Coadministration Therapy Research Articles

Pharmacokinetic Drug-Drug Interactions Involving Antiretroviral Agents: An Update.

Antiretroviral therapy is the recognized treatment for human immunodeficiency virus (HIV) infection involving several antiviral agents. Even though highly active antiretroviral therapy has been proven to be very effective in suppressing HIV replication, the antiretroviral drugs, belonging to different pharmacological classes, present quite complex pharmacokinetic properties such as extensive drug metabolism and transport by membrane-associated drug carriers. Moreover, due to uncomplications or complications in HIV-infected populations, an antiretroviralbased multiple-drug coadministration therapy strategy is usually applied for treatment effect, thus raising the possibility of drug-drug interactions between antiretroviral drugs and common drugs such as opioids, stains, and hormonal contraceptives. Herein, thirteen classical antiretroviral drugs approved by US Food and Drug Administration were summarized. Besides, relative drug metabolism enzymes and transporters known to interact with those antiretroviral drugs were detailed and described. Furthermore, one after the summarized antiretroviral drugs, the drug-drug interactions between two antiretroviral drugs or antiretroviral drug - conventional medical drugs of the past decade were discussed and summarized. This review is intended to deepen the pharmacological understanding of antiretroviral drugs and promote more secure clinical applications for antiretroviral drugs to treat HIV.

Phase I Targeted Combination Trial of Sorafenib and GW5074 in Patients with Advanced Refractory Solid Tumors.

Background: Combination therapy with the administration of GW5074 and sorafenib significantly induced necrotic death in various cancer cells in vivo, as well as prolonging the survival of an animal disease model due to significant suppression of the primary and metastatic lesions. We sought to determine the safety, tolerability, pharmacokinetics, and anti-tumor activity of this co-administration therapy in patients with refractory advanced solid cancers. Methods: Twelve patients were enrolled. Eligible subjects received different dosages of GW5074 in one of the three dose cohorts (Cohort 1: 750 mg daily, Cohort 2: 1500 mg daily, Cohort 3: 750 mg twice daily) plus 200 mg of sorafenib daily to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) at phase 1. Furthermore, the expression level of phosphorylated DAPKS308 in primary tumor, metastatic tumor, and circulating tumor cells (CTC) were evaluated to investigate the relationship between biomarker and the efficacy profile. Results: Among the 12 enrolled patients in this phase 1 trial, most adverse effects (AE) were grade 1, with two being grade 3. The most frequent AE of all grades were weight loss and hypertension, occurring in 16.7% of participants. Eight patients (66.7%) had the disease controlled by receiving co-administration therapy of GW5074 and sorafenib. GW5074 was found to have poor absorption, as increasing the dosage did not result in a significant increase in the bioavailability of GW5074 in subjects. Furthermore, the expression level of phosphorylated DAPKS308 in tumor and CTCs were correlated with the disease control rate (DCR) and duration of response (DOR). Conclusions: Co-administration therapy of GW5074 and sorafenib demonstrated a favorable safety profile and showed anti-tumor activity in a variety of tumor types. However, the solubility of GW5074 is not satisfactory. A future phase 2a trial will be carried out using the new salted form that has been proven to be more effective.

Clinical and Laboratory Patterns of Multisystem Inflammatory Syndrome in Children Related to Coronavirus Disease 2019 in the West of Iran

Background: Multisystem inflammatory syndrome in children (MIS-C) was first warned by the National Health Service in England following coronavirus disease 2019 (COVID-19) pandemic. Objectives: We aimed to evaluate the clinical and laboratory findings of MIS-C to be used for timely diagnosis and preventing possible complications. Methods: This descriptive study was conducted on 47 patients under 21 years old diagnosed with MIS-C. Results: We found that 25 (53.2%) patients were male, and the median age of participants was 5.58 years. The most common clinical manifestations were fever, rash, conjunctival injection, mucous membrane changes, periorbital edema, gastrointestinal symptoms, respiratory distress, tachycardia, and swollen hands and feet. C-reactive protein and erythrocyte sedimentation rate were elevated in 85 and 45.5% of cases at presentation, respectively. Chest X-ray (CXR) was performed for all cases, and a computed tomography (CT) scan was carried out for patients with severe pulmonary symptoms or abnormal CXR. The results of most CT scans were normal. Decreased myocardial function in echocardiography was detected in more than half of the cases. All patients received intravenous immunoglobulins, and more than 90% received steroids as co-administration therapy or second-line treatment. Conclusions: According to our findings, simultaneous fever, diarrhea, vomiting, and limb or periorbital edema is a key feature for MIS-C diagnosis. Moreover, the evidence of COVID-19 should be assessed in suspected cases of toxic shock syndrome or Kawasaki disease due to highly similar manifestations of these two diseases with MIS-C secondary to COVID-19.

