Relative bioavailability of budesonide/glycopyrrolate/formoterol fumarate triple therapy delivered using next generation propellants with low global warming potential.

INTRODUCTION: The climate crisis poses an immediate threat to human health and well-being, demanding urgent adaptions across sectors, including healthcare. The development of pressurized metered dose inhalers (MDIs) with greater sensitivity to the climate emergency using novel propellants with lower global warming potentials (GWPs), but comparable pharmacokinetic (PK) parameters to currently marketed MDIs, is a vital step toward reducing the impact of healthcare for respiratory disorders on climate change. This study evaluated the relative bioavailabilities of the individual components of a fixed-dose combination of budesonide/glycopyrrolate/formoterol fumarate (BGF) 160/9/4.8 µg per actuation between three different propellant formulations. METHODS: Healthy male participants (aged 18-60 years) were randomized into a single-blind, three-period, single-dose, single-center, crossover study (NCT04600505). The PK and safety and tolerability profiles of BGF MDI formulated with two novel propellants with low GWP (hydrofluoroolefin-1234ze [HFO]; hydrofluorocarbon-152a [HFC]) were compared with BGF MDI formulated with the propellant used in the currently marketed reference product (hydrofluoroalkane-134a [HFA]). The study included a screening period, three treatment periods (with 3- to 7-day washout periods between each dose), and a follow-up. The primary PK parameters assessed were maximum observed plasma concentration (Cmax), area under the plasma concentration curve (AUC) from time zero extrapolated to infinity (AUCinf), and AUC from time zero to the time of the last quantifiable analyte concentration (AUClast). The study was not powered to statistically demonstrate bioequivalence. RESULTS: Forty-seven participants completed the study, and 24 participants were evaluable for PK assessments. Systemic exposure, based on geometric mean ratios (90% confidence interval), to each BGF component from the test propellants delivered in a standard MDI was comparable with the reference propellant for AUClast (HFO vs. HFA: budesonide, 107.30 [94.53, 121.90]; glycopyrrolate, 106.10 [86.18, 130.60]; formoterol, 98.13 [86.44, 111.40]; HFC vs. HFA: budesonide, 98.80 [84.59, 115.40]; glycopyrrolate, 99.71 [80.84, 123.00]; formoterol, 107.00 [88.82, 128.90]); AUCinf (where evaluable) and Cmax followed the same trend. There were no serious adverse events or adverse events leading to treatment discontinuation. No new safety signals were observed. CONCLUSIONS: Systemic BGF component exposure was similar for both test propellants (HFO and HFC) compared with the HFA reference propellant, with an acceptable safety profile in the studied population. Therefore, both novel low GWP propellants show strong potential as candidates for development of MDIs with greater sensitivity to the climate crisis, a vital step toward ameliorating the detrimental impact of healthcare on the environment. Further investigation in larger studies is warranted.

Pharmacokinetics of budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler formulated using co-suspension delivery technology after single and chronic dosing in patients with COPD.

BACKGROUND: Budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI), formulated using co-suspension delivery technology, is a triple fixed-dose combination in late-stage clinical development for chronic obstructive pulmonary disease (COPD). METHODS: We conducted two studies to characterize the pharmacokinetic (PK) profile of BGF MDI in patients with COPD: (i) a phase I, open-label, single and chronic (7-day) dosing study (NCT03250182) with one treatment arm (BGF MDI 320/18/9.6 µg); and (ii) a PK sub-study of KRONOS (NCT02497001), a phase III, randomized, double-blind study in which patients received 24 weeks' treatment with BGF MDI 320/18/9.6 µg, glycopyrrolate/formoterol fumarate (GFF) MDI 18/9.6 µg, budesonide/formoterol fumarate (BFF) MDI 320/9.6 µg, or budesonide/formoterol fumarate dry powder inhaler (BUD/FORM DPI) 320/9 µg. PK parameters in both studies included maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve from 0 to 12h (AUC0-12). RESULTS: In the phase I PK study (30 patients), budesonide and glycopyrronium Cmax were comparable after single and chronic dosing of BGF MDI (accumulation ratio [RAC] 95% and 107%, respectively) whereas Cmax for formoterol was slightly higher after chronic dosing (RAC 116%). AUC0-12 for budesonide, glycopyrronium, and formoterol were higher following chronic versus single dosing, with an RAC of 126%, 179%, and 143%, respectively. After 7 days' dosing, AUC0-12 and Cmax for all three components of BGF MDI were similar to those in the KRONOS PK sub-study (202 patients) at Week 24. In the latter sub-study, Cmax and AUC0-12 at Week 24 were generally comparable across treatments for budesonide (geometric mean ratios [GMR] of 96%-109% for BGF MDI vs BFF MDI or BUD/FORM DPI), glycopyrronium (GMR of 88%-100% for BGF MDI vs GFF MDI), and formoterol (GMR of 80%-113% for BGF MDI vs GFF MDI or BFF MDI). CONCLUSIONS: Steady-state PK parameters of budesonide, glycopyrronium, and formoterol were similar after 7 days' dosing in the phase I PK study and after 24 weeks in the KRONOS PK sub-study. Systemic exposure to budesonide, glycopyrronium, and formoterol was generally comparable across treatments in the KRONOS PK sub-study, suggesting no meaningful drug-drug or within-formulation PK interactions.

