Ann Allen

The clinical pharmacokinetics of a new pharmacokinetically enhanced formulation of amoxicillin/clavulanate

BACKGROUND A new oral pharmacokinetically enhanced formulation of the broad-spectrum antibiotic amoxicillin/clavulanate has been developed to provide more effective therapy against resistant pathogens than is provided by currently available formulations by maintaining therapeutically useful plasma amoxicillin concentrations for a longer period after dosing. OBJECTIVE This study explored the pharmacokinetics of the new oral formulation of amoxicillin/clavulanate in healthy male and female subjects. METHODS A single oral dose of pharmacokinetically enhanced amoxicillin/clavulanate (2000/125 mg; 16:1 ratio) was administered to subjects at the start of a meal. After dosing, blood samples were collected at frequent intervals up to 12 hours, and plasma was assayed for amoxicillin and clavulanate concentrations using validated procedures. The new formulation consisted of 1 layer of immediate-release amoxicillin and clavulanate and another of sustained-release amoxicillin in a proportion such that for an amoxicillin minimum inhibitory concentration (MIC) of 4 microg/mL, the time above the MIC (T >MIC) would be approximately > or = 40% over a 12-hour dosing interval. RESULTS The study enrolled 24 and 31 healthy male and female subjects, respectively. Their mean age was 35 years (range, 18-58 years) and mean body weight was 69 kg (range, 51-86 kg). After the expected sharp peak in plasma amoxicillin concentration, there appeared to be a slower decline with the pharmacokinetically enhanced formulation than is usually seen with conventional formulations, and there was evidence of a second amoxicillin absorption phase. The mean T >MIC for an amoxicillin MIC of 4 microg/mL was 49.4% of a 12-hour dosing interval, a value that cannot be achieved with existing approved doses and formulations of amoxicillin/clavulanate. By 12 hours, plasma amoxicillin concentrations were very low (approximately 0.05 microg/mL), suggesting no expectation of notable dose-to-dose accumulation on repeat dosing with a BID regimen. The terminal half-lives of amoxicillin (1.27 hours) and clavulanate (1.03 hours) with the new formulation were similar to those of existing formulations of amoxicillin/clavulanate. No deaths or serious adverse events were reported. CONCLUSIONS The enhanced pharmacokinetic profile of amoxicillin/clavulanate seen in this study suggests that this formulation is likely to be highly effective for the oral treatment of infections caused by bacteria--including beta-lactamase-producing organisms--and strains with amoxicillin MICs < or = 4 microg/mL.

Inhaled fluticasone furoate/vilanterol does not affect hypothalamic-pituitary-adrenal axis function in adolescent and adult asthma: randomised, double-blind, placebo-controlled study.

Fluticasone furoate (FF) is a novel inhaled corticosteroid with 24‐h activity. FF is in development as a once‐daily treatment for asthma as monotherapy and in combination with vilanterol (VI), a long‐acting β2 agonist. Corticosteroids can have systemic effects on hypothalamic‐pituitary‐adrenal (HPA) axis function, potentially resulting in cortisol suppression.

Pharmacokinetics and pharmacodynamics of intravenous and inhaled fluticasone furoate in healthy Caucasian and East Asian subjects

AIM The aim of the study was to evaluate the pharmacokinetics (PK) of inhaled and intravenous (i.v.) fluticasone furoate (FF) in healthy Caucasian, Chinese, Japanese and Korean subjects. METHOD This was an open label, randomized, two way crossover study in healthy Caucasian, Chinese, Japanese and Korean subjects (n = 20 per group). Inhaled FF (200 μg for 7 days, then 800 μg for 7 days from a dry powder inhaler [DPI]) was administered in one treatment period and i.v.FF (250 μg infusion) in the other. FF PK and serum cortisol (inhaled 200 μg only) were compared between the ethnic groups using analysis of variance. P450 CYP3A4 activity and safety were also assessed. RESULTS Ethnic differences in i.v. FF PK were accounted for by body weight differences. CYP3A4 activity was similar across the groups. Higher FF systemic exposure was seen following inhaled dosing in Chinese, Japanese and Korean subjects compared with Caucasian subjects. Absolute bioavailability was greater (36%–55%) in all East Asian groups than for Caucasian subjects following inhaled FF 800 μg. Deconvolution analysis suggested inhaled FF resided in the lung of East Asian subjects longer than for Caucasians (time for 90% to be absorbed [t90]: 29.1–30.8 h vs. 21.4 h). In vitro simulation method predicted comparable delivered lung dose across ethnic groups. Serum cortisol weighted mean was similar between Caucasians and Chinese or Koreans, while in Japanese was on average 22% lower than in Caucasians. All FF treatments were safe and well tolerated. CONCLUSION Modestly higher (<50%) FF systemic exposure seen in East Asian subjects following inhaled dosing was not associated with a clinically significant effect on serum cortisol, suggesting that a clinical dose adjustment in East Asian subjects is not required.

