A phase II dose-ranging study of the phosphodiesterase inhibitor K-134 in patients with peripheral artery disease and claudication.

BACKGROUND: Phosphodiesterase inhibitors have been shown to improve claudication-limited exercise performance in patients with peripheral artery disease. K-134, a novel phosphodiesterase inhibitor, was evaluated in a phase II trial incorporating an adaptive design to assess its safety, tolerability, and effect on treadmill walking time. DESIGN: Patients with peripheral artery disease were randomized to receive placebo (n = 87), K-134 at a dose of 25 mg (n = 42), 50 mg (n = 85), or 100 mg (n = 84), or cilostazol at a dose of 100 mg (n = 89), each twice daily for 26 weeks. Peak walking time (PWT) was assessed using a graded treadmill protocol at baseline and after 14 and 26 weeks of treatment. A Data and Safety Monitoring Board-implemented adaptive design was used that allowed early discontinuation of unsafe or minimally informative K-134 arms. RESULTS: As determined by the prospectively defined adaptive criteria, the 25-mg K-134 arm was discontinued after 42 individuals had been randomized to the arm. During the 26-week treatment period, PWT increased by 23%, 33%, 37%, and 46% in the placebo, 50-mg K-134, 100-mg K-134, and cilostazol arms, respectively (primary analysis placebo vs 100-mg K-134 arm not statistically significant, P = .089). Secondary analyses showed that cilostazol significantly increased PWT after 14 weeks of treatment and that the 100-mg K-134 dose and cilostazol both increased PWT vs placebo after 14 and 26 weeks in those individuals who completed the 26-week trial and were compliant with the study drug, or when the data were analyzed using a mixed-effects model incorporating all time points. K-134 had tolerability and adverse effect profiles similar to that of cilostazol. Both drugs were associated with an increase in withdrawals before study completion due to adverse events compared with placebo. CONCLUSIONS: K-134 was generally well tolerated. K-134 at a dose of 100 mg twice daily did not affect PWT according to the primary analysis, but K-134 and cilostazol both increased PWT when analyzed using a mixed-effects model and in the per-protocol population.

Comparison of the safety, tolerability, and pharmacokinetic profile of a single oral dose of pitavastatin 4 mg in adult subjects with severe renal impairment not on hemodialysis versus healthy adult subjects.

Pitavastatin is a novel statin recently approved in the United States as an adjunctive therapy with diet to reduce elevated total cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, and triglycerides and to increase high-density lipoprotein cholesterol. This open-label study enrolled 16 subjects as follows: group A: 8 adult subjects with severe renal impairment who were not on hemodialysis (estimated glomerular filtration rate of 15-29 mL/min/1.73 m2) and group B: 8 healthy adult subjects (estimated glomerular filtration rate ≥80 mL/min/1.73 m2). On day 1, the subjects received a single oral dose of pitavastatin 4 mg and remained in the clinic on days 1-3 for safety and pharmacokinetic assessments. Comparing group A with group B, the geometric mean ratio of AUC(0-inf) for pitavastatin was 1.36 (90% confidence interval, 0.88-2.11). For Cmax, the corresponding ratio was 1.18 (90% confidence interval, 0.68-2.02). There were no severe treatment-emergent adverse events (AEs), serious AEs, deaths, or treatment-emergent AEs leading to study drug discontinuation. A single dose of pitavastatin 4 mg was safe and well tolerated by the subjects in this study with severe renal impairment, who were not on hemodialysis.

A phase 1 clinical trial of the sigma-2 receptor complex allosteric antagonist CT1812, a novel therapeutic candidate for Alzheimer's disease.