Ethnic pharmacokinetic comparison of budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI) between Asian and Western healthy subjects.

BACKGROUND: The Phase III KRONOS study (NCT02497001) found the fixed-dose combination triple therapy budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI) to be efficacious and well tolerated versus corresponding dual therapies in patients with moderate-to-very severe COPD from North America, China and Japan. However, pharmacokinetic (PK) studies of other drugs have shown that ethnic factors (e.g. genetic factors affecting drug metabolism) can affect the bioavailability of drugs which may impact upon efficacy and safety outcomes. METHODS: This was a post-hoc analysis of data from four randomised, double-blind Phase I studies of BGF MDI 320/18/9.6 µg and 160/18/9.6 µg in Chinese (NCT03075267), Japanese (NCT02197975) and Western (NCT01980615, NCT02189304) healthy subjects. PK properties (area under the plasma concentration-time curve 0-12 h post-dose [AUC0-12] and maximum plasma concentration, [Cmax]) were recorded following single and repeated dosing of BGF MDI 320/18/9.6 µg or 160/18/9.6 µg. Potential ethnic differences in the PK properties of budesonide, glycopyrrolate and formoterol in Chinese, Japanese and Western healthy subjects were derived by non-compartmental analysis, and ethnic insensitivity factors evaluated based on criteria from the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, Guideline E5 Ethnic Factors in the Acceptability of Foreign Clinical Data. RESULTS: The analyses included data from 64 Chinese, 31 Japanese and 169 Western subjects. Overall, PK properties following single or repeated dosing of BGF MDI were similar across Chinese, Japanese and Western subjects. After single dosing at either dose level, AUC0-12 and Cmax for budesonide, glycopyrrolate and formoterol appeared generally similar for Asian (Chinese and Japanese) versus Western subjects, with most geometric least squares mean ratios within the range of 0.92-1.22. The exception was that Cmax for glycopyrrolate was slightly lower in Asian versus Western subjects (0.6-0.7). Of the 10 ethnic insensitivity factors evaluated, six were met for budesonide, nine for glycopyrrolate and nine for formoterol, suggesting that BGF MDI can be classified as an ethnically insensitive drug. CONCLUSIONS: Overall, these analyses suggest no appreciable ethnic differences in the PK of BGF MDI across Chinese, Japanese and Western healthy subjects.

Metabolism and disposition of lesinurad, a uric acid reabsorption inhibitor, in humans.

The objectives of this study were to determine the absolute bioavailability of lesinurad and to characterized its disposition in humans. The oral bioavailability assessment was performed using a clinical design of simultaneous dosing of a therapeutic oral dose of lesinurad with an intravenous infusion of [14C]lesinurad microdose. The bioavailability of lesinurad was determined to be 100%. The disposition of lesinurad in humans involves hepatic oxidation and renal elimination following administration of oral [14C]lesinurad dose. Metabolism of lesinurad occurred post-systemically with low circulating levels of metabolites <3% of total radioactivity as 74.2% of total radioactivity was attributed to lesinurad. In vitro metabolism studies identified CYP2C9 as the predominant isoform, and summation of metabolites indicated that it was responsible for ∼50% of metabolism.

Verinurad combined with febuxostat in Japanese adults with gout or asymptomatic hyperuricaemia: a phase 2a, open-label study.