Review on Arakoda (Tafenoquine) and its approach as an Anti-Malarial Agent.

Tafenoquine is an analogue of primaquine with an improved therapeutic and safety profile. It has a long half-life and activity against liver-stage malaria parasites, so may be useful for chemoprophylaxis. Antimalarial agents are drugs used for the treatment or prophylaxis of malaria. Malaria is caused by four species of Plasmodium, such as Plasmodium falciparum, P. malariae, P. ovale, and P. vivax. Arakoda contains tafenoquine succinate, an antimalarial agent for oral administration. The molecular formula of tafenoquine succinate is C24H28F3N3O3∙C4H6O4 and its molecular weight is 581.6 as the succinate salt. It is given in prophylaxis of malaria patient aged 18 years older. Tafenoquine is active against pre-erythrocytic (liver) and erythrocytic (asexual) forms as well as gametocytes of Plasmodium species. G6PD test is performed before giving the drug. Analytical studies were on NMR, IR, MS, HPLC, Flourimetry analysis. In vitro studies have shown that tafenoquine presents an average 50% inhibitory concentration of 0.436mcg against blood stages of seven strains of P. falciparum. The long‐acting 8‐aminoquinoline tafenoquine (TQ) co-administered with chloroquine (CQ) may radically cure Plasmodium vivax malaria. Coadministration therapy was evaluated for a pharmacokinetic interaction and for pharmacodynamic, safety and tolerability characteristics. Volume of distribution. The activation of tafenoquine needs the activity of CYP 2D6 liver microsomal enzyme. Routes of elimination are through feces.

Clinical predictors of the use of co-administration therapy with ezetimibe in patients with chronic ischemic heart disease

Background and Aims: Statins are the lipid lowering treatment of choice for hyperlipidemia. Combination therapy with ezetimibe should be used in situations where LDL-c objectives cannot be achieved.

Synergistic effect of the pro-apoptosis peptide kla-TAT and the cationic anticancer peptide HPRP-A1.

In this study, a peptide-peptide co-administration therapy between hybrid peptide kla-TAT and cationic anticancer peptide HPRP-A1 was designed to increase the anticancer activity of the combination peptides through synergistic effect. kla is a pro-apoptotic peptide which could induce rapid cancer cell apoptosis by disruption the mitochondrial membrane when internalized the cells. To enhance more kla peptides pass through cell membrane, a double improvement strategy was designed by chemically conjugation with cell penetration peptide TAT as well as co-administration with cationic membrane active peptide HPRP-A1, and the double anticancer mechanism of the kla-TAT peptide and HPRP-A1 including membrane disruption and apoptosis induction was verified through in vitro experiments. The CompuSyn synergism/antagonism analysis showed that kla-TAT acted synergistically with HPRP-A1 against a non-small cell lung cancer (NSCLC) A549 cell line. The anticancer activities of the two peptides were dramatically increased by co-administration, under the mechanism of cell membrane disruption, caspase-dependent apoptosis induction, as well as cyclin-D1 down-regulation based G1 phase arrest. We believe that the synergic therapeutic strategy would be a meaningful method for the anticancer peptides used in cancer treatment.

Immunosuppressive Agents for the Treatment of Primary Sclerosing Cholangitis: A Systematic Review and Meta-Analysis

Objectives: Currently, there are no effective therapeutic agents for patients with primary sclerosing cholangitis (PSC). This study aimed to evaluate the safety and efficiency of immunosuppressive agents (IAs) for the treatment of PSC. Methods: The literatures were searched using the following keywords singly or in combination: PSC, treatments, IAs. The primary outcome was defined as the need for liver transplantation or mortality. Results: Two hundred sixty six patients from 7 eligible studies were analyzed. IAs had no remarkable effects on the rate of mortality or liver transplantation (relative risk, RR 1.02, 95% CI 0.58-1.62, p = 0.92). Subgroup analyses showed no significant effect of IAs co-administration therapy (IAs co-administered with ursodeoxycholic acid, IA co-administered with IA; RR 1.41, 95% CI 0.40-4.95, p = 0.60). IAs caused adverse events (AEs) such as diarrhea, abdominal pain, and pruritus (RR 1.81, 95% CI 1.07-3.07, p = 0.03). IAs therapy did not significantly improve markers of liver function except for aspartate transaminase (weighted mean difference -9.76, 95% CI -12.92 to -6.6, p < 0.001). Conclusion: IAs administrated as either monotherapy or combination therapy do not reduce the risk of mortality or liver transplantation. IAs monotherapy is associated with AEs.