BACKGROUND: Elayta (CT1812) is a novel allosteric antagonist of the sigma-2 receptor complex that prevents and displaces binding of Aß oligomers to neurons. By stopping a key initiating event in Alzheimer's disease, this first-in-class drug candidate mitigates downstream synaptotoxicity and restores cognitive function in aged transgenic mouse models of Alzheimer's disease. METHODS: A phase 1, two-part single and multiple ascending dose study was conducted in 7 and 4 cohorts of healthy human subjects, respectively. In part A, healthy, young subjects (<65 years old) received CT1812 doses ranging from 10 to 1120 mg (6:2 active to placebo [A:P] per cohort). In part B, subjects were administered 280, 560, and 840 mg once daily for 14 days (8:2 A:P per cohort). An elderly cohort, aged 65-75 years, was dosed at 560 mg once daily for 14 days (7:2 A:P). Serum concentrations of CT1812 in part B were measured on day 3 and 14 and cerebrospinal fluid concentrations on day 7 or 9. Cognitive testing was performed in the healthy elderly cohort at baseline and at day 14 of treatment. RESULTS: Treatment with CT1812 was well tolerated in all cohorts. Adverse events were mild to moderate in severity and included headache and GI tract symptoms. Plasma concentrations of drug were dose proportional across two orders of magnitude with minimal accumulation over 14 days. Cognitive scores in the healthy elderly cohort were similar before and after treatment. CONCLUSIONS: CT1812 was well tolerated with single dose administration up to 1120 mg and with multiple dose administration up to 840 mg and 560 mg in healthy young and healthy elderly subjects, respectively. CT1812 is currently being studied in early phase 2 trials in patients with Alzheimer's disease.

Comparison of the lipid-lowering effects of pitavastatin 4 mg versus pravastatin 40 mg in adults with primary hyperlipidemia or mixed (combined) dyslipidemia: a Phase IV, prospective, US, multicenter, randomized, double-blind, superiority trial.

PURPOSE: Results from a Phase III, European, non-inferiority trial in elderly (age ≥65 years) patients with primary hyperlipidemia or mixed (combined) dyslipidemia demonstrated significantly greater reductions in LDL-C for pitavastatin versus pravastatin across 3 pair-wise dose comparisons (1 mg vs 10 mg, 2 mg vs 20 mg, and 4 mg vs 40 mg, respectively). The present study investigated whether pitavastatin 4 mg is superior to pravastatin 40 mg in LDL-C reduction in adults (18-80 years old) with primary hyperlipidemia or mixed (combined) dyslipidemia. METHODS: This was a Phase IV, multicenter, randomized, double-blind, double-dummy, active-control superiority study conducted in the United States. Patients with baseline LDL-C levels of 130 to 220 mg/dL (inclusive) and triglyceride levels ≤400 mg/dL after a 6-week washout/dietary stabilization period were randomized to 12 weeks of once-daily treatment with either pitavastatin 4 mg or pravastatin 40 mg. FINDINGS: A total of 328 subjects (164 per treatment arm) were randomized (mean age, 57.9 years [76% were aged <65 years]; 49.4% women; mean body mass index, 30.2 kg/m(2)) to treatment. The median percent change in LDL-C from baseline to the week 12 endpoint was -38.1% for pitavastatin 4 mg and -26.4% for pravastatin 40 mg; the difference in median percent change between treatments was -12.5% (P < 0.001). Differences between treatments in median percent reductions from baseline for apolipoprotein B, total cholesterol, and non-HDL-C were also significant in favor of pitavastatin (P < 0.001). Both treatments significantly (P < 0.001) increased HDL-C and decreased triglycerides, but the differences between treatments were not statistically significant. The overall rate of treatment-emergent adverse events was 47.6% (78 of 164) for pitavastatin and 44.5% (73 of 164) for pravastatin. Myalgia was reported by 3 patients (1.8%) in the pitavastatin group and by 4 patients (2.4%) in the pravastatin group. There were no reports of myositis or rhabdomyolysis. IMPLICATIONS: Pitavastatin 4 mg demonstrated superior LDL-C reductions compared with pravastatin 40 mg after 12 weeks of therapy in adults with primary hyperlipidemia or mixed (combined) dyslipidemia. There were no new safety findings in the trial. Clinical Trials.gov identifier: NCT01256476.

Steady-state pharmacokinetics of darunavir/ritonavir and pitavastatin when co-administered to healthy adult volunteers.

