Michael Gillen

Pharmacokinetic and pharmacodynamic comparison of hydrofluoroalkane and chlorofluorocarbon formulations of budesonide

AIMS A hydrofluoroalkane formulation of budesonide pressurized metered-dose inhaler has been developed to replace the existing chlorofluorocarbon one. The aim of this study was to evaluate the pharmacokinetic and pharmacodynamic characteristics of both formulations. METHODS Systemic bioavailability and bioactivity of both hydrofluoroalkane and chlorofluorocarbon pressurized metered-dose inhaler formulations at 800 µg twice daily was determined during a randomized crossover systemic pharmacokinetic/pharmacodynamic study at steady state in healthy volunteers. Measurements included the following: plasma cortisol AUC(24h) [area under the concentration-time curve (0-24 h)], budesonide AUC(0-12h) and C(max) . Clinical efficacy was determined during a randomized crossover pharmacodynamic study in asthmatic patients receiving 200 µg followed by 800 µg budesonide via chlorofluorocarbon or hydrofluoroalkane pressurized metered-dose inhaler each for 4 weeks. Methacholine PC(20) (primary outcome), exhaled nitric oxide, spirometry, peak expiratory flow and symptoms were evaluated. RESULTS In the pharmacokinetic study, there were no differences in cortisol, AUC(0-12h) [area under the concentration-time curve (0-12 h)], T(max) (time to maximum concentration) or C(max) (peak serum concentration) between the hydrofluoroalkane and chlorofluorocarbon pressurized metered-dose inhaler. The ratio of budesonide hydrofluoroalkane vs. chlorofluorocarbon pressurized metered-dose inhaler for cortisol AUC(24h) was 1.02 (95% confidence interval 0.93-1.11) and budesonide AUC(0-12h) was 1.03 (90% confidence interval 0.9-1.18). In the asthma pharmacodynamic study, there was a significant dose response (P < 0.0001) for methacholine PC(20) (provocative concentration of methacholine needed to produce a 20% fall in FEV(1) ) with a relative potency ratio of 1.10 (95% confidence interval 0.49-2.66), and no difference at either dose. No significant differences between formulations were seen with the secondary outcome variables. CONCLUSIONS Hydrofluoroalkane and chlorofluorocarbon formulations of budesonide were therapeutically equivalent in terms of relative lung bioavailability, airway efficacy and systemic effects.

Pharmacokinetics of Budesonide and Formoterol Administered Via 1 Pressurized Metered-Dose Inhaler in Patients With Asthma and COPD

In 3 open‐label studies, the systemic bioavailability of budesonide and formoterol administered via pressurized metered‐dose inhaler (pMDI) or dry powder inhaler (DPI) formulations was evaluated in asthma (24 children, 55 adults) or chronic obstructive pulmonary disease (COPD; n =26) patients. Treatments were administered at doses high enough to estimate pharmacokinetic parameters reliably. Two of the studies included an experimental budesonide pMDI formulation. In study 1 (asthma, adults), budesonide area under the curve (AUC) was 32% and 31% lower and maximal budesonide concentration (Cmax) 45% and 56% lower after budesonide/formoterol pMDI and budesonide pMDI versus budesonide DPI. Formoterol AUC and Cmax were 13% and 39% lower after budesonide/formoterol pMDI versus formoterol DPI. In study 2 (asthma, children), budesonide AUC and Cmax were 27% and 41% lower after budesonide/formoterol pMDI versus budesonide DPI + formoterol DPI. In study 3 (COPD/asthma, adults), budesonide AUC and Cmax were similar and formoterol AUC and Cmax 18% and 22% greater after budesonide/formoterol pMDI versus budesonide pMDI + formoterol DPI (COPD). Budesonide and formoterol AUC were 12% and 15% higher in COPD versus asthma patients. In conclusion, systemic exposure generally is similar or lower with budesonide/formoterol pMDI versus combination therapy via separate DPIs or monotherapy and comparable between asthma and COPD patients.