Influence of Renal and Hepatic Impairment on the Pharmacokinetic and Pharmacodynamic Properties and Tolerability of Fluticasone Furoate and Vilanterol in Combination

BACKGROUND Renal and hepatic disease may lead to alterations in drug absorption, distribution, and elimination, and, therefore, the potential effect of renal and hepatic impairment should be investigated in drugs under development. OBJECTIVE To assess the effects of renal and hepatic impairment on the pharmacokinetic and pharmacodynamic properties and tolerability of fluticasone furoate/vilanterol (FF/VI) administered in combination. METHODS Two open-label, parallel-group studies were conducted. Eligible study participants included adults with severe renal impairment (CrCl <30 mL/min) and those with mild, moderate, or severe hepatic impairment (by Child-Pugh classification). Patients were matched with healthy subjects. Participants received 7 days of inhaled FF/VI 200/25 or 100/12.5 μg (severe hepatic impairment only) once daily in the morning. Lack of effect was defined as an upper 90% confidence limit of the C(max) and AUC geometric mean impaired:healthy ratios (GMRs) of <2. RESULTS Study participants included patients with severe renal impairment (n = 9) or with mild (n = 9), moderate (n = 9), or severe (n = 8) hepatic impairment, together with matched healthy subjects (n = 9 per study). Lack of effect of severe renal impairment was demonstrated with FF (GMRs [90% CI]: C(max), 0.96 [0.57-1.61]; AUC(0-24), 0.91 [0.60-1.38]) and VI (C(max), 0.70 [0.49-1.00]; AUC(0-24), 1.56 [1.27-1.92]). Day-7 dose-normalized FF AUC(0-24) was greater in the groups with mild, moderate, and severe hepatic impairment than in healthy subjects (GMRs [90% CI]: 1.34 [0.82-2.20], 1.83 [1.11-2.99], and 1.75 [1.05-2.91], respectively); lack of effect was not demonstrated. There was no effect of hepatic impairment on dose-normalized VI C(max) or AUC(0-24). Apart from reduced serum cortisol weighted mean (0-24 hour) in patients with moderate hepatic impairment (34% reduction [90% CI, 11%-51%] compared with healthy subjects), there was no evidence of a difference in heart rate, serum potassium, or 24-hour serum cortisol between patients with severe renal impairment of any hepatic impairment and healthy subjects. No safety concerns were identified in any of the groups with impairment or their matched healthy controls. CONCLUSIONS Severe renal impairment had no apparent clinically relevant effects on the pharmacokinetic or pharmacodynamic properties or tolerability of FF/VI. Hepatic impairment had no apparent effect on VI systemic exposure but increased FF exposure. Fluticasone furoate was associated with reduced serum cortisol in patients with moderate hepatic impairment. These data suggest that caution should be exercised when prescribing FF/VI in patients with moderate or severe hepatic impairment due to a risk for unwanted systemic corticosteroid effects associated with increased FF systemic exposure. Clinicaltrials.gov identifiers: NCT01266941 and NCT01266980.

A repeat-dose thorough QT study of inhaled fluticasone furoate/vilanterol combination in healthy subjects.