LHD-Modified Mechanism-Based Liposome Coencapsulation of Mitoxantrone and Prednisolone Using Novel Lipid Bilayer Fusion for Tissue-Specific Colocalization and Synergistic Antitumor Effects.

Coencapsulation liposomes are of interest to researchers because they maximize the synergistic effect of loaded drugs. A combination regimen of mitoxantrone (MTO) and prednisolone (PLP) has been ideal for tumor therapy. MTO and PLP offer synergistic antitumor effects confirmed by several experiments in this research. The deduced synergistic mechanism is regulation of Akt signaling pathway including the targets of p-Akt, p-GSK-3β, p-s6 ribosomal protein, and p-AMPK by MTO reactivating PLP-induced apoptosis. The liposome fusion method is adopted to create coencapsulation liposomes (PLP-MTO-YM). Low molecular weight heparin-sodium deoxycholate conjugate (LHD) then is used as a targeting ligand to prove target binding and inhibition of angiogenesis. LHD-modified liposomes (PLP-MTO-HM) have a high entrapment efficiency around 95% for both MTO and PLP. DSC results indicate that both drugs interacted with liposomes to prevent drug leak during liposome fusion. DiD-C6-HM dyes colocalize well to tumor tissue, and coadministration of DiD-HM and C6-CM did not achieve dye colocalization until 24 h after administration. In both CT26 and B16F10 mouse model, PLP-MTO-HM shows a significantly higher tumor inhibition rate relative to the coadministration of MTO-HM and PLP-CM (p < 0.05 or p < 0.01). Thus, the coencapsulation system (PLP-MTO-HM) offers ideal antitumor effects relative to coadministration therapy due to enhanced synergistic effect, and this suggests a promising future for the tumor targeting vectors.

Pharmacokinetic interactions and safety evaluations of coadministered tafenoquine and chloroquine in healthy subjects

The long-acting 8-aminoquinoline tafenoquine (TQ) coadministered with chloroquine (CQ) may radically cure Plasmodium vivax malaria. Coadministration therapy was evaluated for a pharmacokinetic interaction and for pharmacodynamic, safety and tolerability characteristics. Healthy subjects, 18-55 years old, without documented glucose-6-phosphate dehydrogenase deficiency, received CQ alone (days 1-2, 600 mg; and day 3, 300 mg), TQ alone (days 2 and 3, 450 mg) or coadministration therapy (day 1, CQ 600 mg; day 2, CQ 600 mg + TQ 450 mg; and day 3, CQ 300 mg + TQ 450 mg) in a randomized, double-blind, parallel-group study. Blood samples for pharmacokinetic and pharmacodynamic analyses and safety data, including electrocardiograms, were collected for 56 days. The coadministration of CQ + TQ had no effect on TQ AUC0-t , AUC0-∞ , Tmax or t1/2 . The 90% confidence intervals of CQ + TQ vs. TQ for AUC0-t , AUC0-∞ and t1/2 indicated no drug interaction. On day 2 of CQ + TQ coadministration, TQ Cmax and AUC0-24 increased by 38% (90% confidence interval 1.27, 1.64) and 24% (90% confidence interval 1.04, 1.46), respectively. The pharmacokinetics of CQ and its primary metabolite desethylchloroquine were not affected by TQ. Coadministration had no clinically significant effect on QT intervals and was well tolerated. No clinically significant safety or pharmacokinetic/pharmacodynamic interactions were observed with coadministered CQ and TQ in healthy subjects.

