Pharmacokinetics and Pharmacodynamics of the SGLT2 Inhibitor Remogliflozin Etabonate in Subjects with Mild and Moderate Renal Impairment.

Remogliflozin etabonate (RE), the prodrug of remogliflozin, is an inhibitor of the sodium glucose-dependent renal transporter 2 (SGLT2), enabling urinary glucose excretion to reduce hyperglycemia for the treatment of type 2 diabetes. Renal function declines more rapidly in patients with type 2 diabetes, making it difficult or unsafe to continue on some antidiabetic therapeutics. In an initial effort to understand the potential utility of RE in patients with renal impairment, the pharmacodynamics and pharmacokinetics of RE were evaluated in a single oral dose (250 mg) in patients with renal impairment as compared with control subjects. As shown by pharmacodynamic measurements of urinary glucose excretion, there was no clinically significant reduction in the ability of remogliflozin to inhibit SGLT2. In addition, there were no significant changes in area under the curve (from 0 to infinity) or half-life of remogliflozin, suggesting renal impairment does not alter the pharmacokinetics of remogliflozin. In contrast to other SGLT2 inhibitors which accumulate in patients with renal impairment, adjustment of the dosage of RE in subjects with mild or moderate renal impairment is not indicated based on the observations in this study.

Pharmacokinetics of 3 times a day dosing of oral treprostinil in healthy volunteers.

BACKGROUND: Treprostinil diolamine (oral treprostinil) is an orally available prostacyclin analog that was developed for the treatment of pulmonary arterial hypertension. This study aimed to evaluate the pharmacokinetics (PK), safety, and tolerability of 3 times daily (TID) dosing of oral treprostinil. METHODS: This was a 9-day, open-label, single-center study in which 19 healthy subjects received 0.5 mg oral treprostinil TID for 7 days. On the morning of day 1, subjects received a single 0.5 mg dose and on days 2-7, subjects received 3 doses of 0.5 mg oral treprostinil with a meal (at approximately 8 AM, 2 PM, and 8 PM). On the morning of day 8, subjects received a final 0.5 mg dose. Intensive 24-hour PK sampling occurred after the AM doses on days 1, 7, and 8. Additional trough plasma samples were collected before the morning and evening doses on days 4, 5, and 6. RESULTS: Nineteen subjects (9 men, 10 women) with a mean age of 35.2 years (range, 20-54 years) were enrolled. The majority of subjects were white (n = 17). The mean (% CVb) Cmax was 0.538 (37%), 0.714 (51%), and 0.559 (45%) ng/mL on days 1, 7, and 8, respectively. After a single dose on day 1 (first dose) and day 8 (last dose), mean (CVb%) AUC0-24 was 2.45 (26%) and 2.96 (28%) h·ng·mL, respectively. The mean (% CVb) steady-state AUC0-24 after TID regimen (on day 7) was 6.53 (34%) h·ng·mL, which was not significantly different from mean AUC0-∞ (7.39 h·ng·mL) on day 1 adjusted for 3 doses. Mean apparent t1/2 was similar on days 1, 7, and 8 (1.1-1.4 hours). Trough concentrations of treprostinil were comparable across study days ranging from 0.046 to 0.053 ng/mL before the AM dose and from 0.27 to 0.39 ng/mL before the evening dose. Steady state was achieved within 2 days of TID dosing. Treprostinil PK after TID dosing of oral treprostinil follows linear kinetics and can be predicted based on PK data after a single dose. Sixteen adverse events occurred in 7 subjects and included prostacyclin related adverse events such as headache, diarrhea, and jaw pain. CONCLUSIONS: Three times daily dosing of 0.5 mg oral treprostinil for 7 days was well tolerated in healthy subjects and provided sustained plasma exposure throughout the day at steady state without drug accumulation. This study provides data to support further evaluation of TID dosing regimen of oral treprostinil.

Safety and pharmacokinetics of 120 mg/kg versus 60 mg/kg weekly intravenous infusions of alpha-1 proteinase inhibitor in alpha-1 antitrypsin deficiency: a multicenter, randomized, double-blind, crossover study (SPARK).

Augmentation therapy with the approved dose of 60 mg/kg weekly intravenous (IV) alpha-1 proteinase inhibitor (alpha1-PI), achieves a trough serum level of 11 µM in individuals with alpha-1 antitrypsin deficiency (AATD), yet this is still below the level observed in healthy individuals. This study assessed the safety and pharmacokinetic profile of weekly infusions of a 120 mg/kg dose of alpha1-PI in 30 adults with AATD. Subjects with symptomatic, genetically determined (genotypes PI*ZZ, PI*Z(null), PI*(null)(null) or PI*(Z)Mmalton) AATD were randomly assigned to weekly infusions of 60 or 120 mg/kg alpha1-PI (Prolastin-C®) for 8 weeks before crossing over to the alternate dose for 8 weeks. Adverse events (AEs) (including exacerbations), vital signs, pulmonary function tests, and laboratory assessments were recorded. Pharmacokinetic measurements included AUC0-7days, Cmax, trough, tmax, and t1/2, based on serum alpha1-PI concentrations. In total for both treatments, 112 AEs were reported, with exacerbation of COPD being the most frequent, consistent with the subjects' diagnoses. Mean steady-state serum alpha1-PI concentrations following 120 mg/kg weekly IV alpha1-PI were higher than with the 60 mg/kg dose and mean trough concentrations were 27.7 versus 17.3 µM, respectively. Dose proportionality was demonstrated for AUC0-7days and Cmax, with low inter-subject variability. The 120 mg/kg alpha1-PI weekly dose was considered to be safe and well tolerated, and provided more favorable physiologic alpha1-PI serum levels than the currently recommended 60 mg/kg dose. The effect of this dosing regimen on slowing and/or preventing emphysema progression in subjects with AATD warrants further investigation.

