frequent in the GSK1322322-treated group. Treatment with GSK1322322 and linezolid was associated with ≥20% decreases from the baseline in the lesion area in 73% (36/49) and 92% (24/26) of the patients, respectively, at the 48-h assessment and in 96% (44/46) and 100% (25/25) of the patients, respectively, at the 72-h assessment. Reductions in exudate/pus, pain, and skin infection scores were comparable between the GSK1322322 and linezolid treatments. The clinical success rates within the intent-to-treat population and the per-protocol population that completed this study were 67 and 91%, respectively, in the GSK1322322-treated group and 89 and 100%, respectively, in the linezolid-treated group. These results will be used to guide dose selection in future studies with GSK1322322 to optimize its tolerability and efficacy in patients with ABSSSIs. (This study has been registered at ClinicalTrials.gov under registration no. NCT01209078 and at http://www.gsk-clinicalstudyregister.com [PDF113414].)

Safety, tolerability and pharmacokinetics of repeat dosing of the antibiotic GSK1322322, a peptide deformylase inhibitor: a randomized placebo-controlled study

OBJECTIVES GSK1322322 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: PDF112668), the safety, tolerability and pharmacokinetics of single and repeat oral-dose GSK1322322 (500-1500 mg) in healthy adult and elderly volunteers were evaluated. PATIENTS AND METHODS Part A included GSK1322322 doses of 500, 750, 1000 and 1500 mg in healthy adults; Part B evaluated 1000 mg of GSK1322322 in healthy elderly volunteers. Volunteers received a single morning dose of a powder-in-bottle formulation of GSK1322322 or placebo on day 1, no dosing on day 2 and twice-daily dosing on days 3-12. RESULTS Of 52 enrolled volunteers, 40 and 12 volunteers were treated with GSK1322322 and placebo, respectively. Mean plasma GSK1322322 trough concentration increased with increasing dose and reached steady-state after 2 days of repeat dosing. After single dosing of GSK1322322, maximum plasma concentration and exposure (AUC) were dose proportional from 500 to 1500 mg. However, after repeat dosing, AUC values at steady-state increased slightly more than proportionally, possibly because of a slightly longer terminal elimination t½ after repeat dosing (compared with single-dose t½) at higher doses (1000 and 1500 mg). There was no age effect or diurnal variation in the GSK1322322 pharmacokinetic profile. GSK1322322 was generally well tolerated-all adverse events were mild to moderate in intensity. CONCLUSIONS Repeat oral GSK1322322 (500-1500 mg) for 10 days was well tolerated. These data warrant further clinical investigation of GSK1322322.

Safety, tolerability, and pharmacokinetics of oral and intravenous administration of GSK1322322, a peptide deformylase inhibitor

GSK1322322 is the first in a new class of antibiotics that targets peptide deformylase (PDF), an essential bacterial enzyme required for protein maturation. This randomized, double‐blind, placebo‐controlled, eight‐cohort phase I trial enrolled 62 healthy volunteers to assess safety, tolerability, and pharmacokinetic profiles of GSK1322322. GSK1322322 was administered as a single oral or intravenous (IV) dose, escalating from 500 to 3,000 mg or repeat IV doses escalating from 500 to 1,500 mg twice daily. Upon repeat IV administration, GSK1322322 exhibits linear pharmacokinetics over time upon repeat doses as shown by time‐invariant pharmacokinetics. A dose‐proportional increase in area under concentration‐time curve was observed after single or repeat IV dosing, whereas clearance at steady state remained generally unchanged across doses. There was minimal accumulation of GSK1322322 after repeat IV twice‐daily administration. After oral tablet doses of GSK1322322 1,000 and 1,500 mg, absolute bioavailability was 69% and 56%, respectively. GSK1322322 administration at single and repeat IV doses and at supratherapeutic single IV doses of 2,000 and 3,000 mg was associated with mild‐to‐moderate drug‐related adverse events. On the basis of the pharmacokinetics and tolerability demonstrated in this study, GSK1322322 has the potential to become the first‐in‐class PDF inhibitor for clinical use.