AIMS This study was designed as a thorough QT (TQT) study to evaluate the effects of fluticasone furoate(FF)/vilanterol (VI) in healthy subjects. Supportive data from a TQT study conducted with FF are also presented. METHODS This was a randomized, placebo-and positive-controlled, double-dummy, double-blind, four-way crossover study, in which healthy subjects (n = 85) were randomized to 7 days of once-daily treatment of FF/VI (200/25 or 800/100 μg) or placebo or single-dose oral moxifloxacin (single-blind, 400 mg). In the supportive TQT study, subjects (n = 40) were randomized to single-dose inhaled FF(4000 μg), oral moxifloxacin (400 mg) or placebo. RESULTS There was a lack of effect of FF/VI (200/25 μg) on QTcF (Fridericias correction); all time-matched mean differences from baseline relative to placebo (0–24 h) were <5 ms, with upper 90% confidence intervals (CI) of <10 ms. At 800/100 μg, FF/VI had no significant clinicaleffect on QTcF except at 30 min postdose when the 90% CI was >10 ms [mean (90% CI), 9.6 ms (7.2, 12.0)]. No effect on QTci (individually corrected) was observed at either strength of FF/VI, with mean time-matched treatment differences <5 ms at all time points [upper 90% CIs <10 ms (0–24 h)]. Assay sensitivity was confirmed; moxifloxacin prolonged QTcF and QTci, with time-matched mean differences from baseline relative toplacebo of >10 ms (1–8 h postdose). CONCLUSIONS Repeat once-daily dosing of FF/VI (200/25 μg), which is the highest therapeutic strength used in phase III studies, is not associated with QTc prolongation in healthy subjects. Supratherapeutic strength FF/VI (800/100 μg) demonstrated a small transient effect on QTcF but not on QTci.

Pharmacokinetics of fluticasone furoate, umeclidinium, and vilanterol as a triple therapy in healthy volunteers.

Objective: Two single-center, four-way, single-dose, crossover studies assessed the systemic exposure, systemic pharmacodynamics (PD), and safety profile of the closed triple fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) therapy compared with dual therapies. These are the first studies where pharmacokinetic (PK) profile assessment was possible for this inhaled triple fixed-dose combination product. Methods: Healthy volunteers were randomized to receive 4 consecutive inhalations (each administered as a single dose) via a single ELLIPTA® dry powder inhaler: in study 1 (CTT116415/NCT01691547), FF/UMEC/VI at total doses of 400/500/100 μg, FF/UMEC 400/500 μg, UMEC/VI 500/100 μg, or FF/VI 400/100 μg; in study 2 (200587/NCT01894386), FF/UMEC/VI at total doses of 400/500/100 μg or 400/250/100 μg, FF/VI 400/100 μg, or UMEC/VI 250/100 μg. PK and PD parameters and safety were assessed. Results: Of 88 subjects, 95% completed both studies and received all planned treatments. Total systemic exposure was similar for FF, UMEC, and VI when administered as a triple therapy compared with FF/VI and UMEC/VI. No clinically significant systemic PD findings were detected. The incidence of adverse events was low and similar across treatment arms. Conclusions: Systemic exposure to all three components of the closed triple therapy, following single-dose delivery, was similar to that seen with the dual therapies FF/VI and UMEC/VI. The delivered lung dose and safety profile of all three agents, delivered via a single inhaler, are expected to be similar to those of the dual therapies.

The safety, pharmacokinetics and pharmacodynamics of a combination of fluticasone furoate and vilanterol in healthy Japanese subjects.