The Utility of In Vitro Data in Making Accurate Predictions of Human P-Glycoprotein-Mediated Drug-Drug Interactions: A Case Study for AZD5672

To support drug development and registration, Caco-2 cell monolayer assays have previously been set up and validated to determine whether candidate drugs are substrates or inhibitors of human P-glycoprotein (P-gp). In this study, the drug-drug interaction (DDI) potential of N-(1-{(3R)-3-(3,5-difluorophenyl)-3-[4-methanesulfonylphenyl]propyl}piperidin-4-yl)-N-ethyl-2-[4-methanesulfonylphenyl]acetamide (AZD5672) was assessed accordingly, and a subsequent clinical digoxin interaction study was performed. AZD5672 (1–500 μM) demonstrated concentration-dependent efflux across cell monolayers, which was abolished in the presence of ketoconazole and quinidine, identifying AZD5672 as a P-gp substrate. In addition, P-gp-mediated digoxin transport was inhibited in a concentration-dependent manner by AZD5672 (IC50 = 32 μM). Assessment of the calculated theoretical gastrointestinal inhibitor concentration ([I2]) and predicted steady-state maximum total plasma inhibitor concentration ([I1]) indicated the potential for a DDI at the intestinal but not the systemic level after the predicted therapeutic dose of AZD5672 (100 mg). A clinical study was performed and the plasma pharmacokinetics [observed maximum plasma drug concentration (Cmax) and area under the plasma concentration versus time curve from 0 to 72 h postdose (AUC0–72 h)] of orally dosed digoxin (0.5 mg) were found to be unaffected by coadministration of AZD5672 (50 mg) at steady state. In contrast, a 150-mg dose of AZD5672 significantly increased digoxin Cmax and AUC0–72 h by 1.82- and 1.33-fold, respectively. Concentration-time profile comparisons indicated that digoxin elimination was unchanged by AZD5672, and the interaction was most likely to have resulted from inhibition of intestinal P-gp leading to increased digoxin absorption. The observed dose-dependent clinically significant interaction was accurately predicted using calculated [I2] and in vitro P-gp inhibition data, confirming AZD5672 to be a P-gp inhibitor in vivo.

Pharmacokinetics of budesonide and formoterol administered via a series of single-drug and combination inhalers: four open-label, randomized, crossover studies in healthy adults.

Objective: To investigate the pharmacokinetics of budesonide and formoterol administered concomitantly in healthy adults.

Evaluation of efficacy and safety of budesonide delivered via two dry powder inhalers

