Single- and multiple-dose safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of ASP0367, or bocidelpar sulfate, a novel modulator of peroxisome proliferator-activated receptor delta in healthy adults: Results from a phase 1 study.

INTRODUCTION/AIMS: ASP0367, or bocidelpar sulfate, is an orally administered small molecule that potently and selectively modulates peroxisome proliferator-activated receptor δ (PPARδ) to address mitochondrial dysfunction occurring in diseases including primary mitochondrial myopathy and Duchenne muscular dystrophy. The objectives of this first-in-human trial were to evaluate the safety/tolerability, pharmacokinetics, and pharmacodynamics of ASP0367 in healthy participants. METHODS: In this double-blind phase 1 study, adult participants were randomized to single or multiple ascending oral doses of ASP0367 or placebo. The study duration was 1 and 14 days, respectively. Pharmacokinetic parameters under fed conditions were also evaluated. RESULTS: A total of 64 (single-dose cohort) and 37 (multiple-dose cohort) participants were included in the study. After single doses of 1 to 120 mg, ASP0367 was rapidly absorbed, with median time to maximum plasma concentration (tmax ) of 1.50 to 2.24 hours under fasting conditions; ASP0367 concentrations declined in a multiphasic manner after reaching maximum plasma concentration. Under fed conditions, tmax was delayed 1.7 hours. After multiple once-daily doses, mean half-life of ASP0367 10 to 75 mg ranged from 14.1 to 17.5 hours; steady state was reached after 4 days. Negligible accumulation was observed after repeated dosing. No participants receiving ASP0367 discontinued treatment, and all treatment-emergent adverse events were mild to moderate in severity; none were considered drug-related. No clinically significant changes were observed on laboratory or electrocardiographic evaluation. Treatment- and dose-dependent upregulation of six PPARδ target genes was observed with single and multiple doses of ASP0367. DISCUSSION: ASP0367, or bocidelpar sulfate, was well tolerated; rapid absorption, roughly dose-proportional bioavailability, and effects on PPARδ target genes were demonstrated in healthy adult participants.

NPT-IIb Inhibition Does Not Improve Hyperphosphatemia in CKD.

INTRODUCTION: Serum phosphate levels are insufficiently controlled in many patients with end-stage renal disease (ESRD), and novel therapeutic strategies are needed. Blocking intestinal phosphate absorption mediated by sodium-dependent phosphate co-transporter type 2b (NPT-IIb) holds promise; thus, we evaluated the efficacy, safety, tolerability, and pharmacokinetics of the novel and specific small molecule NPT-IIb inhibitor ASP3325 for the first time in humans. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 1a single (n = 88) and multiple (n = 36) ascending dose study in healthy subjects, and a randomized, open-label, uncontrolled, phase 1b study in hyperphosphatemic ESRD patients on hemodialysis (single oral dose, n = 5; multiple oral doses, n = 17). Primary efficacy measures were urinary phosphate and fecal phosphorous excretion (healthy subjects) and serum phosphate level (ESRD patients). RESULTS: No time- or dose-dependent changes in urinary phosphate or fecal phosphorous excretion were observed following single/multiple ASP3325 doses for 7 days in healthy subjects. In ESRD patients, ASP3325 administered 3 times daily for 2 weeks before or after a meal did not reduce serum phosphate levels. ASP3325 was safe and well tolerated in both populations. CONCLUSION: NPT-IIb inhibition with ASP3325 was not effective in reducing serum phosphate levels in ESRD patients. The relevance of NPT-IIb in humans and feasibility of oral NPT-IIb inhibitors for treatment of hyperphosphatemia in ESRD remain uncertain.

Renal glucose handling: impact of chronic kidney disease and sodium-glucose cotransporter 2 inhibition in patients with type 2 diabetes.

