Kelly Hardes

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.

Efficacy and safety of once-daily GW870086 a novel selective glucocorticoid in mild-moderate asthmatics: a randomised, two-way crossover, controlled clinical trial.

Abstract Objective: To assess the efficacy of inhaled, repeat doses (28 days) of the glucocorticoid agonist GW870086, which has been designed to inhibit gene transrepression of the glucocorticoid receptor while preserving its transactivation. Methods: This was a randomised, placebo-controlled, two-way crossover study, approved by the independent ethics committees of the study centres. Subjects with FEV1 40–85% of the predicted normal value (n = 36) received GW870086 (1 mg, once-daily) and placebo. Results: No significant change from baseline in forced expiratory volume in one second (FEV1) was seen following administration of GW8780086 1 mg relative to placebo; mean FEV1 (day 28), relative to placebo, was (95% confidence intervals [CI]) −0.077 L (−0.192, 0.038). A moderate positive placebo response was observed on Days 14 and 28: Mean FEV1 (95% CI) was 0.115 L (0.040, 0.189) and 0.115 L (0.019, 0.212), respectively. The placebo response was more notable in treatment period 1 and was larger than the response to GW870086 1 mg on day 28, irrespective of period. Peak expiratory flow rate results were consistent with FEV1 and no difference was seen between the GW870086 and placebo for rescue medication usage. Conclusion: This total lack of effect suggests that repeat-dose GW8700861 mg has suboptimal efficacy in mild to moderate asthma.

Effects of Moderate Hepatic Impairment on the Pharmacokinetic Properties and Tolerability of Umeclidinium and Vilanterol in Inhalational Umeclidinium Monotherapy and Umeclidinium/Vilanterol Combination Therapy: An Open-Label, Nonrandomized Study

BACKGROUND The long-acting muscarinic antagonist umeclidinium (UMEC) is approved as a monotherapy, and in combination with the long-acting β2-agonist vilanterol (VI), as a once-daily inhaled maintenance bronchodilator therapy for chronic obstructive pulmonary disease in the US and EU; they are not indicated for the treatment of asthma. Preclinical and clinical data suggest that UMEC and VI are predominantly eliminated by the liver. OBJECTIVES The objectives of the study were to evaluate the effects of moderate hepatic impairment on the plasma and urinary pharmacokinetic properties of each drug, and on the tolerability of inhalational UMEC/VI 125/25 µg and UMEC 125 µg. METHODS This open-label, nonrandomized study was conducted in patients with moderate hepatic impairment (Child-Pugh score, 7-9) and in healthy volunteers (control). Patients and volunteers were administered a single dose of UMEC/VI 125/25 µg, and, after a 7- to 14-day washout period, repeat-dose UMEC 125 µg once daily for 7 days. Primary end points were the plasma pharmacokinetic properties of single- and repeat-dose UMEC and VI. Secondary end points were the urinary pharmacokinetic properties of UMEC, and the tolerability of each treatment. RESULTS All 18 enrolled patients and volunteers (12 men, 6 women; mean age, 53.6 years) completed the study. Mean systemic exposures of UMEC and VI were similar or numerically lower in patients with moderate hepatic impairment compared with those in healthy volunteers, but the differences were not clinically significant. UMEC accumulations with 7-day dosing of UMEC were similar between patients with moderate hepatic impairment and healthy volunteers. UMEC/VI 125/25 µg and UMEC 125 µg were well-tolerated, with no safety concerns identified. CONCLUSIONS The administration of UMEC/VI 125/25 µg or UMEC 125 µg in patients with moderate hepatic impairment did not result in clinically relevant increases in UMEC or VI exposures compared with those in healthy volunteers. Based on these findings, no dose adjustment for UMEC/VI or UMEC is warranted in patients with moderate hepatic impairment.