Objectives: Verinurad (RDEA3170) is a high-affinity inhibitor of the URAT1 transporter in clinical development for treating gout and asymptomatic hyperuricaemia. The aim of this Phase 2a, randomized, open-label study was to investigate the multiple-dose pharmacodynamics, pharmacokinetics and safety of oral verinurad combined with febuxostat vs febuxostat alone and verinurad alone. Methods: Japanese male subjects aged 21-65 years with gout (n = 37) or asymptomatic hyperuricaemia (n = 35) and serum urate (sUA) ⩾8 mg/dl were randomized to febuxostat (10, 20, 40 mg) in combination with verinurad (2.5-10 mg), verinurad alone (2.5-15 mg), febuxostat alone (10, 20, 40 mg) or benzbromarone alone (50 mg). There were four treatment periods per cohort and each treatment period was 7 days. Study drugs were administered once-daily after breakfast. Plasma, serum and urine samples were measured at pre-set intervals on days -1, 7, 14, 21 and 28. Results: Verinurad combined with febuxostat decreased sUA in dose-dependent manner, providing greater sUA lowering than febuxostat alone at the same dose (P < 0.001). Urinary uric acid excretion rate was increased by verinurad, reduced by febuxostat and comparable to baseline for verinurad combined with febuxostat. Verinurad from 2.5 mg to 15 mg was well tolerated, with no withdrawals due to adverse events. Laboratory assessments showed no clinically meaningful changes during combination treatment. Conclusion: Verinurad combined with febuxostat decreased sUA dose-dependently while maintaining uric acid excretion similar to baseline. All dose combinations of verinurad and febuxostat were generally well tolerated. These data support continued investigation of oral verinurad in patients with gout. Trial registration: ClinicalTrials.gov, https://clinicaltrials.gov, NCT02317861.

Metabolism and Disposition of Verinurad, a Uric Acid Reabsorption Inhibitor, in Humans.

Verinurad (RDEA3170) is a second generation selective uric acid reabsorption inhibitor for the treatment of gout and asymptomatic hyperuricemia. Following a single oral solution of 10-mg dose of [14C]verinurad (500 µCi), verinurad was rapidly absorbed with a median time to occurrence of maximum observed concentration (Tmax) of 0.5 hours and terminal half-life of 15 hours. In plasma, verinurad constituted 21% of total radioactivity. Recovery of radioactivity in urine and feces was 97.1%. Unchanged verinurad was the predominant component in the feces (29.9%), whereas levels were low in the urine (1.2% excreted). Acylglucuronide metabolites M1 (direct glucuronidation) and M8 (glucuronidation of N-oxide) were formed rapidly after absorption of verinurad with terminal half-life values of approximately 13 and 18 hours, respectively. M1 and M8 constituted 32% and 31% of total radioactivity in plasma and were equimolar to verinurad on the basis of AUC ratios. M1 and M8 formed in the liver were biliary cleared with complete hydrolysis in the GI tract, as metabolites were not detected in the feces and/or efflux across the sinusoidal membrane; M1 and M8 accounted for 29.2% and 32.5% of the radioactive dose in urine, respectively. In vitro studies demonstrated that CYP3A4 mediated the formation of the N-oxide metabolite (M4), which was further metabolized by glucuronyl transferases (UGTs) to form M8, as M4 was absent in plasma and only trace levels were present in the urine. Several UGTs mediated the formation of M1, which could also be further metabolized by CYP2C8. Overall, the major clearance route of verinurad is metabolism via UGTs and CYP3A4 and CYP2C8.

Effect of a spacer on total systemic and lung bioavailability in healthy volunteers and in vitro performance of the Symbicort® (budesonide/formoterol) pressurized metered dose inhaler.

INTRODUCTION: Many patients with chronic obstructive pulmonary disease or asthma experience difficulties in coordinating inhalation with pressurized metered-dose inhaler (pMDI) actuation. The use of a spacer device can improve drug delivery in these patients. The aim of this study was to establish the relative bioavailability of single doses of Symbicort® (budesonide/formoterol) pMDI 160/4.5 µg/actuation (2 actuations) used with and without a spacer device. In addition, an in vitro study was conducted to characterize performance of the inhaler when used in conjunction with a spacer device. METHODS: A Phase I, randomized, open-label, single-dose, single-center, crossover study in 50 healthy volunteers (NCT02934607) assessed the relative bioavailability of single-dose Symbicort® pMDI 160/4.5 µg/actuation (2 actuations) with and without a spacer (AeroChamber Plus® Flow-Vu®). Inhaled doses were administered without or with activated charcoal (taken orally) to estimate total systemic exposure and exposure through the lung, respectively. The in vitro study characterized the effect of the spacer with respect to delivered dose, fine particle dose, and dose during simulated breathing of budesonide and formoterol. RESULTS: In terms of total systemic exposure, use of the spacer increased the relative bioavailability determined by AUC(0-last) and Cmax by 68% (spacer:no spacer treatment ratio, 167.9%; 90% CI, 144.1 to 195.6) and 99% (ratio, 198.7%; 90% CI, 164.4 to 240.2) for budesonide, and 77% (ratio, 176.6%; 90% CI, 145.1 to 215.0) and 124% (ratio, 223.6%; 90% CI, 189.9 to 263.3) for formoterol, respectively, compared with pMDI alone. Similarly, the lung exposure of budesonide and formoterol increased (AUC(0-last) and Cmax by 146% [ratio, 246.0%; 90% CI, 200.7 to 301.6] and 127% [ratio, 226.5%; 90% CI, 186.4 to 275.4] for budesonide, and 173% [ratio, 272.8%; 90% CI, 202.5 to 367.4] and 136% [ratio, 236.2%; 90% CI, 192.6 to 289.6] for formoterol, respectively) when the pMDI was administered through the spacer. When assessed by AUC(0-last) quartile without spacer, subjects in the lowest exposure quartile (indicating poor inhalation technique) with Symbicort® pMDI 160/4.5 µg/actuation (2 actuations) had markedly increased total systemic and lung exposure when the same dose was administered with the spacer. In contrast, for subjects in the highest exposure quartile with pMDI alone, total systemic and lung exposure of formoterol and budesonide was similar with and without the spacer. In the in vitro study, the fine particle dose (<5 µm) of both budesonide and formoterol from the spacer at delay time (i.e. pause period after actuation) = 0 s (instantaneous) after actuation was similar to the fine particle dose when not using the spacer. The delivered doses of budesonide and formoterol from the spacer were both lower compared with the doses administered without the spacer. There was also a decrease in delivered dose with increasing delay time. CONCLUSIONS: The clinical study demonstrated that in subjects with poor inhalation technique the use of the AeroChamber Plus® Flow-Vu® spacer increased the bioavailability of Symbicort® pMDI to a level observed in subjects with good inhalation technique without a spacer. The findings from the in vitro study support the fine particle dose characteristics of Symbicort® pMDI with the AeroChamber Plus® Flow-Vu® spacer.

