Abstract Purpose Fostamatinib, a spleen tyrosine kinase inhibitor and prodrug of the active metabolite R406, is being developed as an anti-inflammatory drug for several indications for which ...polypharmacy is likely. Digoxin, indicated for congestive cardiac failure, may be used for certain supraventricular dysrhythmias. The studies reported herein examined whether fostamatinib and R406 are inhibitors of P-glycoprotein (P-gp) in vitro and evaluated the effect of fostamatinib on the pharmacokinetic parameters of digoxin to understand drug–drug interaction (DDI) potential in the clinic. Methods Inhibition of P-gp–mediated digoxin transport by fostamatinib and R406 was determined across Caco-2 cell monolayers. Apparent permeability of digoxin was determined and used to calculate efflux ratios and percentage inhibition. Half maximal inhibitory concentrations (IC50 ) and theoretical gastrointestinal concentration I2 (dose in moles per 250 mL) were calculated to gauge clinical DDI potential. In a subsequent Phase I study, the plasma concentration–time profiles and resulting pharmacokinetic parameters were examined across 2 treatment periods: (1) oral digoxin loading dose of 0.25 mg BID on day 1 and 0.25 mg once daily on days 2 to 8, and (2) oral digoxin 0.25 mg once daily and oral fostamatinib 100 mg BID on days 9 to 15. Findings Fostamatinib (but not R406) was determined to be a P-gp inhibitor in vitro (IC50 = 3.2 μM). On the basis of a theoretical gastrointestinal concentration (I2 )/IC50 ratio of 216 (I2 = 691 μM), predictions indicated the potential for absorption-based DDI in vivo through inhibition of intestinal P-gp. In the clinical study, when digoxin was co-administered with fostamatinib, digoxin levels were higher before dosing and throughout the dosing interval, and an increase in exposure to digoxin was observed. Co-administration led to a 1.70-fold increase in digoxin maximum plasma concentration at steady state (Cmax,ss ) versus digoxin administration alone (2.18 vs 1.32 ng/mL). Median digoxin time of Cmax was earlier when digoxin was co-administered with fostamatinib (1.00 vs 1.48 hours). The digoxin AUC during the dosing interval at steady state was increased 1.37-fold with co-administration. No severe or serious adverse events or deaths were reported. Implications Fostamatinib was confirmed to be a P-gp inhibitor in vitro and in vivo, and a DDI with digoxin was apparent. Co-administration of digoxin and fostamatinib was generally well tolerated. However, continued review of digoxin response and dose is advisable should these agents be prescribed concomitantly. ClinicalTrials.gov identifier: NCT01355354.
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.
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 (AUC
τ
) was 19.42 h and 2.0, respectively, for aclidinium; and 14.06 h and 1.4, respectively, for formoterol. Steady-state maximum concentration (
C
max,ss
) and AUC
τ
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: AUC
τ
79.0%,
C
max
84.5%; day 5: AUC
τ
82.2%,
C
max
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.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The current study examined whether the Avoidance and Fusion Questionnaire for Youth (AFQ-Y; L. A. Greco, W. Lambert, & R. A. Baer, 2008), a self-report measure of psychological inflexibility for ...children and adolescents, might be useful for measuring psychological inflexibility for adults. The psychometric properties of the AFQ-Y were examined using data from a college student sample (N = 387) and a clinical sample of patients with anxiety disorders (N = 115). The AFQ-Y, but not the Acceptance and Action Questionnaire-II (AAQ-II; F. W. Bond et al., in press), demonstrated a reading level at or below the recommended 5th or 6th grade reading level. The AFQ-Y also demonstrated adequate reliability (internal consistency), factorial validity, convergent and discriminant validity, and concurrent validity predicting psychological symptoms. Moreover, the AFQ-Y showed incremental validity over the AAQ-II in predicting several psychological symptom domains. Implications for the assessment of psychological inflexibility are discussed.
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
14
Clesinurad 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
14
Clesinurad 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.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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.
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).
A total of 81 adult males completed the study. Following single doses of verinurad, maximum observed plasma concentration (C
) and area under the plasma concentration-time curve (AUC) increased in a dose-proportional manner; C
occurred at 0.5-0.75 hours and 1.25 hours in the fasted and fed states, respectively. Food decreased AUC by 23% and C
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.
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.
World War II could not have been fought and won without the crucial role played by the U.S. Merchant Marine. Crewed by civilian seamen in peacetime, and carrying much of the nation's ocean-borne ...commerce, the Merchant Marine is often considered the "fourth arm of defense" in wartime. And, as such, it provided the vital logistical support for beachheads in all theaters of operation around the world during the war.
The 20 Merchant Marine veterans of World War II featured in this oral history served in all theaters of war, and most had at least one ship - some two - torpedoed, bombed, shelled or mined out from under them. Some became prisoners of the Japanese for the duration, working on the infamous River Kwai Bridge. Many spend time in lifeboats or on flimsy rafts under extremely harsh conditions after the loss of a ship. And one - Donald Zubrod - endured 42 days in a lifeboat with several others before their eventual rescue very close to death's door.
Credited during the war for often paying for their service "with some of their own blood" as they brought bombs, bullets, and butter to others, American merchant mariners actually suffered a loss rate that was a close second to only the Marine Corps during the conflict. Yet, their role still remains little known and understood.
The collection of eye-witness accounts will go a long way to helping set the record straight at long last.
Background and Objectives
Lesinurad is a selective uric acid reabsorption inhibitor (SURI) under investigation for the treatment of gout. This study elucidated the interaction of lesinurad with major ...liver and kidney transporters in vitro and evaluated the drug–drug interactions (DDIs) of lesinurad and atorvastatin, metformin, and furosemide in clinical studies.
Methods
Lesinurad interaction with membrane transporters was evaluated in validated transporter-expressing cell systems and analyzed by liquid scintillation counting. Healthy male subjects (ages 18–65 years; body mass index 18–32 kg/m
2
) received atorvastatin (40 mg;
n
= 28) with or without lesinurad 200 or 400 mg, or received metformin (850 mg;
n
= 12) or furosemide (40 mg;
n
= 11) with or without lesinurad 400 mg. Plasma concentrations of each concomitant drug were determined by validated liquid chromatography with tandem mass spectrometry methods.
Results
Lesinurad interacted in vitro with OATP1B1, OCT1, and OAT1/3 transporters. Co-administration of lesinurad 200 mg did not significantly alter plasma exposure (maximum concentration
C
max
and area under the concentration–time curve AUC) of total atorvastatin (atorvastatin + hydroxyl-metabolites) or atorvastatin, while co-administration of lesinurad 400 mg increased the
C
max
of total atorvastatin and atorvastatin by 17–26 %, but had no effect on AUC. Co-administration of lesinurad 400 mg had no effect on the plasma exposure of metformin. Furosemide plasma AUC was reduced by 31 % in the presence of lesinurad 400 mg, but furosemide renal clearance and diuretic activity were unchanged.
Conclusions
No clinically relevant DDIs were observed between lesinurad and substrates of major liver or kidney transporters.
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.
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 concentration–time curve (AUC) increased with increasing dose in Japanese subjects. Steady state was achieved in 5–7 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.
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