Craig A. Sponseller

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-&tgr;) and maximum concentration (Cmax) 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 AUC0-&tgr; for pitavastatin with lopinavir/ritonavir versus pitavastatin alone was 80.0 (90% confidence interval: 73.4 to 87.3) and Cmax was 96.1 (90% confidence interval: 83.6 to 110.4). Median Tmax 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

Abstract 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 5u2009mg 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 4u2009mg or rosuvastatin 40u2009mg 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 1.73u2009±u20090.18 (nu2009=u200942) on day 14 before starting statin dosing, to 1.78u2009±u20090.29 (nu2009=u200942) on day 22 at treatment end; the difference in INR was not significant (pu2009=u20090.219). For rosuvastatin, mean INR increased significantly from 1.74u2009±u20090.20 (nu2009=u200943) at baseline to 1.90u2009±u20090.30 (nu2009=u200943) at treatment end (pu2009<u20090.001). Rosuvastatin caused a significantly greater increase in INR than pitavastatin (pu2009<u20090.001). Conclusion: Steady-state INR during warfarin treatment did not change significantly when pitavastatin 4u2009mg was added to the regimen, while a significant increase was observed when rosuvastatin 40u2009mg 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.

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.

Abstract: 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 AUC0–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.

Pitavastatin versus pravastatin in adults with HIV-1 infection and dyslipidaemia (INTREPID): 12 week and 52 week results of a phase 4, multicentre, randomised, double-blind, superiority trial

BACKGROUNDnPeople living with HIV-1 infection are at greater risk for cardiovascular disease than seronegative adults. Treatment of dyslipidaemia with statins has been challenging in people with HIV because of an increased potential for drug interactions due to competing cytochrome P450 metabolism between statins and commonly used antiretroviral agents. Neither pitavastatin nor pravastatin depend on cytochrome P450 for primary metabolism. We aimed to assess the safety and efficacy of pitavastatin versus pravastatin in adults with HIV and dyslipidaemia.nnnMETHODSnIn the INTREPID (HIV-infected patieNts and TREatment with PItavastatin vs pravastatin for Dyslipidemia) randomised, double-blind, active-controlled, phase 4 trial (INTREPID, we recruited adults aged 18-70 years with controlled HIV (with CD4 counts >200 cells per μL and HIV-1 RNA <200 copies per mL) on antiretroviral therapy for at least 6 months and dyslipidaemia (LDL cholesterol 3·4-5·7 mmol/L and triglycerides ≤4·5 mmol/L) from 45 sites in the USA and Puerto Rico. Patients being treated with darunavir, or who had homozygous familial hypercholesterolaemia or any condition causing secondary dyslipidaemia, or a history of statin intolerance, diabetes, or coronary artery disease were not eligible. We randomly assigned patients (1:1) to pitavastatin 4 mg or pravastatin 40 mg with matching placebos once daily orally for 12 weeks, followed by a 40 week safety extension. Randomisation was stratified by viral hepatitis B or C coinfection and computer-generated. Investigators, patients, study staff, and those assessing outcomes were masked to treatment group. The primary endpoint was percentage change in fasting serum LDL cholesterol from baseline to week 12 and the primary efficacy analysis was done in the modified intention-to-treat population. The safety analysis included all patients who took at least one dose of study medication. This study is registered with ClinicalTrials.gov, number NCT01301066.nnnFINDINGSnBetween Feb 23, 2011, and March 29, 2013, we randomly assigned 252 patients to the pitavastatin (n=126) or pravastatin group (n=126). LDL cholesterol reduction was 31·1% with pitavastatin and 20·9% with pravastatin (least squares mean difference -9·8%, 95% CI -13·8 to -5·9; p<0·0001) at 12 weeks. At week 52, four patients (3%) in the pitavastatin group and six (5%) in the pravastatin group had virological failure, with no significant difference between treatments. Both treatments had neutral effects on glucose metabolism parameters. 85 patients treated with pitavastatin (68%) and 88 patients treated with pravastatin (70%) reported treatment-emergent adverse events, and these caused study discontinuation in six patients (5%) versus five patients (4%). No serious adverse event occurred in more than one participant and none were treatment-related according to investigator assessment. The most common treatment-emergent adverse events were diarrhoea in the pitavastatin group (n=12, 10%) and upper respiratory tract infection in the pravastatin group (n=14, 11%). 11 treatment-emergent serious adverse events were noted in seven patients (6%) in the pitavastatin group (atrial septal defect, chronic obstructive pulmonary disease, chest pain, diverticulitis, enterovesical fistula, gastroenteritis, viral gastroenteritis, herpes dermatitis, multiple fractures, respiratory failure, and transient ischaemic attack) and four events in three patients (2%) in the pravastatin group (cerebrovascular accident, arteriosclerosis coronary artery, myocardial infraction, and muscle haemorrhage). In the pravastatin treatment group, one additional patient discontinued due to an adverse event (prostate cancer that was diagnosed during the screening period, 42 days before first dose of study treatment, and therefore was not a treatment-emergent adverse event).nnnINTERPRETATIONnThe INTREPID results support guideline recommendations for pitavastatin as a preferred drug in the treatment of dyslipidaemia in people with HIV.nnnFUNDINGnKowa Pharmaceuticals America and Eli Lilly and Company.