Effect of H2 Blockade and Food on Single-Dose Pharmacokinetics of GSK1322322, a Peptide Deformylase Inhibitor Antibacterial

ABSTRACT GSK1322322 is first in a new class of antibiotics, peptide deformylase inhibitors, and is active against multidrug-resistant respiratory and skin pathogens. Part 1 of this phase 1, randomized, single-dose (1,000 mg) study in 20 healthy volunteers compared the relative bioavailability of three different tablet formulations of GSK1322322 (fast release, intermediate release, and slow release) to that of the previously studied powder-in-bottle formulation to assess the optimal formulation for progression into clinical trials. Part 2 assessed the effect of a high-fat meal and drug interaction with an H2 blocker and an H2 blocker plus vitamin C on the pharmacokinetic profile of GSK1322322. Of the three tablet formulations, fast-release GSK1322322 provided pharmacokinetic profiles similar to those of the powder-in-bottle reference formulation (∼93% relative bioavailability) and was selected for progression in part 2. When GSK1322322 was administered with a high-fat meal, the maximum observed plasma concentration (Cmax) was reduced by 20%, and the time to maximum plasma concentration (Tmax) was delayed by 1.9 h. The exposure (area under the concentration-time curve [AUC]) increased by ∼20% compared to that in volunteers in the fasted state. Coadministration of GSK1322322 with an H2 blocker resulted in a slight delay in absorption (Tmax ∼0.75 h later) and 58 and 38% decreases in the Cmax and AUC0–∞ values, respectively, compared to GSK1322322 alone. This effect was reversed with vitamin C intake (i.e., no delay in Tmax and the Cmax and AUC0–∞ values decreased by only 21 and 12%, respectively). GSK1322322 was generally well tolerated, and most adverse events were mild in intensity during both parts of the study.

Penetration of GSK1322322 into Epithelial Lining Fluid and Alveolar Macrophages as Determined by Bronchoalveolar Lavage

ABSTRACT GSK1322322 is a potent peptide deformylase inhibitor with in vitro and in vivo activity against multidrug-resistant skin and respiratory pathogens. This report provides plasma and intrapulmonary pharmacokinetics, safety, and tolerability of GSK1322322 after repeat (twice daily intravenous dosing for 4 days) dosing at 1,500 mg. Plasma samples were collected over the last 12-hour dosing interval of repeat dosing following the day 4 morning dose (the last dose). Bronchoalveolar lavage samples were collected once in each subject, either before or at 2 or 6 h after the last intravenous dose. Plasma area under the concentration-time curve (AUC0–τ) was 66.7 μg · h/ml, and maximum concentration of drug in serum (Cmax) was 25.4 μg/ml following repeat doses of intravenous GSK1322322. The time course of epithelial lining fluid (ELF) and alveolar macrophages (AM) mirrored the plasma concentration-time profile. The AUC0–τ for ELF and AM were 78.9 μg · h/ml and 169 μg · h/ml, respectively. The AUC0–τ ratios of ELF and AM to total plasma were 1.2 and 2.5, respectively. These ratios increased to 3.5 and 7.4, respectively, when unbound plasma was considered. These results are supportive of GSK1322322 as a potential antimicrobial agent for the treatment of lower respiratory tract bacterial infections caused by susceptible pathogens. (This study has been registered at ClinicalTrials.gov under registration number NCT01610388.)

Application of a Stable Isotope Approach to Evaluate Impact of Changes in Manufacturing Parameters for an Immediate‐Release Tablet

There is continued emphasis from the various worldwide regulatory agencies to ensure that the pharmaceutical industry fully understands the products they are developing. This emphasis is seen via development of quality‐by‐design (QbD) publications and guidelines generated by the International Committee on Harmonization. The challenge to meet these expectations is primarily associated with the generation of in vivo data (eg, pharmacokinetic data) that is resource intensive. A technique reducing the resources needed to generate this in vivo data permits a more extensive application of QbD principles. This paper presents the application of stable isotopes in pharmacokinetic studies. The data show that the use of stable isotopes can significantly reduce the number of subjects required for a study. This reduction in subjects thus translates into a significant reduction in resources and time needed to generate the required in vivo data to support QbD.