OBJECTIVE: Ipragliflozin, a sodium-glucose cotransporter 2 inhibitor, stimulates glycosuria and lowers glycemia in patients with type 2 diabetes (T2DM). The objective of this study was to assess the pharmacodynamics of ipragliflozin in T2DM patients with impaired renal function. RESEARCH DESIGN AND METHODS: Glycosuria was measured before and after a single ipragliflozin dose in 8 nondiabetic subjects and 57 T2DM patients (age 62 ± 9 years, fasting glucose 133 ± 39 mg/dL, mean ± SD) with normal renal function (assessed as the estimated glomerular filtration rate [eGFR]) (eGFR1 ≥90 mL · min(-1) · 1.73 m(-2)), mild (eGFR2 ≥60 to <90), moderate (eGFR3 ≥30 to <60), or severe reduction in eGFR (eGFR4 ≤15 to <30). RESULTS: Ipragliflozin significantly increased urinary glucose excretion in each eGFR class (P < 0.0001). However, ipragliflozin-induced glycosuria declined (median [IQR]) across eGFR class (from 46 mg/min [33] in eGFR1 to 8 mg/min [7] in eGFR4, P < 0.001). Ipragliflozin-induced fractional glucose excretion (excretion/filtration) was 39% [27] in the T2DM patients (pooled data), similar to that of the nondiabetic subjects (37% [17], P = ns). In bivariate analysis of the pooled data, ipragliflozin-induced glycosuria was directly related to eGFR and fasting glucose (P < 0.0001 for both, r(2) = 0.55), predicting a decrement in 24-h glycosuria of 15 g for each 20 mL/min decline in eGFR and an increase of 7 g for each 10 mg/dL increase in glucose above fasting normoglycemia. CONCLUSIONS: In T2DM patients, ipragliflozin increases glycosuria in direct, linear proportion to GFR and degree of hyperglycemia, such that its amount can be reliably predicted in the individual patient. Although absolute glycosuria decreases with declining GFR, the efficiency of ipragliflozin action (fractional glucose excretion) is maintained in patients with severe renal impairment.

Combination treatment with ipragliflozin and metformin: a randomized, double-blind, placebo-controlled study in patients with type 2 diabetes mellitus.

BACKGROUND: Ipragliflozin (ASP1941) is a selective sodium glucose cotransporter 2 inhibitor in clinical development for the treatment of patients with type 2 diabetes mellitus (T2DM). OBJECTIVES: The primary objective was to evaluate the safety profile and tolerability of ipragliflozin as a glucose-lowering agent in combination with stable metformin therapy in patients with T2DM. A secondary objective was to evaluate the effect of ipragliflozin on the pharmacokinetic (PK) properties of metformin. METHODS: Thirty-six patients with T2DM stable on metformin therapy (850, 1000, or 1500 mg bid) were randomized in a double-blind manner to receive ipragliflozin (300 mg qd; n = 18) or matching placebo (n = 18) for 14 days. Safety profiles, including monitoring of hypoglycemic events, treatment-emergent adverse events (TEAEs), laboratory measurements, and vital signs were assessed throughout the study. The PK properties of metformin and ipragliflozin were determined in plasma. The geometric mean ratio and its 90% CI for the maximum plasma concentration and AUC(0-10) were calculated for metformin + ipragliflozin (day 14) versus metformin alone (day -1). Pharmacodynamic properties were assessed by measurement of urinary glucose excretion over 24 hours (UGE(0-24)). RESULTS: All the TEAEs, except 1, were mild. Fifteen TEAEs were observed in the ipragliflozin group (7 of 18 patients [38.9%]), and 19 TEAEs were observed in the placebo group in (8 of 18 patients [44.4%]). Treatment-related TEAEs were reported by 3 of 18 patients (16.7%) receiving metformin + ipragliflozin and by 5 of 18 patients (27.8%) receiving metformin + placebo. No hypoglycemic events (blood glucose level <54 mg/L [to convert to millimoles per liter, multiply by 0.0555]) were observed. The geometric mean ratios for C(max) and AUC(0-10) of metformin + ipragliflozin versus metformin alone were 1.11 (90% CI, 1.03-1.19) and 1.18 (90% CI, 1.08-1.28), respectively. After ipragliflozin treatment, UGE(0-24) on day 14 (74.9 g) was significantly higher than that in the placebo group (3.6 g) and at baseline (3.3 g). CONCLUSIONS: Combination treatment for 14 days with ipragliflozin and metformin was well tolerated in patients withT2DM without hypoglycemia. The addition of ipragliflozin (300 mg qd) to metformin therapy did not result in a clinically relevant change in the PK properties of metformin. ClinicalTrials.gov identifier: NCT01302145.

Effect of Ipragliflozin (ASP1941), a novel selective sodium-dependent glucose co-transporter 2 inhibitor, on urinary glucose excretion in healthy subjects.

BACKGROUND: Hyperglycaemia is associated with serious complications, significant morbidity and death. Despite the availability of a wide range of therapeutic options, many patients with diabetes mellitus fail to achieve or maintain recommended glycaemic goals. Ipragliflozin (ASP1941) is a novel, selective inhibitor of the sodium-dependent glucose co-transporter 2, which is highly expressed in the proximal tubules of the kidneys. It suppresses renal glucose reabsorption and increases urinary glucose excretion (UGE), potentially providing an insulin-independent treatment option for type 2 diabetes. METHODS: This multiple ascending-dose study assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of ipragliflozin in healthy subjects after single doses and multiple once-daily doses for 10 days (dose levels: 5-600 mg). RESULTS: Ipragliflozin was well tolerated following single and multiple once-daily oral dosing. Ipragliflozin was rapidly absorbed with a median time to reach the maximum plasma concentration of 1.3 hours after the last dose. The area under the plasma concentration-time curve increased proportionally with increasing dose. The mean elimination half-life was 12 hours following the last dose. Ipragliflozin dose dependently increased UGE up to a maximum of approximately 59 g (327 mmol) of glucose excreted over 24 hours following multiple doses, without affecting plasma glucose levels in healthy subjects. CONCLUSION: Administration of ipragliflozin was well tolerated and resulted in a rapid, dose-dependent increase in glucosuria. Pharmacodynamic and pharmacokinetic data suggest that ipragliflozin is suitable for prolonged once-daily oral treatment.