OBJECTIVE To evaluate the safety, pharmacokinetics and pharmacodynamics of fluticasone furoate (FF) and vilanterol (VI) administered alone or in combination in three Phase I studies in healthy Japanese male subjects. MATERIALS FF, VI and FF/VI inhalation powder in a novel dry powder inhaler (nDPI). METHODS Study A: 48 subjects received the first dose on Day 1, followed by a 4-day washout and once-daily (OD) repeat doses of FF 200, 400 or 800 μg or placebo from Day 5 to Day 11 (7 days). Study B: 32 subjects received repeat doses of VI (12.5, 25 μg) OD for 7 days. Study C: 16 subjects received single doses of FF (800 μg), VI (50 μg), FF/VI (800/50 μg) and placebo. RESULTS Overall, there were no safety concerns and no major differences were found in treatment-related adverse events when FF and VI were administered alone or in combination. Peak plasma concentration of FF and VI following repeat dosing was up to two times higher compared with the single dose. Individual pharmacokinetic parameters of FF and VI differed when co-administered but the differences from monotherapy were not clinically significant. Repeat dosing of FF affected weighted mean (0 - 24 hours) serum cortisol with FF 200, 400 and 800 μg resulting in respective reductions from placebo of 32%, 38% and 97%, respectively. Mean maximum heart rate (0 - 4 hours) was comparable between placebo, VI 12.5 and 25 μg over 7 days of dosing; for single dosing of FF/VI 800/50 and VI 50 μg, heart rate was comparable (70 and 73 bpm, respectively) and this was higher than FF 800 μg (66 bpm) or placebo (64 bpm), but the difference was not clinically significant. CONCLUSIONS In healthy Japanese subjects, no safety concerns were found following repeat dosing of FF and VI or single dosing of FF, VI and FF/VI. Systemic exposure to FF and VI increased in a dose-dependent manner. Serum cortisol level was suppressed by 97% after 7 days repeat administration of FF at a dose of 800 μg. Heart rate with a single dose of VI 50 μg was higher than that of placebo, though not to a clinically significant extent.

Tolerability of Fluticasone Furoate/Vilanterol Combination Therapy in Children Aged 5 to 11 Years With Persistent Asthma

BACKGROUND Asthma is a chronic disease afflicting millions of children worldwide. Short-acting β2-agonist reliever medications and inhaled corticosteroid (ICS) maintenance therapies are effective treatments; however, many children remain uncontrolled with short-acting β2-agonist and ICS treatment, in which case guidelines recommend adding a long-acting β2-agonist. OBJECTIVE We sought to investigate the safety profile, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) properties of the long-acting β2-agonist vilanterol (VI) combined with the ICS fluticasone furoate (FF) administered via the ELLIPTA dry powder inhaler (GlaxoSmithKline, London, United Kingdom) in children aged 5 to 11 years with persistent asthma. METHODS In this randomized, double-blind, repeated-dose, 2-way crossover study, data from 8- to 11-year-old children with asthma were reviewed before those from 5- to 7-year-old children with asthma. Patients received once-daily FF/VI, 100/25 µg, or FF, 100 µg, in the morning for 14 days, followed by a ≥7-day washout period before switching to the other treatment for 14 days; the study duration was ≤11 weeks. Primary end points were adverse events (AEs), clinical laboratory measurements, peak expiratory flow, maximum heart rate, blood pressure, and electrocardiographic parameters. Secondary end points comprised PK (AUC0-4, Cmax) and PD (serum potassium [0-4 hours], serum cortisol [0-12 hours], and glucose [0-4 hours]) parameters on day 14. RESULTS Twenty-six children were randomized (58% boys; mean age, 8.1 years). No clinically significant changes in the primary end points were observed. Five patients reported 4 and 2 AEs with FF/VI and FF therapy, respectively. After FF/VI or FF treatment, the geometric mean ratios (90% CIs) for FF AUC0-4 (1.02 [0.86-1.22]) and FF Cmax (0.98 [0.65-1.48]) were similar. For serum glucose (0-4 hours) concentration, a difference of 0.50 mM (95% CI, 0.19-0.82 mM) was observed for FF/VI versus FF; no differences were observed for other PD parameters. No AEs were judged to be serious or treatment related. The PK profile of FF did not seem to be altered by VI and was not affected by age or sex. The significance of an increased serum glucose level is difficult to judge as measurements were taken from nonfasted patients. Results can be compared only with active treatment, and the ability to generalize is limited by the small number of patients in this single-center study. CONCLUSIONS Once-daily repeated dosing of FF/VI, 100/25 µg, using the ELLIPTA dry powder inhaler was as well tolerated as FF, 100 µg, in this small, selected population of 5- to 11-year-old, mostly white/caucasian children with persistent asthma.

Efficacy and safety profile of fluticasone furoate administered once daily in the morning or evening: a randomized, double-blind, double-dummy, placebo-controlled trial in adult and adolescent patients with persistent bronchial asthma.