ABSTRACT Background: The dry powder inhaler (DPI) device for budesonide inhalation powder 200 μg (DPI‑A*) was redesigned to improve dosing consistency and provide new features (budesonide inhalation powder 90 μg and 180 μg; DPI‑B†). Objective: Two multicenter, parallel-group, double-blind, randomized, 12-week studies compared the efficacy and safety of budesonide delivered via each DPI versus placebo, and the systemic exposure of budesonide from each device. Methods: Asthmatic adults with mild-to-moderate asthma (N = 621) and patients 6–17 years with mild asthma (N = 516) received budesonide DPI‑B 360 μg or DPI‑A 400 μg twice-daily (total daily dose 720 μg or 800 μg), budesonide DPI‑B 180 μg or DPI‑A 200 μg once daily (total daily dose 180 μg or 200 μg), or matching placebo. Change in forced expiratory volume in 1 second (FEV1) and secondary variables (asthma symptoms, β2-adrenergic agonist use, peak expiratory flow [PEF], and withdrawals due to worsening asthma) versus placebo were measured. Results: In both studies, FEV1 significantly ( p < 0.05) improved for all active treatments versus placebo except once-daily budesonide DPI‑B 180 μg in adults. In the adult study, significantly ( p < 0.05) greater improvements in all secondary variables occurred with all active treatments versus placebo. In the pediatric/adolescent study, improvements in AM/PM PEF were significantly (p ≤ 0.011) greater with twice-daily budesonide DPI‑B 360 μg versus placebo. Numerically fewer patients in all active-treatment groups withdrew due to worsening asthma versus placebo. Adverse event profiles were similar among groups. In the pediatric/adolescent study, no significant differences in mean 24-h urine cortisol or cortisol : creatinine ratio assessments were observed between the active treatment groups and the placebo group. Although pharmacokinetic variables were generally similar across subgroups in the adult (n = 77) and pediatric/adolescent (n = 32) studies, pairwise treatment comparisons of twice-daily budesonide DPI‑B 360 μg versus DPI‑A 400 μg and once-daily budesonide DPI‑B 180 μg versus DPI‑A 200 μg showed large variability for the area under the drug plasma concentration–time curve over the dosing interval and the maximum detected drug plasma concentration. Conclusions: The efficacy and safety of budesonide DPI‑A and DPI‑B versus placebo were demonstrated across the low to medium inhaled corticosteroid dose range in children ≥ 6 years with very mild asthma and adolescents and adults with mild-to-moderate asthma. The study is limited by the evaluation of only two doses for each product in both studies. Additionally, the studies were not designed to test equivalence or noninferiority between the active products. Pharmacokinetic characterization was limited because of the small sample sizes.

Pharmacokinetics, pharmacodynamics, and tolerability of verinurad, a selective uric acid reabsorption inhibitor, in healthy adult male subjects

Purpose Verinurad (RDEA3170) is a selective uric acid reabsorption inhibitor in clinical development for the treatment of gout and asymptomatic hyperuricemia. The aim of this study was to evaluate the pharmacokinetics, pharmacodynamics, and tolerability of verinurad in healthy adult males. Subjects and methods This was a Phase I, randomized, double-blind, placebo-controlled, single and multiple ascending dose study. Panels of eight male subjects received a single oral dose of verinurad or placebo in either a fasted or fed state; panels of 10–12 male subjects received ascending doses of once-daily verinurad or placebo in a fasted state for 10 days. Serial blood and urine samples were assayed for verinurad and uric acid. Safety was assessed by adverse event (AE) reports, laboratory tests, vital signs, and electrocardiograms (ECGs). Results A total of 81 adult males completed the study. Following single doses of verinurad, maximum observed plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC) increased in a dose-proportional manner; Cmax occurred at 0.5–0.75 hours and 1.25 hours in the fasted and fed states, respectively. Food decreased AUC by 23% and Cmax by 37%−53%. There was a modest accumulation of verinurad following multiple daily doses. Verinurad reduced serum urate levels by up to 62% (40 mg, single dose) and 61% (10 mg, multiple dose). The increase in urinary excretion of uric acid was greatest in the first 6 hours after dosing and was still evident ≥24 hours for verinurad doses ≥2 mg. Verinurad was well tolerated at all doses. No serious AEs, severe AEs, discontinuations due to AEs, or clinically significant laboratory or ECG abnormalities were reported. Conclusion Single and multiple doses of verinurad were well tolerated, absorption was rapid, and exposure was dose proportional. Verinurad increased urinary uric acid elimination and resulted in sustained reductions in serum urate. These data support further clinical evaluation of once-daily verinurad as a treatment for gout.