PITAVASTATIN 4 MG PROVIDES SIGNIFICANTLY GREATER REDUCTION IN LDL-C COMPARED TO PRAVASTATIN 40 MG WITH NEUTRAL EFFECTS ON GLUCOSE METABOLISM: PRESPECIFIED SAFETY ANALYSIS FROM THE SHORT-TERM PHASE 4 PREVAIL US TRIAL IN PATIENTS WITH PRIMARY HYPERLIPIDEMIA OR MIXED DYSLIPIDEMIA

Recent studies showed that some statins may impair glucose metabolism. In a reanalysis of WOSCOPS, individual risk of diabetes with pravastatin was reported as null. Limited information is available on the glycemic effect of a recently approved statin, pitavastatin. The objective of this

Metabolic syndrome is associated with muscle symptoms among statin users

BACKGROUNDnMuscle symptoms have been associated with statin use, but the relationship of statin-associated muscle symptoms with metabolic syndrome (MS) has not been reported previously.nnnOBJECTIVEnTo evaluate the relationships between MS and its individual components with statin-associated muscle symptoms.nnnMETHODSnData were analyzed from the Understanding Statin Use in America and Gaps in Education (USAGE) study. Modified criteria to define the MS were used based on self-reported survey data.nnnRESULTSnAmong USAGE subjects, the MS was present in 1364 of 3992 men (34.2%) and in 1716 women of 6149 women (27.9%). Subjects with the MS were 19% more likely (Pxa0=xa0.0002) to report new or worsening muscle symptoms while on a statin. Three MS criteria-increased BMI, elevated triglycerides (TG), and low high-density lipoprotein cholesterol (HDL-C)-were associated with increased odds of muscle symptoms, by 18%, 32%, and 28%, respectively (all Pxa0<xa0.001). The presence of MS also predicted increased odds of having discontinued a statin due to muscle symptoms (13% higher, Pxa0=xa0.043). Among criteria for the MS, elevated TG (38% higher odds, Pxa0<xa0.0001) and low HDL-C (37% higher odds, Pxa0=xa0.0003) were positively associated with statin discontinuation, whereas hypertension (13% lower odds, Pxa0=xa0.019) and diabetes mellitus (12% lower odds, Pxa0=xa0.036) were inversely associated.nnnCONCLUSIONnUSAGE participants with MS were more likely to report experiencing muscle symptoms while taking a statin and to have discontinued a statin due to muscle symptoms. This appears to be attributable mainly to associations of muscle symptoms with elevated TG and low HDL-C levels. Additional research is warranted to confirm and further investigate these associations.

Steady-State Pharmacokinetics of Darunavir/Ritonavir and Pitavastatin when Co-administered to Healthy Adult Volunteers

BackgroundThe 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.ObjectivesThe 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.MethodsThis 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 90xa0% 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 (AUC0–τ)] and for peak exposure [i.e. the maximum plasma concentration (Cmax)] of the two treatments were within the 80–125xa0% range.ResultsTwenty-eight subjects (mean age 30.5xa0years) were enrolled, and pharmacokinetic data were available for 27 subjects. For pitavastatin, the GMRs and 90xa0% CIs for the AUC0–τ and Cmax 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 90xa0% CIs for the AUC0–τ and Cmax ratios were within 80–125xa0% with pitavastatin co-administration. No significant safety issues were reported.ConclusionDarunavir/ritonavir decreased total exposure to pitavastatin by 26xa0%, while peak exposures were similar. Pitavastatin did not influence the pharmacokinetics of darunavir or ritonavir. There is limited interaction between pitavastatin and darunavir/ritonavir.