Pharmacokinetic Interactions of Valsartan and Hydrochlorothiazide: An Open-Label, Randomized, 4-Period Crossover Study in Healthy Egyptian Male Volunteers

BackgroundCo-administration of valsartan (VAL) and hydrochlorothiazide (HCT) has been used to regulate blood pressure. Compliance with a multiple medication regimen can be difficult for some patients; therefore, a combination of VAL + HCT tablets may be a suitable alternative. ObjectiveThis study was conducted to compare the rate and extent of absorption of VAL and HCT after oral administration as a fixed-dose combination (FDC) tablet and concomitant administration of the individual drugs under fasting conditions in healthy Egyptian subjects. The study was extended to investigate any potential interaction between VAL and HCT. MethodsThis study was conducted as an open-label, randomized study with 2 parts (parts I and II), with each part consisting of 4 single-dose treatment periods with a crossover design and 2-week washout periods. Blood samples were collected up to 48 hours postdose, and plasma was analyzed for VAL and HCT concentrations by using HPLC. The pharmacokinetic properties of each drug after co-administration of VAL and HCT were compared with those of each drug administered alone. Tolerability was assessed by physical examination and verbally questioning subjects regarding their well-being and any feelings of discomfort. All events reported by the subjects were recorded in adverse-event forms. ResultsForty-eight healthy subjects were enrolled (24 in each part), and all subjects completed the study. None of the participants showed any sign of adverse drug reactions during or after the completion of the study. Statistical analysis confirmed that the 90% CIs for AUC and Cmax of VAL/HCT FDC and VAL + HCT were within the commonly accepted bioequivalence range of 0.8 to 1.25. As a result, from an in vivo pharmacokinetic perspective, 1 FDC tablet could be considered interchangeable in medical practice with the 2 individual reference tablets. However, the 90% CIs between VAL alone and when administered with HCT, either as FDC or concomitantly, indicated the presence of an interaction between VAL and HCT, which would significantly decrease the systemic exposure and intensity of VAL absorption. The co-administration of HCT with VAL decreased the AUC and Cmax of HCT nonsignificantly compared with administration of HCT alone. ConclusionsBoth VAL/HCT FDC and VAL + HCT were well tolerated. The safety/efficacy profile of VAL + HCT co-administration therapy could be extended to the VAL/HCT FDC tablet. The interaction of HCT with other angiotensin-receptor blockers should be investigated to determine whether this interaction is limited to VAL or if other angiotensin-receptor blockers have the same pharmacokinetic interactions. Further studies are necessary to determine the role of efflux and influx transporters on VAL and HCT disposition and pharmacokinetics.

Cognitive effects of diphenyl diselenide and estradiol treatments in ovariectomized mice

This study investigated the effects of co-administration of diphenyl diselenide [(PhSe)2] and 17β-estradiol (E2) on spatial reference, recognition, and working memories in ovariectomized (OVX) female mice. Sixty-day-old female adult Swiss mice were submitted to ovariectomy. From the 30th until 32nd day after ovariectomy, different doses of (PhSe)2 (0.5–10mg/kg p.o.) were administrated to OVX mice 30min before each training of Morris Water Maze (MWM) test in order to find the highest subeffective dose for this drug. After that, OVX mice were divided into four groups: Oil, (PhSe)2, E2, and (PhSe)2+E2. (PhSe)2 (0.5mg/kg) and E2 (0.1mg/kg) were administered to OVX mice from 30th to 32nd day after surgery, 30min before the training phases of behavioral tests (Open Field, MWM, Object Recognition, and T-maze). Our results demonstrated that 0.5mg/kg (PhSe)2 plus 0.1mg/kg E2 combined treatment improved spatial memory in the MWM test. By contrast, this same co-administration therapy was not effective in ameliorating neither delayed spontaneous alternation in the T-maze test nor object recognition memory deficits in OVX mice, although the dose of 0.5mg/kg (PhSe)2 enhanced per se the object recognition memory in OVX mice. In conclusion, the current behavioral data suggest that a combination of (PhSe)2 plus E2 treatment seems to be a promising alternative to treat the cognitive decline related to menopause. Further studies should be conducted in order to determine an effective dose for (PhSe)2 plus E2 therapy on Object Recognition and T-maze tests.