Pharmacokinetics, safety, and tolerability of solifenacin in patients with renal insufficiency.

To evaluate the pharmacokinetics, safety, and tolerability of solifenacin in patients with mild, moderate, or severe renal disease, eighteen patients with renal disease and six healthy volunteers received a single oral dose of solifenacin (10 mg). Pharmacokinetic parameters were assessed from blood samples drawn over a 360-h period. Safety and tolerability were also evaluated. Total mean +/- S.D. exposure (ng . h/mL) to solifenacin in healthy individuals (1190 +/- 403) was increased in patients with renal disease (mild: 1784 +/- 792, moderate: 1559 +/- 555, severe: 2530 +/- 700), and elimination half-life (mean +/- S.D. [h]) was prolonged (healthy: 68.2 +/- 27.2, mild: 89.1 +/- 34.5, moderate: 90.6 +/- 27.3, severe: 111 +/- 38.3). A significant correlation was found between creatinine clearance and pharmacokinetic parameters for exposure and apparent oral clearance. No deaths or serious adverse events occurred during the study. Solifenacin 10 mg was well tolerated in patients with renal disease. Solifenacin displays a higher exposure and a prolonged half-life in patients with renal impairment, especially severe. Therefore, while no special cautions are necessary for patients with mild/moderate renal impairment, patients with severe renal impairment should receive no more than 5 mg solifenacin once daily.

Pharmacokinetic effect of ketoconazole on solifenacin in healthy volunteers.

Solifenacin succinate (YM905) is a new, once-daily, orally administered muscarinic receptor antagonist designed to treat overactive bladder. The metabolism of solifenacin involves hepatic cytochrome P450 (CYP) 3A4; therefore, the pharmacokinetics of solifenacin may be affected by drugs that inhibit CYP3A4. This study aimed to examine the effects of co-administration of ketoconazole, a potent CYP3A4 inhibitor, on the pharmacokinetics of solifenacin in healthy volunteers. In a single-site, open-label, monosequence, crossover study, 17 healthy men and women aged 18 to 65 years received a single 10 mg oral dose of solifenacin, which is is the highest available dose. After a 14-day wash-out period, they began 20 days of oral ketoconazole at a dose of 200 mg once daily. A single 10 mg dose of solifenacin was administered again on day 7 of ketoconazole treatment. Pharmacokinetics was assessed using the standard measurements of maximum plasma concentration (Cmax), time to Cmax, area under the curve (AUC), and elimination half-life (t1/2). Co-administration of ketoconazole resulted in a 1.43 times increase in the C(max) of solifenacin and an approximately 2 times increase in AUC. The mean t1/2 of solifenacin was extended from 49.3 to 77.5 hr whereas time to Cmax did not change. No substantial increase in the overall rate of adverse events, and no significant effects on vital signs, electrocardiography, clinical laboratory values, or physical examinations were noted. Administration of 200 mg ketoconazole once daily in healthy male volunteers resulted in a 2 times increase in exposure of a single 10 mg dose of solifenacin. Since ketoconazole is one of the strongest inhibitors of CYP3A4, it is expected that co-administration of other CYP3A4 inhibitors will not result in a stronger increase in solifenacin exposure.

Pharmacokinetic interaction of solifenacin with an oral contraceptive containing ethinyl estradiol and levonorgestrel in healthy women: a double-blind, placebo-controlled study.

