Safety, local tolerability and pharmacokinetics of ceftaroline fosamil administered in a reduced infusion volume

Abstract

Aims

The standard dose of ceftaroline fosamil for patients with normal renal function is 600 mg diluted in 250 ml by 60 min intravenous infusion every 12 h. This two part phase I trial (NCT01577589) assessed safety and local tolerability of multiple ceftaroline fosamil 50 ml and 250 ml infusions, and pharmacokinetics following single administrations of each infusion volume.

Methods

Part A was a placebo-controlled, double-blind, multiple dose crossover study. Twenty-four healthy subjects were randomized to simultaneous, bilateral ceftaroline fosamil 600 mg and placebo infusions in each arm (50 ml then 250 ml or vice versa) every 12 h for 72 h, with a ≥ 4.5 day washout. Local tolerability was evaluated by the Visual Infusion Phlebitis scale, with scores ≥2 considered infusion site reactions (ISRs). Part B was an open label crossover study. Ten subjects were randomized to single 50 ml and 250 ml ceftaroline fosamil 600 mg infusions on days 1 and 3 (washout on day 2). Blood samples for pharmacokinetic analysis were taken over 24 h.

Results

In part A, four subjects (16.7%) experienced ISRs, all of which were associated with placebo infusions. No ISRs were reported for either ceftaroline fosamil 50 ml or 250 ml. Plasma pharmacokinetics (ceftaroline fosamil, active ceftaroline and an inactive metabolite) were similar following single 50 ml and 250 ml infusions in part B.

Conclusions

No new safety concerns were identified for ceftaroline fosamil 600 mg 50 ml compared with 250 ml. These findings suggest infusion volumes down to 50 ml may be used in patients with fluid intake restrictions.

What Is Already Known about This Subject

• Ceftaroline fosamil (a β-lactam cephalosporin), is typically administered as 600 mg 1 h intravenous infusions in 250 ml every 12 h.

• Reduced ceftaroline fosamil infusion volumes could provide dosing flexibility, enabling management of patients with restricted fluid intake, such as hypervolaemia, chronic hyponatraemia, renal insufficiency or chronic heart failure.

What This Study Adds

• Infusion volume (50 ml or 250 ml) had no impact on local tolerability following repeated ceftaroline fosamil 600 mg infusions (six doses) into the same venous catheter over 72 h.

• Plasma pharmacokinetics (ceftaroline fosamil, ceftaroline and an inactive metabolite) were comparable following single 50 ml and 250 ml infusions.

Introduction

Ceftaroline fosamil is a new β-lactam cephalosporin antibiotic for intravenous (i.v.) administration licensed in the European Union and elsewhere for the treatment of adult patients with community-acquired pneumonia (CAP) and complicated skin and soft tissue infections (cSSTI), and for similar indications in the United States 1,2. Ceftaroline, the active metabolite of the pro-drug ceftaroline fosamil, has in vitro activity against Gram-positive (including methicillin-resistant Staphylococcus aureus [MRSA]) and common Gram-negative pathogens associated with CAP and cSSTI 3,4. The clinical and microbiological efficacy and safety of ceftaroline fosamil have been demonstrated in four phase III trials in patients with skin and skin structure infections (NCT00424190/NCT00423657) and community-acquired bacterial pneumonia (NCT00621504/NCT00509106), although notably the pneumonia trials did not include patients with MRSA infections 5,6.

The recommended dose of ceftaroline fosamil for patients with normal renal function is 600 mg every 12 h by 60 (±10) min i.v. infusion, and 400 mg every 12 h for patients with creatinine clearance (CL_cr) between 30 and 50 ml min⁻¹. The dry powder drug is reconstituted in 20 ml of sterile water and then typically diluted in a 250 ml infusion bag (containing 0.9% sodium chloride, 5% dextrose, 0.45% sodium chloride and 2.5% dextrose, or lactated Ringer's solution; 1,2). This dosage and infusion volume (equivalent to a total drug infusion concentration of 2.2 mg ml⁻¹) was used in the phase III clinical trials of ceftaroline fosamil 5,6.