Co-Administration Therapy Modulates Immunity to FVIII In Hemophilia A Mice

Abstract 1219Our long-term objective is the development of novel therapies for the safe and effective treatment of hemophilia. In particular a safe and economic prophylactic modality to prevent inhibitors development is therefore highly desirable. To this end we have explored strategies to modulate inhibitor development based on the co-administration of FVIII with other proteins, specifically albumin and IVIG. We hypothesise that such co-administration may modulate immunity to FVIII and result in a safe and cost-effective therapy. Based on some published evidence that FIX and vWF may have a modulatory effect on FVIII, we reasoned that perhaps albumin might also play an immunomodulatory effect on FVIII. We have developed a protocol for infusing recombinant FVIII in hemophilia A mice modelled on the current therapy of hemophiliacs, and in response to this protocol hemophilia mice develop high titre of inhibitors. Thus, this model can be used to assess potential immununomodulatory strategies.Groups of hemophilia A mice (n=5) were infused weekly IV with 2IU rFVIII for a total of 4 weeks. Three of these groups of mice were also administered human albumin (either 25mg IV, 25mg IP, or 500mg IV) at the same time as FVIII. Mice were bled before the treatment and weekly for the 4 weeks, and total antibodies to FVIII were detected by ELISA. Importantly, while mice receiving FVIII had high antibody titer and were in good health, there was significant mortality in the mice treated with FVIII and albumin. Interestingly, the surviving mice had a very low antibody titre, statistically significant from mice receiving only rFVIII.Given the mortality, another experiment was designed to test the effect of reduced doses of albumin. Groups of hemophilia A mice (n=5) were infused IV with a weekly injection of 2IU rFVIII for a total of 4 weeks supplemented with either 25μg, 50μg or 100μg of human albumin. Mice were bled at weekly intervals until the end of the experiment (day 28), and the titre of anti-FVIIII antibodies was determined. Most All mice survived the entire treatment and were found in good health. Further, the FVIII antibody titre in the group that received albumin was detectable, but significantly reduced with respect to the mice that received only FVIII. Marked variability among individual mice was observed.A group of hemophilia A mice (n=5) received weekly IP injections of 2IU rFVIII. Another group of mice received the same regimen of FVIII in addition to human IVIG (1g/kg). A third group of hemophilia mice received 2IU rFVIII and a higher dose of human IVIG (2g/kg). These doses mimic the established human IVIG regimen. Mice were bled before treatment and at weekly intervals thereafter. The titre of anti-FVIII antibodies in mice was determined by ELISA. By day 21, the antibody titre in mice injected with FVIII was high, as expected. In contrast, the titre in mice receiving FVIII and IVIG was low, and comparable to that of all the mice prior to the treatment (na•ve mice), strongly suggesting an immune modulatory effect by IVIG (Figure 1). Our data supports the limited use of IVIG to treat inhibitors. [Display omitted] Our findings suggest that co-administration of FVIII with albumin and IVIG can modulate the humoral immune response to recombinant human FVIII in hemophilia mice. Further, the observed effect appears to be dependent on the dose of albumin co-administered. It is hypothesized that the observed modulation is due to antigen competition, as previously speculated. Importantly, while IVIG was well tolerated by mice, very serious adverse effects were observed in mice treated with high doses of albumin. Interestingly, even the high dose used represents a small fraction of the physiological levels of albumin in human plasma, which is 3–5 g/dL. IVIG, in contrast, is a known modulator of the immune response in humans, and the study of this modulatory effect in a hemophilia mouse may lead to novel therapeutic strategies, relevant for the management of hemophilia. Disclosures:No relevant conflicts of interest to declare.

In vivo and In vitro Drug Interactions Study of Glimepride with Atorvastatin and Rosuvastatin

Aim of this investigation was to study the in vivo and in vitro drug interaction of glimepride with atorvastatin and rosuvastatin. In vitro drug interaction of glimepride with atorvastatin and rosuvastatin was studied using human pooled liver microsomes and evaluated using high performance liquid chromatography. In vivo pharmacokinetic drug interaction of glimepride (6 mg/kg) in coadministration with atorvastatin (60 mg/kg) and rosuvastatin (60 mg/kg) were studied in rats and analyzed using liquid chromatography tandem mass spectrometry (LC–MS/MS). In in vitro study, atorvastatin decreased its own metabolism as well as the metabolism of glimepiride. Rosuvastatin coadministration with glimepride reduced the metabolism of glimepride and increased the metabolism of its own. In in vivo study, concentration in plasma, Cmax, AUC(0–t) and AUC(0–∞) (area under the concentration-time curve, AUC) of glimepride was increased significantly in coadministration with atorvastatin whereas there was no significant change was observed in the case of coadministration with rosuvastatin. Half life (T1/2) and volume of distribution (Vd) of glimepride decreased significantly with both atorvastatin and rosuvastatin. Elimination rate constant, Kel of glimepride increased significantly with both atorvastatin and rosuvastatin. Clearance (Cl) of glimepride decreased significantly but the decrease was more with atorvastatin than with rosuvastatin. It is concluded that glimepride metabolism is little affected by rosuvastatin in vitro, which agreed with the negligible interaction in in vivo study. Thus, from safety point of view rosuvastatin is better to prescribe as a coadministration therapy with glimepiride. On the other hand, atorvastatin could cause an increase in the bioavailability of glimepride per oral and also significantly decrease the metabolism of glimerpride in in vitro study. This may pose a positive implication in clinical practice.