BACKGROUND Fluticasone furoate (FF) is an inhaled corticosteroid that is structurally and functionally distinct from fluticasone propionate and is under development as a once-daily therapy for asthma. OBJECTIVE The objective of this study was to estimate the treatment differences (with 95% CI) in efficacy and safety profile between FF administered once daily in the morning and evening via Rotadisk Diskhaler (see text) in patients with persistent asthma. No hypothesis testing was performed for this comparison. METHODS This was a randomized, double-blind, double-dummy, placebo-controlled, parallel-group study. Patients (ages 16-55 years; peak expiratory flow [PEF] 50%-90% predicted) were randomized to receive 1 of 3 doses of FF Rotadisk or placebo daily for 4 weeks. The sponsor, GlaxoSmithKline, designed the study and selected the study sites. The primary end point was change from baseline in daily trough (pretreatment, prebronchodilator) PEF during the treatment period with FF Rotadisk 100 μg once daily in the morning compared with 100 μg once daily in the evening. Other end points included change from baseline in forced expiratory volume in 1 second, asthma symptom score, adverse events (AEs), 24-hour urinary cortisol excretion, and FF pharmacokinetics. RESULTS Five hundred and seventy-five patients (mean age 36.6 years, 56.9% female) formed the intent-to-treat population and were randomly allocated to FF Rotadisk 100 μg once daily in the morning (n = 144), FF Rotadisk 100 μg once daily in the evening (n = 146), FF Rotadisk 250 μg once daily in the evening (n = 142), or placebo (n = 143). Of these patients, 526 (91.5%) completed the study. A smaller proportion of patients in the placebo group (86.7%) than in the active treatment groups completed the study. Mean difference in PEF change from baseline with FF Rotadisk 100 μg once daily in the morning relative to evening was +13.4 L/min (95% CI, 2.3-24.4). However, morning trough values might have been affected by higher placebo response after morning dosing (18.8 vs 8.8 L/min). Trough PEF improved relative to placebo (P ≤ 0.005), with little difference between FF Rotadisk 100 μg morning (19 L/min) and evening (16 L/min) dosing, as with other efficacy measures. Frequencies of all-cause AEs were similar with FF Rotadisk (32%-39%, 2 serious AEs) and placebo (37%, 1 serious AE). No serious AEs were deemed by the investigator to be related to study treatment. Twenty-four-hour urinary cortisol increased from baseline in all groups, but the increase was significantly lower with FF Rotadisk 250 μg group than placebo. CONCLUSION FF Rotadisk administered once daily in the morning or evening was well tolerated and associated with improvements in lung function and asthma symptoms compared with placebo. Improvements seen for FF Rotadisk 100 μg appear to be comparable for morning and evening dosing. Clinical.trials.govNCT01499446.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Vilanterol, a Novel Inhaled Long-Acting β-Agonist, in Children Aged 5–11 Years with Persistent Asthma: A Randomized Trial

This multi‐center, randomized, double‐blind, placebo‐controlled, two‐way crossover study was designed to characterize the safety, tolerability, pharmacokinetic, and pharmacodynamic profile of single and once‐daily repeat doses of vilanterol 25 µg in children aged 5–11 years. Twenty‐eight children with persistent asthma received a single inhaled dose of vilanterol 25 µg or placebo via the ELLIPTA™ dry powder inhaler (DPI) on Day 1, followed 7 days later by once‐daily treatment for 7 days. Nine (33%) subjects reported adverse events (AEs) with vilanterol 25 µg and 6 (23%) with placebo. No serious or drug‐related AEs were reported; 3 subjects experienced upper respiratory tract infection (URTI) with vilanterol 25 µg versus none with placebo. Similar pharmacokinetic profiles of vilanterol 25 µg were observed irrespective of age or gender. No clinically relevant changes in heart rate, Fridericias correction (QTcF), maximum glucose or minimum potassium parameters were observed during treatment with vilanterol 25 µg compared with placebo treatment. Vilanterol was well‐tolerated and no long‐acting ß2‐agonist (LABA)‐mediated AEs were observed. The pharmacokinetic profile of vilanterol 25 µg suggests exposure is similar regardless of age or gender in a pediatric population aged 5–11 years.