Fluid and electrolyte disorders such as hypervolaemic and euvolaemic hyponatraemia are common complications in hospitalized patients with CAP 7 and some severe bacterial skin infections 8,9, and are associated with a wide range of medical conditions including congestive heart failure, liver cirrhosis and renal failure 10. Hyponatraemia can result in neurological and cognitive sequelae, increased mortality, length of hospital stay and healthcare resource utilization 11. Restriction of fluid intake is a mainstay of management for hypervolaemia and chronic hyponatraemia 10. Therefore, careful consideration of overall daily fluid load, including i.v. and oral routes of intake, is required for these patients receiving treatment in hospital for other acute conditions. Moreover, some conditions that result from infectious processes (for example, acute respiratory distress syndrome secondary to pneumonia), as well as venous access infections in patients with end-stage renal disease, necessitate careful management of fluid intake, including i.v. volumes 12,13.

Since there are limited data on the tolerability and pharmacokinetics (PK) of ceftaroline fosamil administered at concentrations >2.2 mg ml⁻¹, we conducted a phase I placebo-controlled trial in healthy subjects to (i) assess the impact of multiple doses of a reduced ceftaroline fosamil infusion volume (50 ml instead of 250 ml) on safety and local tolerability and (ii) compare the PK profiles of the two infusion volumes.

Methods

Study design

This was a single centre, double-blind, placebo-controlled phase I study (clinicaltrials.gov identifier NCT01577589; sponsor protocol number D3720C00015) conducted at Hammersmith Medicines Research, London, UK. The protocol was approved by an independent ethics committee (Welwyn Clinical Pharmacology Ethics Committee), and the study was performed in accordance with the Declaration of Helsinki and the International Conference on Harmonization/Good Clinical Practice, and applicable regulatory requirements. All subjects provided written informed consent.

The study was separated into two parts, designed to assess local tolerability and safety (part A) and PK and safety (part B) of ceftaroline fosamil 600 mg diluted in 250 ml (2.4 mg ml⁻¹) or 50 ml (12 mg ml⁻¹) infusion solution in healthy subjects. Part A had a placebo-controlled, double-blind, multiple dose, two way crossover design. Subjects were randomized (1:1) to one of two treatment sequences, each comprising two treatment periods separated by a ≥4.5 day washout period (Table 1). Each treatment period consisted of a series of six 1 h infusions of active drug and six simultaneous, bilateral placebo infusions in opposite arms administered over 72 h (Table 1). Within each treatment period, all infusions in each arm were given via a single i.v. access site, but different veins were used in each period, and the arm infused with active treatment was switched from the first period to the second. Hence the randomization was stratified by the ordering of infusion, to balance any potential arm effects and to avoid confounding arm with period effects. I.v. cannula insertions for study drug infusion were performed by a qualified healthcare professional using a standard aseptic technique. In accordance with UK and US guidelines and routine hospital practice, all cannulae were to be removed if the access site showed signs of phlebitis or inflammation.

Table 1.

Part A treatment sequences

Sequence	Period	Left arm	Right arm
Sequence 1	1	Ceftaroline fosamil 600 mg 50 ml infusion	Placebo 250 ml infusion
	2	Placebo 50 ml infusion	Ceftaroline fosamil 600 mg 250 ml infusion
Sequence 2	1	Ceftaroline fosamil 600 mg 250 ml infusion	Placebo 50 ml infusion
	2	Placebo 250 ml infusion	Ceftaroline fosamil 600 mg 50 ml infusion

Healthy subjects were randomized in a 1:1 ratio to treatment sequence 1 or 2, each consisting of two treatment periods. Each treatment period was a series of six 1 h infusions of active drug and six simultaneous placebo infusions in opposite arms over 72 h. The sequences were designed to avoid administration of active treatment in the same arm for both treatment periods.

Part B was conducted following the completion of part A in a different cohort of subjects, and had an open-label, randomized, single dose, two way crossover design. Subjects were randomized 1:1 to receive either single infusions of ceftaroline fosamil 600 mg in 50 ml on day 1 and 250 ml on day 3, or 250 ml on day 1 and 50 ml on day 3, with a washout on day 2.