Long-term (48-week) safety of ezetimibe 10 mg/day coadministered with simvastatin compared to simvastatin alone in patients with primary hypercholesterolemia

ABSTRACTObjective: This study evaluated the long-term safety and tolerability of ezetimibe/simvastatin coadministration therapy compared to simvastatin monotherapy in patients with primary hypercholesterolemia.Research design and methods: After completing a 12-week randomized, double-blind, placebo-controlled, factorial, 10-armed study comparing ezetimibe 10 mg/simvastatin 10, 20, 40, or 80 mg; simvastatin 10, 20, 40, or 80 mg; ezetimibe 10 mg; or placebo, 768 patients entered a 48-week extension, with randomized, blinded, reassignment of the simvastatin 10 mg, ezetimibe, and placebo groups to one of the ezetimibe/simvastatin groups. Patients previously receiving ezetimibe/simvastatin combination therapy, or simvastatin 20, 40, and 80 mg monotherapy continued the same therapies in this 7-arm extension study. During the extension study, investigators assessed adverse events (AEs).Main outcome measures and results: Ezetimibe/simvastatin (n = 539) and simvastatin monotherapy (n = 229) groups generally had a similar incidence of all clinical AEs (73 vs. 69%), treatment-related AEs (14 vs. 11%), clinical serious AEs (SAE) (5.2 vs. 2.6%), treatment-related SAEs (0.2 vs. 0%), discontinuations due to all clinical AEs (4.5 vs. 2.6%) and discontinuations due to treatment-related AEs (2.8 vs. 2.2%), respectively. The incidence of total laboratory-related AEs for the ezetimibe/simvastatin and simvastatin monotherapy groups was also similar (12.2 vs. 11.9%), as was treatment-related laboratory AEs (6.2 vs. 5.3%), laboratory SAEs (0 vs. 0%), treatment-related laboratory SAEs (0 vs. 0%), discontinuations due to laboratory AEs (3.0 vs. 0.9%) and discontinuations due to treatment-related laboratory AEs (3.0 vs. 0.4%), respectively. There were no cases of myopathy, rhabdomyolysis, or serious hepatotoxicity observed in any group during this extension study.Conclusions: During this 48-week extension study, the coadministration of ezetimibe/simvastatin was generally as well tolerated as simvastatin monotherapy. The direct application of study observations to clinical practice is limited by patient selection criteria and dosage regime, which randomly applied relatively high doses rather than titration which often occurs in clinical practice.

Bioequivalence of an ezetimibe/simvastatin combination tablet and coadministration of ezetimibe and simvastatin as separate tablets in healthy subjects

To assess the bioequivalence of an ezetimibe/simvastatin (EZE/SIMVA) combination tablet compared to the coadministration of ezetimibe and simvastatin as separate tablets (EZE + SIMVA). In this open-label, randomized, 2-part, 2-period crossover study, 96 healthy subjects were randomly assigned to participate in each part of the study (Part I or II), with each part consisting of 2 single-dose treatment periods separated by a 14-day washout. Part I consisted of Treatments A (EZE 10 mg + SIMVA 10 mg) and B (EZE/SIMVA 10/10 mg/mg) and Part II consisted of Treatments C (EZE 10 mg + SIMVA 80 mg) and D (EZE/SIMVA 10/80 mg/mg). Blood samples were collected up to 96 hours post-dose for determination of ezetimibe, total ezetimibe (ezetimibe + ezetimibe glucuronide), simvastatin and simvastatin acid (the most prevalent active metabolite of simvastatin) concentrations. Ezetimibe and simvastatin acid AUC(0-last) were predefined as primary endpoints and ezetimibe and simvastatin acid Cmax were secondary endpoints. Bioequivalence was achieved if 90% confidence intervals (CI) for the geometric mean ratios (GMR) (single tablet/coadministration) of AUC(0-last) and Cmax fell within prespecified bounds of (0.80, 1.25). The GMRs of the AUC(0-last) and Cmax for ezetimibe and simvastatin acid fell within the bioequivalence limits (0.80, 1.25). EZE/ SIMVA and EZE + SIMVA were generally well tolerated. The lowest and highest dosage strengths of EZE/SIMVA tablet were bioequivalent to the individual drug components administered together. Given the exact weight multiples of the EZE/SIMVA tablet and linear pharmacokinetics of simvastatin across the marketed dose range, bioequivalence of the intermediate tablet strengths (EZE/SIMVA 10/20 mg/mg and EZE/SIMVA 10/40 mg/mg) was inferred, although these dosages were not tested directly. These results indicate that the safety and efficacy profile of EZE + SIMVA coadministration therapy can be applied to treatment with the EZE/SIMVA tablet across the clinical dose range.