BACKGROUND: The treatment of hyperlipidaemia in human immunodeficiency virus (HIV)-infected patients has become increasingly important. However, treatment options are limited because of the drug-drug interaction between certain statins and HIV medications metabolized by cytochrome P450 (CYP) enzymes. OBJECTIVES: The primary objective was to investigate the steady-state pharmacokinetics of pitavastatin when co-administered with darunavir/ritonavir. The secondary objective was to investigate the steady-state pharmacokinetics of both darunavir and ritonavir when co-administered with pitavastatin. METHODS: This was a single-centre, open-label, multi-dose, fixed-sequence study in HIV seronegative healthy volunteers. Pitavastatin 4 mg was administered once daily on days 1-5 and on days 12-16, and darunavir 800 mg/ritonavir 100 mg once daily on days 6-16. Pharmacokinetic blood sampling was performed on days 5, 11 and 16. No significant interaction was concluded if the 90 % confidence intervals (CIs) of the geometric mean ratios (GMRs) for total exposure [i.e. the area under the plasma concentration-time curve over a dosing interval at steady state (AUC(0-τ))] and for peak exposure [i.e. the maximum plasma concentration (C(max))] of the two treatments were within the 80-125 % range. RESULTS: Twenty-eight subjects (mean age 30.5 years) were enrolled, and pharmacokinetic data were available for 27 subjects. For pitavastatin, the GMRs and 90 % CIs for the AUC(0-τ) and C(max) ratios with co-administration were 0.74 (0.69-0.80) and 0.96 (0.84-1.09), respectively. For both darunavir and ritonavir, the 90 % CIs for the AUC(0-τ) and C max ratios were within 80-125 % with pitavastatin co-administration. No significant safety issues were reported. CONCLUSION: Darunavir/ritonavir decreased total exposure to pitavastatin by 26 %, while peak exposures were similar. Pitavastatin did not influence the pharmacokinetics of darunavir or ritonavir. There is limited interaction between pitavastatin and darunavir/ritonavir.

Effects of steady-state lopinavir/ritonavir on the pharmacokinetics of pitavastatin in healthy adult volunteers.

OBJECTIVES: Pitavastatin, a statin recently approved in the United States, has a potential benefit of reduced risk of cytochrome P450 (CYP)-mediated drug-drug interaction due to minimal metabolism by the CYP system. The primary objective was to investigate pharmacokinetic (PK) effects of lopinavir/ritonavir 400 mg/100 mg twice daily on pitavastatin 4 mg when coadministered. DESIGN: This was an open-label one-arm study. METHOD: Pitavastatin 4 mg was administered once daily (days 1-5 and days 20-24). Lopinavir/ritonavir 400 mg/100 mg was administered twice daily (days 9-24). Plasma samples for PK assessments were collected on days 5, 19, and 24. Plasma concentrations of analytes were determined by liquid chromatography with tandem mass spectrometric detection methods. RESULTS: PK data were available for 23 of 24 subjects enrolled. For pitavastatin, area under the concentration time curve (AUC0-τ) and maximum concentration (C(max)) were 136.8 ± 52.9 ng·h(-1)·mL(-1) and 58.6 ± 30.4 ng/mL, respectively, when given alone, versus 113.9 ± 53.8 ng·h(-1)·mL(-1) and 58.2 ± 32.7 ng/mL when combined with lopinavir/ritonavir. The geometric mean ratio for AUC(0-τ) for pitavastatin with lopinavir/ritonavir versus pitavastatin alone was 80.0 (90% confidence interval: 73.4 to 87.3) and C(max) was 96.1 (90% confidence interval: 83.6 to 110.4). Median T(max) of pitavastatin was approximately 0.5 hours for both treatments. The PK effect of pitavastatin on lopinavir/ritonavir was minimal. No significant safety issues were reported. CONCLUSIONS: The effect on exposures when pitavastatin and lopinavir/ritonavir are coadministered was minimal. Concomitant use of pitavastatin and lopinavir/ritonavir was safe and well tolerated in healthy adult volunteers.

Effect of pitavastatin vs. rosuvastatin on international normalized ratio in healthy volunteers on steady-state warfarin.