Objectives

The primary objective of part A was to evaluate the local tolerability of multiple ceftaroline fosamil 600 mg 50 ml and 250 ml i.v. infusions into the same vein every 12 h for up to 72 h. The secondary objective was to evaluate the safety of ceftaroline fosamil 50 ml and 250 ml infusions. The primary objective of part B was to characterize the plasma PK profile of ceftaroline following single i.v. infusions of ceftaroline fosamil 600 mg in 50 ml and 250 ml. Secondary objectives were to characterize the PK profiles of ceftaroline fosamil (the pro-drug) and ceftaroline M-1 (a microbiologically inactive metabolite) following each infusion of ceftaroline fosamil, and to evaluate the safety and tolerability of the two regimens.

Subjects

Healthy male and female subjects aged 18–75 years with body mass index (BMI) 18–30 kg m⁻² and body weight ≥50 kg were eligible to participate. Key inclusion criteria included suitability of veins on the back of both hands and both forearms for cannulation or repeated venepuncture. For part A, subjects had to be willing to have both arms used during the study with catheters inserted for up to a maximum of 72 h (six infusions per arm). Key exclusion criteria included a history of clinically significant disease or disorder or other condition which in the opinion of the investigator might place the subject at risk or influence the study results such as history or on-going allergy/hypersensitivity or allergic reaction to any β-lactam antimicrobial or drugs with a similar chemical structure or class as ceftaroline, clinically significant abnormalities in the physical examination, laboratory values, 12-lead electrocardiogram (ECG), or vital signs or CL_cr <80 ml min⁻¹ (Cockcroft & Gault formula). Subjects who participated in part A were not allowed to be enrolled in part B.

Assessments

Part A

Local tolerability of ceftaroline fosamil and placebo infusions was evaluated by the investigator (or a delegate) for each study drug infusion using a Visual Infusion Phlebitis (VIP) scale (0 = no signs of phlebitis, 1 = possibly first signs of phlebitis, 2 = early stage of phlebitis, 3 = medium stage of phlebitis, 4 = advanced stage of phlebitis or the start of thrombophlebitis and 5 = advanced stage of thrombophlebitis). VIP scores for each arm were recorded at pre-dose, 20 min, 40 min, 1 h, 6 h and 12 h post-dose. VIP scores ≥2 were considered infusion site reactions (ISRs). If any subject experienced an ISR, the infusion was to be stopped on that arm (without unblinding the treatment assignment) and the ISR was to be recorded as an adverse event (AE). Scheduled and ongoing infusion(s) on the subject's other arm could continue, as appropriate.

AEs (coded using MedDRA version 15) and serious AEs (SAEs) were recorded at screening, pre-dose, during each day of study drug treatment, at discharge and at a follow-up visit 5–10 days after discharge. All reported AEs and SAEs were categorized by the investigator as possibly related or probably unrelated to the study drug treatment. Clinical chemistry, haematology, urinalysis and 12-lead ECG were assessed before and after completion of each treatment period and at a follow-up visit 5–10 days after discharge.

Part B

Assessments in part B included venous blood sampling for PK analysis at pre-dose (–60 to 0 min prior to the start of the i.v. infusion) and at 20 min, 40 min, end of infusion (within 2 min before the end of the infusion), 65 min, 75 min, 90 min, and 2, 3, 4, 6, 8, 12, 18 and 24 h post-dose.

Safety assessments including AE/SAE reporting and vital signs, clinical chemistry, haematology, urinalysis and 12-lead ECG were performed during treatment and up to 10 days after discharge.