An S-warfarin and AZD1981 interaction: in vitro and clinical pilot data suggest the N-deacetylated amino acid metabolite as the primary perpetrator.

AIM: AZD1981 is an orally bioavailable chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2) receptor antagonist progressed to phase II trials for the treatment of allergic asthma. Previously performed in vitro human hepatocyte incubations identified N-deacetylated AZD1981 as a primary metabolite. We report on metabolite exposure from a clinical excretion balance, on in vitro studies performed to determine the likelihood of a metabolite-dependent drug-drug interaction (DDI) and on a clinical warfarin DDI study. The aim was to demonstrate that N-deacetylated AZD1981 is responsible for the observed interaction. METHODS: The excretion and biotransformation of [14 C]-AZD1981 were studied in healthy male volunteers, and subsequently in vitro cytochrome P450 (CYP) inhibition and hepatocyte uptake investigations were carried out with metabolites and the parent drug. A clinical DDI study using coadministered twice-daily 100 mg and 400 mg AZD1981 with 25 mg warfarin was performed. RESULTS: The excretion balance study showed N-deacetylated AZD1981 to be the most abundant metabolite present in plasma. In vitro data revealed the metabolite to be a weak CYP2C9 time-dependent inhibitor, subject to more active hepatic uptake than the parent molecule. Clinically, the S-warfarin area under the plasma concentration-time curve increased, on average, 1.4-fold [95% confidence interval (CI) 1.22, 1.50] and 2.4-fold (95% CI 2.11, 2.64) after 100 mg (n = 13) and 400 mg (n = 11) AZD1981 administration, respectively. In vitro CYP inhibition and hepatocyte uptake data were used to explain the interaction. CONCLUSIONS: N-deacetylated AZD1981 can be added to the small list of drug metabolites reported as sole contributors to clinical drug-drug interactions, with weak time-dependent inhibition exacerbated by efficient hepatic uptake being the cause.

Effects of ranitidine (antacid), food, and formulation on the pharmacokinetics of fostamatinib: results from five phase I clinical studies.

PURPOSE: Fostamatinib is an orally dosed phosphate prodrug that is cleaved by intestinal alkaline phosphatase to the active metabolite R406. Clinical studies were performed to assess the effect of food and ranitidine on exposure, to support in vitro-in vivo relationships (IVIVR) understanding and formulation transitions and to investigate absolute oral bioavailability. METHODS: A series of in vitro dissolution and clinical pharmacokinetic studies were performed to support the design and introduction of a new formulation, understand the impact of changes in in vitro dissolution on in vivo performance for two fostamatinib formulations, to characterize the effects of food and ranitidine on exposure, and determine the absolute oral bioavailability. RESULTS: The in vivo performance of fostamatinib was generally insensitive to changes in in vitro dissolution performance, although marked slowing of the dissolution rate did impact exposures. Food and ranitidine had minor effects on R406 exposure that were not considered clinically relevant. The absolute oral bioavailability of fostamatinib was 54.6 %. CONCLUSIONS: The absolute oral bioavailability of fostamatinib was ~55 %. Food and ranitidine had minor effects on R406 exposure. An in vitro dissolution versus clinical performance relationship was determined that supported formulation transitions.