OBJECTIVE: Statins have been shown to impact international normalized ratio (INR) when coadministered with warfarin. The aim of this study was to assess the effect of pitavastatin compared with rosuvastatin on steady-state pharmacodynamics (PD) of warfarin by measuring INR in healthy adult subjects. METHODS: Subjects received oral doses of warfarin 5 mg once daily on days 1 through 3. The dose was titrated on days 4 through 9 to reach a steady-state INR of 1.5 to 2.2. Warfarin was continued on days 10 through 21 and pitavastatin 4 mg or rosuvastatin 40 mg was administered once daily on days 14 through 22. After a 14-day washout period, the process was repeated with the alternate statin. STUDY NUMBER: NK-104-4.03US. RESULTS: For pitavastatin, mean INR changed from 1.73 ± 0.18 (n = 42) on day 14 before starting statin dosing, to 1.78 ± 0.29 (n = 42) on day 22 at treatment end; the difference in INR was not significant (p = 0.219). For rosuvastatin, mean INR increased significantly from 1.74 ± 0.20 (n = 43) at baseline to 1.90 ± 0.30 (n = 43) at treatment end (p < 0.001). Rosuvastatin caused a significantly greater increase in INR than pitavastatin (p < 0.001). CONCLUSION: Steady-state INR during warfarin treatment did not change significantly when pitavastatin 4 mg was added to the regimen, while a significant increase was observed when rosuvastatin 40 mg was added. The effect of rosuvastatin on INR was significantly larger than the effect of pitavastatin. This study is limited because it was done in healthy volunteers. Further studies in patient populations are needed to better understand the clinical significance of the results.

Drug-drug interaction study to assess the effects of multiple-dose pitavastatin on steady-state warfarin in healthy adult volunteers.

Warfarin, an antagonist of vitamin K, which inhibits clotting factor synthesis, is prescribed for thrombosis prophylaxis and treatment and is known to have a narrow therapeutic range. Pitavastatin is a potent HMG-CoA reductase inhibitor. In this study, the influence of multiple-dose pitavastatin (4 mg once daily) on steady-state warfarin pharmacodynamic and pharmacokinetic profiles was investigated in 24 healthy male participants whose international normalized ratio (INR) was maintained by individualized doses of warfarin. The ratio of the least squares mean of prothrombin time and INR was 0.989 (90% confidence interval [CI], 0.955-1.023) and 0.993 (0.956-1.209), respectively (test: warfarin + pitavastatin; reference: warfarin only). The geometric mean ratios of C(max) and AUC were 1.034 (90% CI, 0.994-1.075) and 1.066 (1.035-1.099), respectively, for R-warfarin and 1.033 (0.995-1.073) and 1.058 (1.026-1.092), respectively, for S-warfarin. Warfarin pharmacodynamic profiles and pharmacokinetic profiles did not differ between the warfarin monotherapy and the coadministration of pitavastatin and warfarin. No drug-drug interaction between pitavastatin and warfarin was demonstrated.

Transient global amnesia associated with statin intake.

A 57-year-old man treated with statins developed a range of amnestic features that led to concerns he might be suicidal; however, he did not appear to have depression. His problems began after starting rosuvastatin and cleared on discontinuation.

Chemokine receptor CXCR3 desensitization by IL-16/CD4 signaling is dependent on CCR5 and intact membrane cholesterol.

Previous work has shown that IL-16/CD4 induces desensitization of both CCR5- and CXCR4-induced migration, with no apparent effect on CCR2b or CCR3. To investigate the functional relationship between CD4 and other chemokine receptors, we determined the effects of IL-16 interaction with CD4 on CXCR3-induced migration. In this study we demonstrate that IL-16/CD4 induced receptor desensitization of CXCR3 on primary human T cells. IL-16/CD4 stimulation does not result in surface modulation of CXCR3 or changes in CXCL10 binding affinity. This effect does require p56(lck) enzymatic activity and the presence of CCR5, because desensitization is not transmitted in the absence of CCR5. Treatment of human T cells with methyl-beta-cyclodextrin, a cholesterol chelator, prevented the desensitization of CXCR3 via IL-16/CD4, which was restored after reloading of cholesterol, indicating a requirement for intact cholesterol. These studies demonstrate an intimate functional relationship among CD4, CCR5, and CXCR3, in which CCR5 can act as an adaptor molecule for CD4 signaling. This process of regulating Th1 cell chemoattraction may represent a mechanism for orchestrating cell recruitment in Th1-mediated diseases.