Effect of severe renal impairment on umeclidinium and umeclidinium/vilanterol pharmacokinetics and safety: a single-blind, nonrandomized study

Background Umeclidinium and vilanterol, long-acting bronchodilators for the treatment of chronic obstructive pulmonary disease, are primarily eliminated via the hepatic route; however, severe renal impairment may adversely affect some elimination pathways other than the kidney. Objectives To evaluate the effect of severe renal impairment on the pharmacokinetics of umeclidinium and umeclidinium/vilanterol. Methods Nine patients with severe renal impairment (creatinine clearance <30 mL/min) and nine matched healthy volunteers received a single dose of umeclidinium 125 μg; and after a 7- to 14-day washout, a single dose of umeclidinium/vilanterol 125/25 μg. Results No clinically relevant increases in plasma umeclidinium or vilanterol systemic exposure (area under the curve or maximum observed plasma concentration) were observed following umeclidinium 125 μg or umeclidinium/vilanterol 125/25 μg administration. On average, the amount of umeclidinium excreted in 24 hours in urine (90% confidence interval) was 88% (81%–93%) and 89% (81%–93%) lower in patients with severe renal impairment compared with healthy volunteers following umeclidinium 125 μg and umeclidinium/vilanterol 125/25 μg administration, respectively. Treatments were well tolerated in both populations. Conclusion Umeclidinium 125 μg or umeclidinium/vilanterol 125/25 μg administration to patients with severe renal impairment did not demonstrate clinically relevant increases in systemic exposure compared with healthy volunteers. No dose adjustment for umeclidinium and umeclidinium/vilanterol is warranted in patients with severe renal impairment.

Clinical efficacy and tolerability of a novel selective corticosteroid in atopic dermatitis--two randomised controlled trials.

Topical corticosteroids remain the first-line therapy for atopic dermatitis (AD). Hence, we investigated the efficacy and safety profile of a novel selective corticosteroid, GW870086. We performed 2 randomised, double-blind, controlled studies with 25 AD patients and 20 healthy subjects. The changes in the Three-Item Severity (TIS) score and the skin thickness were the primary end points, respectively. The adjusted TIS score (day 22) shows that the novel corticosteroid resulted in a non-significant, but dose-dependent reduction compared to placebo (GW870086 0.2% vs. placebo = -0.38, GW870086 2% vs. placebo = -0.89). Significant skin thinning was observed in the second study on days 14 and 21 when patients were treated with the comparator but not with the novel corticosteroid compared to placebo. The clinical efficacy of the new selective corticosteroid was not superior to placebo, although a dose-dependent improvement upon treatment was noticed without the onset of skin thinning.

A Randomized Dose-Escalation Study of the Safety and Anti-Inflammatory Activity of the p38 Mitogen-Activated Protein Kinase Inhibitor Dilmapimod in Severe Trauma Subjects at Risk for Acute Respiratory Distress Syndrome.

Objectives:There are no current pharmacological therapies for the prevention or treatment of acute respiratory distress syndrome. Early dysregulated inflammation likely plays a role in acute respiratory distress syndrome development and possibly acute respiratory distress syndrome outcomes. p38 mitogen-activated protein kinase is central to the regulation of multiple inflammatory mediators implicated in acute organ dysfunction and is the target for a novel class of cytokine-suppressive anti-inflammatory drugs. In preclinical models, p38 inhibitors reduce lung injury following pancreatitis and burn injury. Design:We conducted a phase IIa, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the safety and tolerability of dilmapimod, a novel p38 mitogen-activated protein kinase inhibitor, in patients at risk for developing acute respiratory distress syndrome admitted with an Injury Severity Score more than 16, excluding head trauma. Enrolled patients received 4- or 24-hour IV dilmapimod infusions at different doses or placebo, daily for 3 days, in four separate cohorts. Setting:Multicenter randomized clinical trial of large, academic trauma centers. Measurements and Main Results:Seventy-seven patients were enrolled. Although adverse events were common in this critically ill population, dilmapimod was well tolerated, with no clinically relevant safety findings. Pharmacokinetic models indicated that the higher dose of 10 mg given as continuous infusion over 24 hours had the most favorable plasma concentration profile. Likewise, measures of soluble inflammatory markers including interleukin-6, C-reactive peptide, interleukin-8, and soluble tumor necrosis factor receptor 1 were most different between this dosing arm and placebo. Although the study was not specifically designed with acute respiratory distress syndrome as an outcome, the number of patients who developed acute respiratory distress syndrome was small (2/77). Conclusions:The novel p38 mitogen-activated protein kinase inhibitor dilmapimod appears well tolerated and may merit further evaluation for prevention of acute respiratory distress syndrome and other organ injury in larger clinical trials. Furthermore, results of this early-phase trial may aid in design of future studies aimed at prevention of acute respiratory distress syndrome and other organ injury.