Characterization of the disposition of fostamatinib in Japanese subjects including pharmacokinetic assessment in dry blood spots: results from two phase I clinical studies.

PURPOSE: The aims of the present study were to characterize the pharmacokinetics of fostamatinib in two phase I studies in healthy Japanese subjects after single- and multiple-dose administration, and to evaluate the utility of dried blood spot (DBS) sampling. METHODS: In study A, 40 Japanese and 16 white subjects were randomized in a double-blind parallel group study consisting of seven cohorts, which received either placebo or a fostamatinib dose between 50 and 200 mg after single and multiple dosing. Pharmacokinetics of R406 (active metabolite of fostamatinib) in plasma and urine was assessed, and safety was intensively monitored. Study B was an open-label study that assessed fostamatinib 100 and 200 mg in 24 Japanese subjects. In addition to plasma and urine sampling (as for study A), pharmacokinetics was also assessed in blood. RESULTS: Mean maximum plasma concentration (C max) and area under total plasma concentration­time curve (AUC) increased with increasing dose in Japanese subjects. Steady state was achieved in 5­7 days for all doses. C max and AUC were both higher in Japanese subjects administered a 150-mg single dose than in white subjects. This difference was maintained for steady state exposure by day 10. Overall, R406 blood concentrations were consistent and ∼2.5-fold higher than in plasma. Minimal (<0.1 %) R406 was excreted in urine. Fostamatinib was well tolerated at all doses. CONCLUSIONS: Fostamatinib pharmacokinetics following single- and multiple-dose administration was approximately dose proportional at all doses ≤150 mg and greater than dose proportional at 200 mg in Japanese subjects. Japanese subjects administered fostamatinib 150 mg had higher exposure than white subjects. R406 could be measured in DBS samples and distributed into red blood cells, and DBS sampling was a useful method for assessing R406 pharmacokinetics.

Bronchodilator effect of single-dose formoterol administered by pressurized metered-dose inhaler in children with asthma aged 6 to <12 years receiving budesonide.

Dose-response of formoterol via pressurized metered-dose inhaler (pMDI) has not been determined in asthmatic pediatric patients aged 6 to <12 years. This study was designed to assess the bronchodilating dose-response of three formoterol pMDI doses in children with stable asthma aged 6 to <12 years receiving twice-daily (b.i.d.) budesonide 160 micrograms. A U.S., multicenter, five-way crossover study compared single doses of formoterol, a long-acting beta-agonist, via pMDI (2.25, 4.5, and 9 micrograms) or dry powder inhaler (12 micrograms; active comparator) and placebo, with a 3- to 14-day washout period between doses. Budesonide pMDI 160 micrograms, an inhaled corticosteroid, was given b.i.d. throughout the study. Fifty-four pediatric patients (mean age, 9.2 years; mean asthma history, 6.1 years) were randomized. All formoterol doses showed significantly higher average 12-hour forced expiratory volume in 1 second (FEV1; area under the curve) versus placebo (primary efficacy). Formoterol pMDI 4.5 and 9 micrograms showed significantly greater average 12-hour FEV1 than formoterol 2.25 micrograms (p = 0.0007 and p = 0.0001, respectively). Formoterol also resulted in significant improvement in maximum FEV1 during the 12-hour treatment period (secondary efficacy) with formoterol 4.5-, 9-, and 12-microgram doses versus placebo and the formoterol 2.25-microgram dose. Bronchodilation was not maintained during the 12-hour dosing interval with formoterol 2.25 micrograms. No serious adverse events were reported. Formoterol pMDI showed generally dose-proportional pharmacokinetics to 9 micrograms, as determined by urinary excretion. Single doses of formoterol pMDI showed a dose-response, with formoterol 9 micrograms exhibiting a maximum response, in pediatric patients aged 6 to <12 years with persistent stable asthma maintained on b.i.d. budesonide pMDI 160 micrograms. Clinical trial NCT01136655, www.clinicaltrials.gov.

Zibotentan Can Be Co-administered with Contraceptives Containing Ethinyl Estradiol and Levonorgestrel: A Pharmacokinetic Drug-Drug Interaction Study.