BACKGROUND: Solifenacin succinate (YM905; Vesicare, Astellas Pharma Inc., Tokyo, Japan) is a new once-daily, orally administered muscarinic receptor antagonist under investigation for the treatment of overactive bladder. OBJECTIVE: The aim of this study was to evaluate the effect of solifenacin on the pharmacokinetic (PK) parameters of an oral contraceptive (OC) containing ethinyl estradiol (EE) and levonorgestrel (LNG). METHODS: In a double-blind, placebo-controlled, 2-period, crossover study, 24 healthy, young, white women received a combined OC (EE 30 microg + LNG 150 microg) daily for two 21-day cycles, separated by a 7-day washout. On day 12 of each cycle, subjects began a 10-day regimen of solifenacin 10 mg QD, which is 2 times the suggested starting dose, or placebo. Subjects crossed over to the other treatment arm for the second cycle. Primary PK end points were C(max) and AUC from time 0 to 24 hours (AUC(0-24 h)) for EE and LNG. Women ranged in age from 20 to 37 years and had a mean body weight of 64 kg, mean height of 167.4 cm, and mean body mass index of 23 kg/m2. Seven women had never smoked, while 5 were former smokers and 12 were regular smokers. Safety assessments included the nature, frequency, and severity of spontaneously reported or observed adverse events, vital signs, electrocardiogram, laboratory values, and physical examination. RESULTS: Statistical analysis of AUC(0-24 h)/product of baseline concentration and total blood sampling time, and C(max)/baseline concentration ratios of solifenacin versus placebo for EE and LNG found the 90% CI to be within the predefined range of 0.8 to 1.25 (EE: 0.854-1.164 and 0.822-1.167; LNG: 0.920-1.125 and 0.910-1.139). The number of samples with non-quantifiable luteinizing hormone (LH) and folliclestimulating hormone (FSH) levels were comparable after administration of the OC with either solifenacin or placebo. The adverse event most frequently reported was dry mouth (solifenacin, n = 25 [9 mild, 13 moderate, and 3 severe] vs placebo, n = 1 [moderate]). There were no clinically relevant effects on vital signs, electrocardiogram, or laboratory parameters. CONCLUSIONS: A PK interaction between solifenacin and the OC containing EE and LNG was not found in this study. Solifenacin was not found to have altered suppression of LH or FSH. The drug was well tolerated in these healthy, young, white, adult female volunteers.

Pharmacokinetics and safety of solifenacin succinate in healthy young men.

The pharmacokinetic profile of solifenacin succinate (YM905; Vesicare), a new once-daily bladder-selective muscarinic receptor antagonist, was examined in 2 controlled trials of healthy young men. A single-dose study evaluated 5-, 10-, 20-, 40-, 60-, 80-, and 100-mg doses. A multidose study evaluated 5-, 10-, 20-, and 30-mg doses. In the single-dose study, mean time to maximal concentration and elimination half-life ranged from 3.3 to 4.8 and from 40.2 to 57.6 hours, respectively; in the multidose study, the corresponding ranges were 2.9 to 5.8 and 45.0 to 64.8. Plasma concentration and area under the curve increased linearly with single doses in both trials. At steady state, a less regular increase was seen, with higher values in the 20-mg group than in the 30-mg group. All doses in the single-dose study were well tolerated. At steady state, only the 30-mg dose was not well tolerated. The most commonly reported adverse events were dry mouth, blurred vision, and headache. Solifenacin 5 and 10 mg, either as single doses or at steady state, had minimal effect on salivary flow, visual nearpoint, and the incidence of adverse events. Solifenacin was well tolerated up to single doses of 100 mg and after multiple doses of 20 mg. Its pharmacokinetic profile makes it suitable for qd administration.

Food does not affect the pharmacokinetics of solifenacin, a new muscarinic receptor antagonist: results of a randomized crossover trial.

AIM: To determine the effect of food ingestion on the pharmacokinetic profile of solifenacin succinate (YM905; Vesicare, a new bladder selective muscarinic receptor antagonist for the treatment of overactive bladder, a chronic disease usually caused by involuntary detrusor muscle contractions during bladder filling. METHODS: A randomized, two-period, crossover study in two groups of 12 healthy men (aged 18-45 years, body weight 60-100 kg, body mass index < or =30). A single 10-mg dose of solifenacin was administered to the first group in the fasting state during period 1 and in the fed state during period 2, and to the second group in the fed state during period 1 and in the fasting state during period 2 (10 mg is two times the suggested starting dose). There was a 14-day washout between treatment periods. Parameters obtained included C(max), AUC(last), and AUC(0-inf), as well as t(1/2), t(max), and t(lag). RESULTS: One subject withdrew during the first period for personal reasons. No statistically or clinically significant pharmacokinetic differences occurred between subjects in the fed and fasting states. All geometric mean ratios were close to 1 (C(max), 1.033; AUC(last), 1.068; AUC(0-inf), 1.040). The 90% confidence intervals (CIs) fell in the predefined no-food-effect boundaries of 0.8-1.25 (C(max), 0.953-1.120; AUC(last), 0.990-1.153; AUC(0-inf), 0.976-1.109). The mean difference in t(1/2) was -3.8 h (90% CI 7.6-0.0). There were no significant differences between the fed and fasting states with regard to t(max) and t(lag) (P > 0.05). CONCLUSIONS: The pharmacokinetics of oral solifenacin was not affected by food ingestion, suggesting that this drug may be administered with or without food. The results observed in this investigation are consistent with those of previous studies of solifenacin.