Effects of renal function on pharmacokinetics and pharmacodynamics of lesinurad in adult volunteers

Introduction Lesinurad is a selective uric acid reabsorption inhibitor approved for the treatment of gout in combination with a xanthine oxidase inhibitor (XOI) in patients who have not achieved target serum uric acid (sUA) levels with an XOI alone. Most people with gout have chronic kidney disease. The pharmacokinetics, pharmacodynamics, and safety of lesinurad were assessed in subjects with impaired renal function. Methods Two Phase I, multicenter, open-label, single-dose studies enrolled subjects with normal renal function (estimated creatinine clearance [eCrCl] >90 mL/min; N=12) or mild (eCrCl 60–89 mL/min; N=8), moderate (eCrCl 30–59 mL/min; N=16), or severe (eCrCl <30 mL/min; N=6) renal impairment. Subjects were given a single oral lesinurad dose of 200 mg (N=24) or 400 mg (N=18). Blood and urine samples were analyzed for plasma lesinurad concentrations and serum and urine uric acid concentrations. Safety was assessed by adverse events and laboratory data. Results Mild, moderate, and severe renal impairment increased lesinurad plasma area under the plasma concentration–time curve by 34%, 54%–65%, and 102%, respectively. Lesinurad plasma Cmax was unaffected by renal function status. Lower renal clearance and urinary excretion of lesinurad were associated with the degree of renal impairment. The sUA-lowering effect of a single dose of lesinurad was similar between mild renal impairment and normal function, reduced in moderate impairment, and greatly diminished in severe impairment. Lesinurad increased urinary urate excretion in normal function and mild renal impairment; the increase was less with moderate or severe renal impairment. Lesinurad was well tolerated by all subjects. Conclusion Lesinurad exposure increased with decreasing renal function; however, the effects of lesinurad on sUA were attenuated in moderate to severe renal impairment.

Pharmacodynamic and pharmacokinetic effects and safety of verinurad in combination with allopurinol in adults with gout: a phase IIa, open-label study

Objectives Verinurad (RDEA3170) is a high affinity, selective uric acid transporter (URAT1) inhibitor indevelopment for treating gout and asymptomatic hyperuricaemia. This phase IIa study evaluated the pharmacodynamics, pharmacokinetics and safety of verinurad combined with allopurinol versus allopurinol alone in adults with gout. Methods Forty-one subjects were randomised into two cohorts of verinurad (2.5–20 mg) plus allopurinol (300 mg once daily) versus allopurinol 300 mg once daily, 600 mg once daily or 300 mg twice daily alone. Each treatment period was 7 days. Serial plasma/serum and urine samples were assayed for verinurad, allopurinol, oxypurinol and uric acid. Results Serum pharmacodynamic data pooled across cohorts demonstrated maximum per cent decreases in serum urate (sUA) from baseline (Emax) at 7–12 hours after verinurad plus allopurinol treatment. Combination treatment decreased sUA in dose-dependent manner: least-squares means Emax was 47%, 59%, 60%, 67%, 68% and 74% for verinurad doses 2.5, 5, 7.5, 10, 15 and 20 mg plus allopurinol 300 mg once daily, versus 40%, 54% and 54% for allopurinol 300 mg once daily, 600 mg once daily and 300 mg twice daily. Verinurad had no effect on allopurinol plasma pharmacokinetics, but decreased oxypurinol Cmax by 19.0%–32.4% and area under the plasma concentration–time curve from time zero to the last measurable time point by 20.8%–39.2%. Verinurad plus allopurinol was well tolerated with no serious adverse events (AEs), AE-related withdrawals or renal-related events. Laboratory values showed no clinically meaningful changes. Conclusion Verinurad coadministered with allopurinol produced dose-dependent decreases in sUA. All dose combinations of verinurad and allopurinol were generally well tolerated. These data support continued investigation of oral verinurad in patients with gout. Trial registration number NCT02498652.

Evaluation of Pharmacokinetic Interactions Between Lesinurad, a New Selective Urate Reabsorption Inhibitor, and CYP Enzyme Substrates Sildenafil, Amlodipine, Tolbutamide, and Repaglinide.