The endothelin A receptor antagonist zibotentan, combined with the sodium-glucose co-transporter-2 inhibitor dapagliflozin, is being investigated for the treatment of chronic kidney disease with high proteinuria. To allow women of childbearing potential access to this treatment, highly effective contraception is required and drug interactions compromising contraception reliability must be avoided. This study investigated the risk of pharmacokinetic (PK) interaction between zibotentan and the contraceptives ethinyl estradiol and levonorgestrel. A single-sequence, within-participant comparison study was conducted in 24 healthy women of non-childbearing potential, comparing the PK of ethinyl estradiol/levonorgestrel alone and with zibotentan. Single oral doses of 0.06 mg ethinyl estradiol/0.3 mg levonorgestrel were administered on Days 1 and 15; zibotentan 10 mg was dosed orally, once-daily through Days 6-19. PK profiles were determined and ethinyl estradiol/levonorgestrel PK was compared between Day 1 and 15 based on geometric least-squares mean ratios of PK parameters, including maximum observed concentration (Cmax) and area under the plasma concentration-time curve from zero to infinity (AUCinf). Co-administration with zibotentan did not affect ethinyl estradiol PK (geometric mean ratio [90% confidence interval] Cmax 1.05 [0.99-1.11], AUCinf 1.00 [0.96-1.05]), while a weak interaction (increased exposure) was observed for levonorgestrel (Cmax 1.12 [1.02-1.23], AUCinf 1.30 [1.21-1.39]), which was regarded as without clinical relevance. Plasma exposure of ethinyl estradiol/levonorgestrel was not reduced by multiple-dose zibotentan. In conclusion, contraception containing ethinyl estradiol/levonorgestrel is regarded possible under zibotentan-containing treatments. This expands choices for women of childbearing potential, supporting diversity in the ZENITH High Proteinuria trial.

Pharmacokinetics, pharmacodynamics, and safety of verinurad with and without allopurinol in healthy Asian, Chinese, and non-Asian participants.

Verinurad is a selective inhibitor of uric acid transporter 1 (URAT1). Here, we assessed the safety, pharmacokinetics, and pharmacodynamics of verinurad + allopurinol and verinurad monotherapy in healthy participants. Studies 1 (NCT03836599) and 2 (NCT02608710) were randomized Phase 1 studies. In Study 1, 12 healthy Asian participants received 24 mg verinurad + 300 mg allopurinol or placebo, and 9 healthy Chinese participants received 12 mg verinurad + 300 mg allopurinol. In Study 2, 24 healthy non-Asian male participants received 12 mg verinurad. Safety analyses included assessment of adverse events (AEs). Pharmacokinetic parameters included maximum concentration (Cmax ) and area under plasma concentration-time curve (AUC) over 24 h (AUCτ ). Pharmacodynamic parameters included percentage change from baseline (day -1) in serum uric acid (sUA) and urinary uric acid (uUA). There were no serious AEs or deaths in either study. In Study 1, steady-state geometric mean (gCV%) Cmax and AUCτ values of verinurad after 7 days' dosing were 73.6 (29.0) ng/mL and 478 (18.4) ng·h/mL, respectively, in healthy Asian participants, and 42.0 (40.1) ng/mL and 264 (36.1) ng·h/mL, respectively, in healthy Chinese participants; in Study 2, gCV% values were 36.3 (36.5) ng/mL and 271 (31.0) ng·h/mL, respectively. sUA decreased and uUA excretion increased compared with baseline following verinurad + allopurinol (Study 1) or verinurad (Study 2). When accounting for dose, the steady-state pharmacokinetics of verinurad following multiple dosing were comparable between healthy Asian and Chinese participants and healthy non-Asian participants. Verinurad treatments were well tolerated, including at higher verinurad exposures than previously evaluated after repeated dosing.

An Evaluation of the Pharmacokinetics, Safety, and Tolerability of Aclidinium/Formoterol Fixed-Dose Combination Administered in Chinese Patients with Moderate-to-Severe Chronic Obstructive Pulmonary Disease.

BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate the pharmacokinetics, safety, and tolerability of aclidinium bromide/formoterol fumarate in patients from China with moderate-to-severe chronic obstructive pulmonary disease (COPD). METHODS: In this open-label, repeat-dose, 5-day pharmacokinetic study (NCT03276078) of inhaled aclidinium bromide/formoterol fumarate 400/12 µg twice daily, plasma concentrations of aclidinium, formoterol, and two aclidinium metabolites (LAS34823, LAS34850) were assessed (days 1 and 5). Adverse event (AE) data were collected. RESULTS: Twenty patients (15 [75%] males) with a mean age of 59.2 years were included. Median (range) time to maximum concentration on days 1 and 5 was 0.08 (0.08-0.50) and 0.08 (0.08-0.50) h, respectively, for aclidinium; and 1.00 (0.08-3.00) and 0.08 (0.08-1.50) h, respectively, for formoterol. Mean elimination half-life and accumulation ratio for area under the concentration-time curve during a dosage interval (AUCτ) was 19.42 h and 2.0, respectively, for aclidinium; and 14.06 h and 1.4, respectively, for formoterol. Steady-state maximum concentration (Cmax,ss) and AUCτ on day 5 were 60.86 pg/mL and 168.80 h·pg/mL, respectively, for aclidinium; and 6.47 pg/mL and 31.98 h·pg/mL, respectively, for formoterol. Aclidinium produced high coefficients of variation (day 1: AUCτ 79.0%, Cmax 84.5%; day 5: AUCτ 82.2%, Cmax 150.0%). Few AEs were reported, typically one per patient. One patient discontinued due to a serious AE (considered possibly unrelated to treatment). CONCLUSIONS: Aclidinium/formoterol 400/12 µg twice daily was well-tolerated in patients from China with moderate-to-severe COPD. Safety findings were consistent with the known safety profile. CLINICAL TRIAL IDENTIFIER: ClinicalTrials.gov, NCT03276078.