Pharmacokinetics of treprostinil diolamine in subjects with end-stage renal disease on or off dialysis.

Treprostinil diolamine sustained release (UT-15C SR) is being evaluated as an oral therapy for pulmonary arterial hypertension. This study evaluated the pharmacokinetics (PKs) of treprostinil following administration of UT-15C SR in subjects with end-stage renal disease (ESRD) compared with healthy subjects with normal renal function (NRF) and the effect of hemodialysis on the PK parameters of treprostinil. Eight ESRD subjects (requiring dialysis, mean creatinine clearance = 11.5 mL/min) received 2 single doses of 1 mg of UT-15C SR (separated by 2 weeks), with the first dose given immediately after dialysis and the second given 4 hours before the start of dialysis. Eight NRF subjects received a single dose of 1 mg of UT-15C SR. The median Cmax, AUC0-inf, and t1/2 of treprostinil were 680 pg/mL, 3240 hours pg/mL, and 2.35 hours, respectively, in ESRD subjects dosed after dialysis and were 551 pg/mL, 3152 hours pg/mL, and 2.05 hours, respectively, in ESRD subjects dosed before dialysis. In comparison, corresponding values were 730 pg/mL, 3726 hours pg/mL, and 3.54 hours, respectively, in NRF subjects. UT-15C SR of 1 mg was well tolerated by NRF and ESRD subjects. The most frequent adverse event was headache and nausea. There was no substantial difference in treprostinil PKs between ESRD and NRF subjects following administration of UT-15C SR tablets. Hemodialysis did not have clinically important effect on treprostinil PK in ESRD subjects.

Pharmacokinetics and relative bioavailability of a fixed-dose combination of enteric-coated naproxen and non-enteric-coated esomeprazole magnesium.

This randomized, 4-way crossover study assessed the single-dose pharmacokinetics and relative bioavailability of naproxen and esomeprazole after administration of a fixed-dose combination tablet of enteric-coated (EC) naproxen 500 mg and non-EC esomeprazole magnesium 20 mg (NAP/ESO tablet). Equivalent doses of an EC naproxen tablet plus an EC esomeprazole magnesium capsule taken concomitantly, an EC naproxen tablet alone, or an EC esomeprazole magnesium capsule alone were used as comparators. Forty healthy adults were randomized to receive 4 study treatments with a washout interval ≥12 days. Naproxen plasma profiles were similar between the NAP/ESO tablet and EC naproxen, although median t(max) was longest for the NAP/ESO tablet (5.3 vs 3.5-4.0 hours). Naproxen C(max), AUC(0-∞), and AUC(0-t) showed bioequivalence between naproxen formulations. The NAP/ESO tablet produced much shorter esomeprazole t(max) than the EC esomeprazole formulation (0.45 vs 2.5 hours). Esomeprazole C(max) and AUCs were comparable between the EC esomeprazole formulation administered with or without EC naproxen but were lower with the NAP/ESO tablet. In conclusion, there are no pharmacokinetic drug interactions between naproxen and esomeprazole. The NAP/ESO tablet is bioequivalent to EC naproxen, and as expected, the bioavailability of non-EC esomeprazole from the NAP/ESO tablet is lower than the EC esomeprazole formulation.

Pharmacokinetic comparability of Prolastin®-C to Prolastin® in alpha1-antitrypsin deficiency: a randomized study.

BACKGROUND: Alpha1-antitrypsin (AAT) deficiency is characterized by low blood levels of alpha1-proteinase inhibitor (alpha1-PI) and may lead to emphysema. Alpha1-PI protects pulmonary tissue from damage caused by the action of proteolytic enzymes. Augmentation therapy with Prolastin® (Alpha1-Proteinase Inhibitor [Human]) to increase the levels of alpha1-PI has been used to treat individuals with AAT deficiency for over 20 years. Modifications to the Prolastin manufacturing process, incorporating additional purification and pathogen-reduction steps, have led to the development of an alpha1-PI product, designated Prolastin®-C (Alpha1-Proteinase inhibitor [Human]). The pharmacokinetic comparability of Prolastin-C to Prolastin was assessed in subjects with AAT deficiency. METHODS: In total, 24 subjects were randomized to receive 60 mg/kg of functionally active Prolastin-C or Prolastin by weekly intravenous infusion for 8 weeks before crossover to the alternate treatment for another 8 weeks. Pharmacokinetic plasma samples were drawn over 7 days following last dose in the first treatment period and over 10 days following the last dose in the second period. The primary end point for pharmacokinetic comparability was area under the plasma concentration versus time curve over 7 days post dose (AUC0₋7 (days)) of alpha1-PI determined by potency (functional activity) assay. The crossover phase was followed by an 8-week open-label treatment phase with Prolastin-C only. RESULTS: Mean AUC0₋7 (days) was 155.9 versus 152.4 mg*h/mL for Prolastin-C and Prolastin, respectively. The geometric least squares mean ratio of AUC0₋7 (days) for Prolastin-C versus Prolastin had a point estimate of 1.03 and a 90% confidence interval of 0.97-1.09, demonstrating pharmacokinetic equivalence between the 2 products. Adverse events were similar for both treatments and occurred at a rate of 0.117 and 0.078 per infusion for Prolastin-C (double-blind treatment phase only) and Prolastin, respectively (p = 0.744). There were no treatment-emergent viral infections in any subject for human immunodeficiency virus, hepatitis B or C, or parvovirus B19 during the course of the study. CONCLUSION: Prolastin-C demonstrated pharmacokinetic equivalence and a comparable safety profile to Prolastin. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00295061.