Analytical methods

Blood samples were collected in pre-chilled 4 ml BD Vacutainer tubes containing spray-dried sodium fluoride/potassium oxalate as anticoagulant and stabilizer for the analysis of ceftaroline fosamil, ceftaroline and ceftaroline M-1. Within 15 min of collection, samples were centrifuged at 1500 g at 4°C for 15 min, and the resulting plasma samples were transferred to NUNC screw-capped polypropylene tubes (0.5 ml each aliquot). The plasma samples were frozen within 15 min of centrifugation and stored at −70°C until analysis. Assays to determine plasma concentrations of ceftaroline fosamil, ceftaroline and ceftaroline M-1 were performed at Covance Bioanalytical Services, LLC (Indianapolis, IN, USA) using validated methods involving protein precipitation followed by liquid chromatography tandem mass spectrometric detection (LC-MS/MS). Two analytical methods were used. Ceftaroline fosamil was analyzed alone using a validated method; whereas ceftaroline and ceftaroline M-1 were analyzed together in a separate method. Each method employed 50 μl plasma samples with the corresponding stable isotope labelled internal standards added to each sample. Precision (%CV) and accuracy (% bias) using three reference quality control samples for each analyte were ≤10.1% and within −4.0% to 0.0% (ceftaroline fosamil), ≤3.7% and within 0.5% to 3.3% (ceftaroline), and ≤4.0% and within −4.0% to 0.2% (ceftaroline M-1), indicating that the assays performed reliably during the analysis of study samples. Sensitivity (i.e. the lower limit of quantification [LLOQ]) was 50.0 ng ml⁻¹ for all analytes. Assay specificity was assessed using blank matrices from six individuals, and demonstrated the lack of significant interference in the chromatographic regions of interest for the analytes (<20% of the response from the single LLOQ used) and internal standard (<5% of internal standard response in the control zero sample).

Incurred sample reproducibility was evaluated for all analytes in a set of 30 randomly selected samples. At least two-thirds of the selected samples demonstrated a change (difference between the reanalysis result and the original result, relative to the mean of the original result and the reanalysis result) of within ±20.0%, thus meeting pre-defined acceptance criteria. All samples were analyzed within the established stability in human plasma stored at −70°C (291 days for ceftaroline fosamil and 161 days for ceftaroline and ceftaroline M-1).

Statistical methods

Given the exploratory nature of the study, sample size was not based on formal statistical considerations and no formal statistical hypothesis testing was performed. For part A, a sample size of 24 subjects was considered sufficient to assess if the repeated doses of the 50 ml ceftaroline fosamil infusion produced an increase in the incidence of ISRs compared with the 250 ml infusion.

Two study populations were defined for analysis purposes. The safety analysis set included all subjects randomized in part A or part B who received at least one administration of study drug (ceftaroline fosamil or placebo), and for whom any post-dose data were available. The PK analysis set included all subjects randomized in part B who received at least one administration of ceftaroline fosamil and had at least one measured concentration of any of the three analytes (ceftaroline fosamil, ceftaroline and ceftaroline M-1) in plasma at a scheduled time point after the start of infusion.

Statistical analyses were performed by Quintiles (Overland Park, KS, USA) and Bloemfontein (South Africa) using SAS® Version 9.2 (SAS Institute Inc., Cary, NC, USA). PK parameters were derived by Quintiles (Overland Park, KS, USA) using non-compartmental methods with WinNonlin® Version 5.2 (Pharsight Corporation, Mountain View, CA, USA).

Results

Subjects

A total of 24 subjects were randomized in part A and 10 subjects were randomized in part B. Subjects' demographic characteristics are shown in Table 2. All subjects completed all study assessments.

Table 2.

Demographic characteristics of subjects enrolled in parts A and B (all subjects)

Variable	Part A	Part B
Number of subjects	24	10
Mean (SD) age (years)	28 (8.0)	30 (9.2)
Male, n (%)	24 (100.0)	10 (100.0)
Mean (SD) BMI (kg m−2)	25 (2.2)	24 (2.6)
Race, n (%)
White	16 (66.7)	6 (60.0)
Black or African American	4 (16.7)	2 (20.0)
Asian	3 (12.5)	1 (10.0)
Other	1 (4.2)	1 (10.0)

Local tolerability (part A)

There were no ISRs (i.e. VIP scores ≥2) reported for the ceftaroline fosamil-treated arms. Four subjects (16.7%) experienced ISRs (VIP score ≥2) in the placebo arms which were reported as AEs (Table 3). These ISRs led to discontinuation of study treatment in the affected arms of all four subjects. However, these subjects were not discontinued from the study and they completed all planned assessments.

Table 3.