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 (IC(50) = 32 µM). Assessment of the calculated theoretical gastrointestinal inhibitor concentration ([I(2)]) and predicted steady-state maximum total plasma inhibitor concentration ([I(1)]) 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 (C(max)) and area under the plasma concentration versus time curve from 0 to 72 h postdose (AUC(0-72 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 C(max) and AUC(0-72 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 [I(2)] and in vitro P-gp inhibition data, confirming AZD5672 to be a P-gp inhibitor in vivo.

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.

Physiologically Based Pharmacokinetic Modelling of Glycopyrronium in Patients With Renal Impairment.

Glycopyrronium bromide, a synthetic anticholinergic agent used to treat patients with chronic obstructive pulmonary disease (COPD), is eliminated from the body by renal excretion and therefore systemic exposure is expected to be increased in patients with decreasing renal function. Despite enrollment of patients with decreasing renal function to evaluate the impact of renal impairment on the pharmacokinetics of glycopyrronium in clinical studies, no patients with severe renal impairment were included. A physiologically based pharmacokinetic (PBPK) model was developed in patients with COPD with normal renal function and used to predict systemic exposure of glycopyrronium in patients with severe renal impairment. The model accurately predicted plasma concentration-time profiles in patients with normal renal function, and mild and moderate renal impairment; the predicted and observed AUC and Cmax in these populations were similar. Compared to patients with normal renal function, a 1.20-, 1.45-, and 1.59-fold increase AUC was predicted in patients with mild, moderate, and severe renal impairment, respectively, suggesting dose adjustment is not necessary in patients with renal impairment. In conclusion, PBPK models, verified with clinical study data from patients with normal renal function, can potentially be used to predict the pharmacokinetics and recommended dose adjustment for patients with renal impairment.

Dose-Ranging and Cumulative Dose Studies of Albuterol Sulfate MDI in Co-Suspension Delivery™ Technology (AS MDI; PT007) in Patients with Asthma: the ASPEN and ANTORA Trials.

BACKGROUND AND OBJECTIVES: Co-suspension Delivery™ Technology has been developed for the administration of albuterol sulfate pressurised inhalation suspension via metered-dose inhaler (AS MDI, PT007). We assessed the efficacy and safety of AS MDI versus Proventil® in order to determine the optimal dose of AS MDI to take to Phase III clinical trials. METHODS: ASPEN (NCT03371459) and ANTORA (NCT03364608) were Phase II, randomised, crossover, multicentre studies of AS MDI versus Proventil® in patients with persistent asthma. In ASPEN, 46 patients received cumulative-dose treatments (90 µg/inhalation using 1 + 1 + 2 + 4 + 8 inhalations at 30-minute intervals) in 1 of 2 possible sequences: AS MDI/Proventil or Proventil/AS MDI. In ANTORA, 86 patients were randomised to one of 10 treatment sequences of AS MDI (90 µg or 180 µg), placebo MDI, or Proventil (90 µg or 180 µg). The primary endpoints were baseline-adjusted forced expiratory volume in 1 second (FEV1) 30 minutes after each cumulative dose (ASPEN) and change from baseline in FEV1 area under the curve from 0 to 6 h (ANTORA). Safety was assessed in both studies. RESULTS: In ASPEN, AS MDI was equivalent to Proventil (within pre-specified bounds of ± 200 mL) following cumulative doses of albuterol up to 1440 µg for the primary endpoint. In ANTORA, 90 µg and 180 µg doses of AS MDI and Proventil were significantly superior to placebo MDI (p < 0.0001), and AS MDI was non-inferior to Proventil at both doses, based on a margin of 100 mL. No new safety concerns were identified. CONCLUSION: The effects of albuterol delivered via AS MDI and Proventil on bronchodilation were equivalent, supporting the selection of AS MDI 180 µg to be taken into Phase III clinical trials, either alone or in combination with an inhaled corticosteroid. TRIAL REGISTRATION NUMBER: ASPEN (NCT03371459); Date of registration: 29/12/2017. ANTORA (NCT03364608); Date of registration: 15/12/2017.