Effects of raloxifene and low-dose simvastatin coadministration on plasma lipids in postmenopausal women with primary hypercholesterolemia

Raloxifene and low-dose simvastatin can each reduce low-density lipoprotein (LDL) cholesterol without affecting high-density lipoprotein (HDL) cholesterol and triglycerides. The objective of this double-blind, 12-week study is to determine whether raloxifene and simvastatin coadministration gives added benefit beyond either monotherapy in affecting fasting lipoproteins and apolipoproteins. Ninety-five postmenopausal women with moderately elevated LDL cholesterol (mean, 146 mg/dL) were randomized to placebo, raloxifene 60 mg/d, simvastatin 10 mg/d, or raloxifene 60 mg/d coadministered with simvastatin 10 mg/d. Raloxifene, simvastatin, and coadministration therapy reduced mean LDL cholesterol by 10.5%, 23.3%, and 31.0% from baseline, respectively ( P < .003 vs baseline; P < .02 vs placebo), and mean apolipoprotein B by 10.4%, 24.2%, and 30.0% from baseline, respectively ( P < .003 vs baseline; P < .02 vs placebo). Each active treatment decreased non-HDL cholesterol compared with placebo ( P < .01). Coadministration treatment was more effective than either monotherapy in reducing LDL cholesterol ( P < .05). Coadministration treatment reduced mean apolipoprotein B ( P < .001) and non-HDL cholesterol ( P < .001) when compared with raloxifene, but was not significantly different when compared with simvastatin. Coadministration therapy increased HDL cholesterol and apolipoprotein A1 levels compared with placebo ( P < .02). No significant effect on triglycerides, very low density lipoprotein cholesterol, and lipoprotein (a) occurred with any active treatment. Raloxifene, simvastatin, and the coadministration therapy were generally well tolerated with clinical adverse effects similar to placebo. No woman had clinically significant elevated liver function tests requiring drug discontinuation. Further data on safety and lipid-lowering effects are needed before raloxifene and statin coadministration may be considered as therapeutic interventions for treating postmenopausal women to achieve National Cholesterol Education Program–Adult Treatment Panel III treatment guidelines.

Efficacy and safety of the coadministration of ezetimibe with fenofibrate in patients with mixed hyperlipidaemia

To examine the efficacy and safety of coadministered ezetimibe (EZE) with fenofibrate (FENO) in patients with mixed hyperlipidaemia. This was a multicentre, randomized, double-blind, placebo-controlled, parallel arm trial in patients with mixed hyperlipidaemia [LDL-cholesterol (LDL-C), 3.4-5.7 mmol/L (2.6-4.7 mmol/L for patients with type 2 diabetes); triglycerides (TG), 2.3-5.7 mmol/L] and no history of coronary heart disease (CHD), CHD-equivalent disease (except for type 2 diabetes), or CHD risk score>20%. A total of 625 patients was randomized in a 1:3:3:3 ratio to one of four daily treatments for 12 weeks: placebo; EZE 10 mg; FENO 160 mg; FENO 160 mg plus EZE 10 mg (FENO+EZE). The primary endpoint compared the LDL-C lowering efficacy of FENO+EZE vs. FENO alone. LDL-C, non-HDL-cholesterol (non-HDL-C), and apolipoprotein B were significantly (P<0.001) reduced with FENO+EZE when compared with FENO or EZE alone. TG levels were significantly decreased and HDL-C was significantly increased with FENO+EZE and FENO treatments when compared with placebo (P<0.001). Coadministration therapy reduced LDL-C by 20.4%, non-HDL-C by 30.4%, TG by 44.0%, and increased HDL-C by 19.0%. At baseline, >70% of all patients exhibited the small, dense LDL pattern B profile. A greater proportion of patients on FENO+EZE and FENO alone treatments shifted from a more atherogenic LDL size pattern to a larger, more buoyant, and less atherogenic LDL size pattern at study endpoint than those on placebo or EZE. All three active therapies were well tolerated. Coadministration of EZE with FENO provided a complementary efficacy therapy that improves the atherogenic lipid profile of patients with mixed hyperlipidaemia.