Summary of VIP scores following multiple ceftaroline fosamil 600 mg and placebo 50 ml and 250 ml i.v. infusions in part A (safety population, n = 24)

VIP score	Number (%) of subjects
	Ceftaroline fosamil (n = 24)		Placebo (n = 24)
	50 ml	250 ml	50 ml	250 ml
0	17 (70.8)	21 (87.5)	19 (79.2)	18 (75.0)
1	7 (29.2)	3 (12.5)	3 (12.5)	4 (16.7)
2	0 (0.0)	0 (0.0)	2 (8.3)	1 (4.2)
3	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
4	0 (0.0)	0 (0.0)	0 (0.0)	1 (4.2)
5	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)

PK profiles (part B)

Ceftaroline plasma concentration-time profiles (Figure 1) and PK parameters (Table 4) were broadly similar following ceftaroline fosamil 50 ml and 250 ml infusions. Geometric mean and individual ceftaroline area under the plasma concentration−time curve from zero to infinity (AUC) and maximum plasma concentration (C_max) are shown in Figure 2.

Figure 1.

Geometric mean (±SD) ceftaroline plasma concentration − time profiles following single ceftaroline fosamil 600 mg 50 ml and 250 ml i.v. infusions in part B (PK analysis population, n = 10) , ceftaroline fosamil 600 mg 50 ml; , ceftaroline fosamil 600 mg 250 ml

Table 4.

Geometric mean (%CV) ceftaroline PK parameters following single ceftaroline fosamil 600 mg 50 ml and 250 ml i.v. infusions in part B (PK analysis population, n = 10)

Parameter	Ceftaroline fosamil infusion volume
	50 ml (n = 10)	250 ml (n = 10)
AUC (μg ml−1 h)	66.8 (19.5)	65.4 (22.6)
AUC(0,12 h) (μg ml−1 h)	65.3 (18.5)	64.1 (21.5)
Cmax (μg ml−1)	29.1 (11.8)	28.2 (15.5)
tmax (h)*	0.97 (0.97–0.98)	1.08 (0.97–1.08)
t1/2,z (h)	2.41 (19)	2.40 (22.9)
MRT (h)	2.81 (17)	2.80 (15.7)
Apparent CL (l h−1)	7.94 (19.5)	8.10 (22.5)
Apparent Vz (l)	27.6 (7.8)	28.1 (9.2)

^*Median (range) presented for t_max. AUC_(0,12 h), area under the plasma concentration−time curve from zero to 12 h after the start of the infusion; CL, total body clearance of drug, from plasma; %CV, coefficient of variation; MRT, mean residence time; t_1/2,z, half-life associated with the terminal slope; t_max, time to maximum plasma concentration; V_z, volume of distribution based on the terminal phase.

Figure 2.

Individual and geometric mean ceftaroline exposure parameters following single ceftaroline fosamil 600 mg 50 ml or 250 ml i.v. infusions in part B (PK analysis population, n = 10) , individual values; , geometric mean

Plasma concentrations for the pro-drug, ceftaroline fosamil, were only quantifiable (>LLOQ) up to 1 h after the end of infusion. Geometric mean (%CV) ceftaroline fosamil plasma AUC values were 2.3 (29.3) and 2.1 (47.5) μg ml⁻¹ h following the 250 and 50 ml infusions, respectively and C_max values were 3.1 (27.4) and 2.6 (39.8) μg ml⁻¹. The PK profile of the microbiologically inactive metabolite of ceftaroline, ceftaroline M-1, was similar following ceftaroline fosamil 50 ml and 250 ml infusions (data not shown).

Safety (parts A and B)

Nine subjects in part A (37.5%) experienced at least one AE (three subjects following treatment with 50 ml ceftaroline fosamil/250 ml placebo, five following 250 ml ceftaroline fosamil/50 ml placebo and one following both treatments). Three subjects in part B (30.0%) experienced at least one AE (two following the 250 ml infusion and one following both the 50 ml and 250 ml infusions). All AEs were considered to be of mild intensity and there were no SAEs.

The most frequently reported AEs in part A were classified as general disorders and administration site conditions, specifically, infusion site phlebitis in three subjects (12.5%) in the placebo arm, infusion site thrombosis in one subject in the placebo arm (4.2%) and feeling of body temperature change in one subject (4.2%) following treatment with 250 ml ceftaroline fosamil/50 ml placebo. The most frequently reported AEs in part B were classified as gastrointestinal disorders and comprised vomiting, salivary hypersecretion and nausea, each occurring in one subject (10.0%). There were no clinically significant changes in laboratory parameters, vital signs or ECG recordings in either part of the study.