Lesinurad is a selective uric acid reabsorption inhibitor approved for the treatment of hyperuricemia associated with gout in combination with xanthine oxidase inhibitors. In vitro assays indicate that lesinurad is an inducer of CYPs in the order CYP3A > CYP2C8 > CYP2C9 > CYP2C19 > CYP2B6 and an inhibitor of CYP2C8 and CYP2C9. To investigate the drug interaction potential of lesinurad, clinical drug interaction studies were conducted. Open‐label studies in volunteers investigated the effects of single‐/multiple‐dose lesinurad on the pharmacokinetics of sildenafil and amlodipine (CYP3A4 induction), tolbutamide (CYP2C9 inhibition/induction), and repaglinide (CYP2C8 inhibition/induction). There was no apparent induction of CYP2C8 and CYP2C9 following repeated lesinurad administration, although no inhibition of CYP2C9 and modest inhibition of CYP2C8 were observed following single‐dose lesinurad. Consistent with in vitro observations, lesinurad (200 mg once daily) was an inducer of CYP3A based on the effects on sildenafil exposure. Sildenafil exposure decreased by approximately 34% for Cmax and AUC when administered with multiple‐dose lesinurad 200 mg and allopurinol 300 mg, relative to sildenafil alone. During lesinurad therapy, the possibility of reduced efficacy of concomitant drugs that are CYP3A substrates should be considered and their efficacy monitored because of induction of CYP3A by lesinurad.

Relative systemic availability of budesonide in patients with asthma after inhalation from two dry powder inhalers

ABSTRACT Background: To improve dosing consistency and product features, budesonide inhalation powder delivered via a dry powder inhaler (DPI) (DPI‑A* 200 μg) was redesigned to include lactose, a newly shaped mouthpiece, and a new dose indicator (DPI‑B*). Budesonide DPI‑B is available in two strengths (90 μg, 180 μg). Objective: To compare the relative rate and extent of the systemic availability of budesonide inhaled via DPI‑A and DPI‑B and test for systemic absorption bioequivalence. Methods: Adults (n =37) with asthma as defined by the American Thoracic Society were randomized in an open-label, crossover, single-center, single-dose study to budesonide DPI‑A 200 μg × 4 inhalations, budesonide DPI‑B 180 μg × 4 inhalations, or budesonide DPI‑B 90 μg × 8 inhalations, on 3 days, each separated by a washout period of ≥ 5 days. Plasma samples were collected immediately before and up to 12 h after dosing. Primary pharmacokinetic variables were area under the drug plasma concentration–time curve from 0 to infinity (AUC0–∞) and maximum plasma concentration (Cmax); plasma concentration at 12 h (C12h) and time to maximum plasma concentration (Tmax) were secondary variables. Treatments were considered bioequivalent if the 90% confidence intervals (CIs) for their AUC0–∞ and Cmax ratios fell between 80 and 125%. Adverse events were collected. Results: The 90% CIs for the ratios of AUC0–∞ and Cmax for budesonide DPI‑A 200 μg and DPI‑B 180 μg and for both budesonide DPI‑B strengths fell between 80% and 125% (AUC0–∞: budesonide DPI‑B 180 μg × 4/DPI‑A 200 μg × 4: 96.3% [90 % CI: 90.9, 102.1]; budesonide DPI‑B 180 μg × 4/DPI‑B 90 μg × 8: 92.2% [90 % CI: 87.0, 97.7]; Cmax: (budesonide DPI‑B 180 μg × 4/DPI‑A 200 μg × 4: 100.4% [95 % CI: 92.1, 109.4]; budesonide DPI‑B 180 μg × 4/DPI‑B 90 μg × 8: 94.4% [90 % CI: 86.6, 102.9]). No differences in C12h and Tmax were found between treatments. All treatments were well tolerated. Conclusions: Budesonide DPI‑A 200 μg and DPI‑B 180 μg have systemic absorption bioequivalence, and DPI‑B 90 μg and 180 μg are dose-strength equivalent when administered at the same dose. These results may not be generalized to all patients with asthma, as this analysis included only patients with mild-to-moderate asthma aged ≥ 19 years.