Pitavastatin 4 mg Provides Significantly Greater Reduction in Remnant Lipoprotein Cholesterol Compared with Pravastatin 40 mg: Results from the Short-term Phase IV PREVAIL US Trial in Patients with Primary Hyperlipidemia or Mixed Dyslipidemia

PURPOSEnRemnants are partially hydrolyzed, triglyceride-rich lipoproteins that are implicated in atherosclerosis. We assessed the adequacy of pitavastatin 4 mg and pravastatin 40 mg in reducing atherogenic lipid parameters beyond LDL-C, in particular remnant lipoprotein cholesterol (RLP-C).nnnMETHODSnFrom the Phase IV, multicenter, randomized, double-blind PREVAIL US (A Study of Pitavastatin 4 mg Vs. Pravastatin 40 mg in Patients With Primary Hyperlipidemia or Mixed Dyslipidemia) trial, we examined lipoprotein cholesterol subfractions using Vertical Auto Profile testing and apolipoproteins B and A-I at baseline and 12 weeks. Participants with primary hyperlipidemia or mixed dyslipidemia had LDL-C levels of 130 to 220 mg/dL and triglyceride levels ≤ 400 mg/dL. In this post hoc analysis, changes in lipid parameters were compared by using ANCOVA.nnnFINDINGSnLipoprotein subfraction data were available in 312 patients (pitavastatin, n = 157; pravastatin, n = 155). Pitavastatin promoted a greater reduction in RLP-C than pravastatin (-13.6 [8.7] vs -9.3 [9.5] mg/dL). Furthermore, the pitavastatin group reported greater reductions in both components of RLP-C (both, P < 0.001): intermediate-density lipoprotein cholesterol (-9.5 [6.3] vs -6.4 [6.6] mg/dL) and very low-density lipoprotein cholesterol subfraction 3 (-4.1 [3.5] vs -2.9 [3.8] mg/dL). There were also greater reductions in the major ratios of risk (apolipoprotein B/apolipoprotein A-I and total cholesterol/HDL-C) (both, P < 0.001). There were no significant changes in HDL-C, its subfractions, or natural log lipoprotein(a)-cholesterol. The mean age was 58.8 ± 8.9 years in the pitavastatin group and 57.0 ± 10.2 years in the pravastatin group.nnnIMPLICATIONSnCompared with pravastatin 40 mg daily, pitavastatin 4 mg provided superior reductions in atherogenic lipid parameters beyond LDL-C, including RLP-C. Future studies are needed investigate the clinical implications of lowering directly measured RLP-C as the principal target. ClinicalTrials.gov identifier: NCT01256476.

SHORT-TERM AND LONG-TERM EFFECTS OF PITAVASTATIN AND SIMVASTATIN ON FASTING PLASMA GLUCOSE IN PATIENTS WITH PRIMARY HYPERLIPIDEMIA OR MIXED DYSLIPIDEMIA AND ≥2 RISK FACTORS FOR CORONARY HEART DISEASE

Recent meta-analyses showed deterioration of glucose metabolism following administration of statins. Limited information is available on the glycemic effect of a recently approved statin, pitavastatin (PTA). In Phase 3 non-inferiority trials, LDL-C reductions with PTA 2 mg and 4 mg were comparable

Greater remnant lipoprotein cholesterol reduction with pitavastatin compared to pravastatin in HIV-infected patients: The INTREPID trial

Objective: Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in those with HIV. An emerging CVD risk factor is triglyceride-rich remnant lipoprotein cholesterol (RLP-C: the sum of intermediate-density lipoprotein and very low-density lipoprotein cholesterol). The effects of statin therapy on lipoprotein subfractions, including RLP-C, in HIV dyslipidemia are unknown. Methods: This is a post hoc analysis of the randomized INTREPID trial (NCT 01301066) comparing pitavastatin 4u200amg daily vs. pravastatin 40u200amg daily in study participants with HIV. We measured apolipoproteins AI and B and lipoprotein cholesterol subfractions separated by density gradient ultracentrifugation at baseline and 12u200aweeks. We compared changes in atherogenic subfractions over 12 weeks in INTREPID participants using analysis of covariance. Results: Lipoprotein subfraction data were available for 213 study participants (pitavastatin nu200a=u200a104, pravastatin nu200a=u200a109). Baseline characteristics were similar between treatment groups. Reductions in RLP-C were significantly greater in the pitavastatin group compared with pravastatin group (−11.6u200amg/dl vs. −8.5u200amg/dl; Pu200a=u200a0.01). Similarly, ratios of risk [apolipoproteins B/apolipoproteins AI, total cholesterol/high-density lipoprotein cholesterol (HDL-C)] showed greater reductions with pitavastatin (Pu200a<u200a0.05). There were no differences in changes in HDL-C, HDL-C subfractions or lipoprotein(a) cholesterol levels. Conclusion: In patients with HIV, pitavastatin 4u200amg/dl lowered both RLP-C and established apolipoprotein and lipid risk ratios more so than pravastatin 40u200amg/dl. The impact of RLP-C reduction on CVD in HIV dyslipidemic patients merits further study.