Discussion

ISRs, which are usually mild and self-resolving, are a known AE associated with cephalosporins and various other classes of parenteral antibiotics. Moreover, it is reasonable to assume that the incidence of ISRs may be related to infusion parameters, specifically drug concentrations in the infusion solution. Compared with the standard 250 ml infusion, a reduced ceftaroline fosamil 600 mg infusion volume of 50 ml did not affect the local tolerability of ceftaroline fosamil, or result in an increased incidence of AEs, following repeated every 12 h infusions in the same vein for up to 72 h (six infusions) in this sample of healthy subjects. In a separate group of healthy subjects, the ceftaroline fosamil infusion volume had minimal impact on geometric mean plasma PK parameters, and the observed PK profiles for the pro-drug and its metabolites following the single 250 ml and 50 ml infusions were consistent with previously reported data 4,14–18.

No new safety concerns were raised for ceftaroline fosamil 600 mg administered as a 50 ml or 250 ml 1 h infusion, either as multiple (part A) or single (part B) doses. Indeed, the safety profile for ceftaroline fosamil in the current study was consistent with that observed in previous studies in healthy subjects and in phase II and III clinical trials 19–21. The only observed ISRs occurred in placebo-treated arms.

The evaluation of local tolerability in part A of the study was carefully controlled, with all ceftaroline fosamil or placebo infusions in each treatment period administered in the same veins, which is likely to mirror ceftaroline fosamil administration in clinical practice. This procedure, together with measures undertaken to stratify the randomization and minimize confounding effects, maximized the robustness of the results. In view of the invasive and potentially painful nature of peripheral i.v. cannulation, courses of six infusions of ceftaroline fosamil over a 72 h period were chosen for part A to optimize the number of doses of study medication that could be given via a single cannula without exceeding the recommended time frame for replacement/removal of i.v. access lines 22,23.

In conclusion, compared with a 250 ml 60 min infusion, a reduced ceftaroline fosamil 600 mg infusion volume of 50 ml also infused over 60 min did not result in increased AEs, or affect the local tolerability of ceftaroline fosamil following repeated administration to the same vein in healthy subjects. These findings support the use of ceftaroline fosamil 600 mg infusion volumes down to 50 ml, providing dosing flexibility for different care settings and for patients with clinical requirements for reduced fluid intake, such as renal failure, congestive heart failure, hypervolaemic or euvolaemic hyponatraemia.

Competing Interests

All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare no support from any organization for the submitted work. TE, MK, HB, JL and MS were employees of AstraZeneca in the previous 3 years and HB also holds shares in/receives dividends from AstraZeneca.

The authors would like to thank Dr Elizabeth Tranter (formerly of Hammersmith Medicines Research, London, UK) for her work as Principal Investigator for the study, personnel at Quintiles (South Africa and USA) involved in data management and statistical analysis of the study results, Yan Li, PhD (AstraZeneca) for providing details around sample preparation and bioanalytical methodology and personnel at Covance (USA) involved in PK sample analysis.

This study was funded by AstraZeneca. Medical writing support was provided by Mark Waterlow of Prime Medica Ltd, Knutsford, Cheshire, UK, funded by AstraZeneca. The design and conduct of the study, as well as analysis of the study data and opinions, conclusions, and interpretation of the data, are the responsibility of the authors.

The results of the study have been presented in part at the 53rd InterScience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), 10–13 September 2013, Denver, CO, USA. Sunzel M, Tranter E, Kujacic M, Broadhurst H, Li J, Edeki T. Safety, Tolerability and Pharmacokinetics (PK) of Ceftaroline Fosamil Administered in Various Infusion Volumes (Poster A-470). http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=1e327bef-dfd2-4d8f-9679-1b8e7d1098f5&cKey=1e770aed-b1d1-426c-8e0c-cdc6cee1d409&mKey={7DD36E88-52C3-4FF1-A5DF-1D00766558B8}