Bioequivalence Studies of a Reformulated Dutasteride and Tamsulosin Hydrochloride Combination Capsule and a Commercially Available Formulation

A dutasteride 0.5 mg and tamsulosin hydrochloride 0.4 mg combination (DTC) capsule (Duodart®) was reformulated to reduce the capsule size and enhance product stability. Bioequivalence of the reformulated DTC capsule with the commercial formulation was evaluated in 2 single‐dose, open‐label, randomized, 2‐way crossover studies in healthy adult male volunteers. Subjects in a fasted or fed state received a single oral dose of either the reformulated DTC or the commercial formulation followed by a 28‐day washout period between treatments. Blood samples were taken predose and up to 72 hours postdose for pharmacokinetic (PK) analysis of dutasteride and tamsulosin serum concentrations. From the serum concentration‐vs‐time data, a noncompartmental method was used to calculate the maximum observed serum concentration (Cmax) and area under the serum concentration‐time curve (AUC0‐t) for dutasteride and tamsulosin, and AUC0‐∞ for tamsulosin. The 90% confidence intervals for the ratios of the Cmax and AUC0‐t (for dutasteride and tamsulosin) and for AUC0‐∞ (for tamsulosin) were all completely contained within the range of 80% to 125%; therefore, the reformulated DTC capsule is bioequivalent to the commercial formulation under both fed and fasted states.

Investigation of metabolism and disposition of GSK1322322, a peptidase deformylase inhibitor, in healthy humans using the entero-test for biliary sampling.

GSK1322322 (N-((R)-2-(cyclopentylmethyl)-3-(2-(5-fluoro-6-((S)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-2-methylpyrimidin-4-yl)hydrazinyl)-3-oxopropyl)-N-hydroxy-formamide) is an antibiotic in development by GlaxoSmithKline. In this study, we investigated the metabolism and disposition of [14C]GSK1322322 in healthy humans and demonstrated the utility of the Entero-Test in a human radiolabel study. We successfully collected bile from five men using this easy-to-use device after single i.v. (1000 mg) or oral administration (1200 mg in a solution) of [14C]GSK1322322. GSK1322322 had low plasma clearance (23.6 liters/hour) with a terminal elimination half-life of ∼4 hours after i.v. administration. After oral administration, GSK1322322 was readily and almost completely absorbed (time of maximal concentration of 0.5 hour; bioavailability 97%). GSK1322322 predominated in the systemic circulation (>64% of total plasma radioactivity). An O-glucuronide of GSK1322322 (M9) circulated at levels between 10% and 15% of plasma radioactivity and was pharmacologically inactive. Humans eliminated the radioactive dose in urine and feces at equal proportions after both i.v. and oral doses (∼45%–48% each). Urine contained mostly unchanged GSK1322322, accounting for 30% of the dose. Bile contained mostly M9, indicating that glucuronidation was likely a major pathway in humans (up to 30% of total dose). In contrast, M9 was found in low amounts in feces, indicating its instability in the gastrointestinal tract. Therefore, without the Entero-Test bile data, the contribution of glucuronidation would have been notably underestimated. An unusual N-dehydroxylated metabolite (a secondary amide) of GSK1322322 was observed primarily in the feces and was most likely formed by gut microbes.

Relative Bioavailability of Fixed-Dose Combinations of Tamsulosin and Dutasteride: Results From 2 Randomized Trials in Healthy Male Volunteers

The relative bioavailabilities of dutasteride/tamsulosin hydrochloride 0.5 mg/0.2 mg fixed‐dose combination (FDC) capsules compared with coadministered reference products (1 dutasteride 0.5‐mg capsule [Avodart®] + 1 tamsulosin hydrochloride 0.2‐mg orally disintegrating tablet [Harnal D®]) were investigated in 2 clinical trials under fasted and fed conditions (ClinicalTrials.gov NCT02184585 and NCT02509104). Both trials were open‐label, randomized, single‐dose, crossover studies in healthy male adults aged 18‐65 years. Trial 1 evaluated 2 formulations (FDC1 and FDC2), and trial 2 evaluated a third formulation (FDC3). The primary end points were dutasteride area under the concentration‐time curve from time 0 to t (AUC(0‐t)) and peak plasma concentration (Cmax) and tamsulosin AUC(0‐∞), AUC(0‐t), and Cmax. The formulations were considered to be bioequivalent if the 90%CIs for the geometric mean ratios for each end point were within the range of 0.80‐1.25. For FDC1 in trial 1, bioequivalence criteria were not met for dutasteride Cmax or AUC in the fasted state or for tamsulosin Cmax in the fasted or fed states. For FDC2 in trial 1, all bioequivalence criteria were met except for tamsulosin Cmax in the fasted state. For FDC3 in trial 2, bioequivalence criteria were met for all dutasteride and tamsulosin end points in both the fed and fasted states. Safety profiles were similar for all FDC formulations and combination treatments.