Relative Bioavailability of Budesonide/Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler Administered With and Without a Spacer: Results of a Phase I, Randomized, Crossover Trial in Healthy Adults.

PURPOSE: The triple combination therapy budesonide/glycopyrrolate/formoterol fumarate in a metered dose inhaler (BGF MDI), formulated by using innovative co-suspension delivery technology, is a new inhaled corticosteroid/long-acting muscarinic antagonist/long-acting ß2-agonist fixed-dose combination for the maintenance treatment of COPD. For some patients, the use of an MDI may be optimized with a spacer. This Phase I study assessed the effect of a spacer on lung exposure, total systemic exposure, and safety of BGF MDI 320/36/9.6 µg in healthy subjects. METHODS: This randomized, open-label, crossover study assessed the pharmacokinetic and safety profiles of BGF MDI in healthy adult subjects who received a single dose of BGF MDI 320/36/9.6 µg (administered as 2 inhalations with 160/18/4.8 µg per actuation) in 4 regimens: without spacer and no charcoal; with spacer and no charcoal; without spacer and with charcoal; and with spacer and with charcoal. Primary objectives were to assess total systemic exposure (without charcoal) and lung exposure (with charcoal) of budesonide, glycopyrronium, and formoterol administered as BGF MDI with and without a spacer. Safety was also assessed. FINDINGS: In total, 56 subjects were randomized (mean age, 29.9 years; 60.7% male, 17.9% former smokers). For systemic exposure (without charcoal), the spacer/without spacer ratio, expressed as a percentage (intrasubject %CV) of Cmax and AUC0-tlast, respectively, was 152.0 (47.5) and 132.8 (43.6) for budesonide, 240.6 (80.2) and 154.7 (73.4) for glycopyrronium, and 165.6 (50.7) and 98.6 (53.8) for formoterol. For lung exposure (with charcoal), the spacer/without spacer ratio percentage (%CV) of Cmax and AUC0-tlast, respectively, was 183.6 (65.9) and 198.4 (71.5) for budesonide, 262.0 (91.8) and 373.9 (120.7) for glycopyrronium, and 222.9 (56.3) and 385.2 (147.0) for formoterol. Subjects who were judged to have suboptimal inhalation technique without a spacer (those in the lowest drug exposure quartile based on AUC0-tlast) had the greatest increase in both total systemic and lung exposure when a spacer was used versus no spacer. Subjects in the highest quartile had a minimal change in both total systemic and lung exposure when the spacer was used. Treatment-emergent adverse events (TEAEs) (all mild/moderate) reported by >1 subject per regimen were headache, cough, and dizziness. One subject withdrew because of TEAEs of headache and presyncope (neither considered treatment-related). IMPLICATIONS: Drug delivery can be improved for subjects with suboptimal MDI inhalation technique when using a spacer device with BGF MDI triple therapy. ClinicalTrials.gov identifier: NCT03311373.

Pharmacokinetics, Pharmacodynamics, and Tolerability of Concomitant Administration of Verinurad and Febuxostat in Healthy Male Volunteers.

Verinurad (RDEA3170) is a selective uric acid reabsorption inhibitor in development for treatment of gout and asymptomatic hyperuricemia. This phase 1, single-blind, multiple-dose, drug-drug interaction study evaluated the pharmacokinetics (PK), pharmacodynamics, and safety/tolerability of verinurad in combination with febuxostat in healthy male volunteers. Twenty-three subjects were randomized and received once-daily doses of verinurad (or placebo) or febuxostat alone (days 1-7 and days 15-21), or verinurad + febuxostat on days 8-14. For combinations, subjects received verinurad 10 mg + febuxostat 40 mg or verinurad 2.5 mg + febuxostat 80 mg. Plasma/serum and urine samples were analyzed for verinurad, febuxostat, and uric acid. Safety was assessed by adverse events and laboratory tests. Febuxostat 40 mg had no effect on plasma exposure of verinurad 10 mg, whereas febuxostat 80 mg increased the maximum observed plasma concentration and the area under the plasma concentration-time curve of verinurad 2.5 mg by 25% and 33%, respectively. Verinurad had no effect on febuxostat PK. Maximal reduction in serum urate was 76% with verinurad 10 mg + febuxostat 40 mg versus verinurad 10 mg (56%) or febuxostat 40 mg (49%) alone and was 67% with verinurad 2.5 mg + febuxostat 80 mg versus verinurad 2.5 mg (38%) or febuxostat 80 mg (57%) alone. Verinurad increased, whereas febuxostat decreased, 24-hour fractional excretion and renal clearance of uric acid. There was no clinically significant drug-drug interaction between verinurad and febuxostat PK. The combination resulted in greater reductions of serum urate than either drug alone and was well tolerated at the studied doses.