Effects of ezetimibe coadministered with simvastatin on C-reactive protein in a large cohort of hypercholesterolemic patients

Objective: This study assessed the effect of coadministration of ezetimibe and simvastatin on high sensitivity C-reactive protein (hs-CRP) in a large subject cohort ( N = 1089). Methods: Data were combined from two nearly identical prospective trials. After dietary stabilization, washout period, and placebo lead-in period, patients with baseline low-density lipoprotein cholesterol (LDL-C) ≥ 3.75–6.50 mmol/l and triglycerides (TG) ≤ 4.0 mmol/l were randomized to one of the following daily treatments for 12 weeks: ezetimibe 10 mg; simvastatin monotherapy (10, 20, 40, or 80 mg); ezetimibe 10 mg plus simvastatin (10, 20, 40, or 80 mg); or placebo. The primary analysis was the percent change in hs-CRP for the pooled ezetimibe plus simvastatin versus simvastatin monotherapy cohorts. Results: Ezetimibe coadministered with simvastatin more than doubled the hs-CRP reduction compared to simvastatin monotherapy (−33.3% versus −14.3%, p < 0.01). At each individual simvastatin dose level, coadministration therapy exerted significant further incremental hs-CRP reductions compared to simvastatin monotherapy. Similar hs-CRP reductions with coadministered ezetimibe and simvastatin were observed in the major subgroups examined (coronary heart disease, gender, age, baseline LDL-C, and body mass index). Conclusion: In this large subject cohort, ezetimibe coadministered with simvastatin significantly reduced hs-CRP, suggesting a possible additional anti-inflammatory/anti-atherosclerotic action of combination therapy compared to simvastatin monotherapy.

Pharmacokinetic interaction between ezetimibe and lovastatin in healthy volunteers*

SUMMARYBackground: Ezetimibe (Zetia†) is a novel inhibitor of intestinal absorption of cholesterol that is approved for the treatment of primary hypercholesterolemia. In a separate pilot study, co-administration of ezetimibe and lovastatin resulted in a significant pharmacodynamic interaction, leading to an additive reduction in LDL-C. The current study was designed to further investigate the potential for pharmacokinetic interaction between ezetimibe and lovastatin.Methods: This was a randomized, open-label, 3-way crossover study in 18 healthy adult volunteers. All subjects received the following treatments orally once daily for 7 days: ezetimibe 10 mg, lovastatin 20 mg, or ezetimibe 10 mg plus lovastatin 20 mg. Plasma samples obtained on day 7 were evaluated for steady-state pharmacokinetics of ezetimibe (unconjugated), total ezetimibe (ezetimibe and ezetimibe-glucuronide conjugate), lovastatin, and β-hydroxylovastatin.Results: Co-administration of ezetimibe with lovastatin did not affect the pharmacokinetics of ezetimibe. There were no significant differences in the exposure to total ezetimibe, ezetimibe-glucuronide and ezetimibe after co-administration with lovastatin vs. ezetimibe given alone. Co-administration of ezetimibe with lovastatin had no significant effect on the exposure to either lovastatin or β-hydroxylovastatin. The point estimates based on the log-transformed Cmax and AUC values for lovastatin and β-hydroxylovastatin were 113% and 119%, respectively, for co-administration of ezetimibe with lovastatin vs. lovastatin administration alone. Co-administration therapy with ezetimibe and lovastatin was safe and well tolerated.Conclusions: Ezetimibe did not significantly affect the pharmacokinetics of lovastatin or β-hydroxylovastatin and vice versa. Co-administration of ezetimibe and lovastatin is unlikely to cause a clinically significant pharmacokinetic drug interaction.

Pharmacodynamic and pharmaco-kinetic interaction between fenofibrate and ezetimibe*

SUMMARYObjective: The cholesterol absorption inhibitor, ezetimibe, significantly decreases low-density lipoprotein-cholesterol (LDL-C) levels in patients with primary hypercholesterolemia. The pharmacodynamic, pharmacokinetic, and safety profiles of ezetimibe and fenofibrate were evaluated alone and after co-administration in 32 subjects with primary hypercholesterolemia.Research design and methods: This was a randomized, evaluator (single)-blind, placebo-controlled, parallel-group study. Subjects with untreated LDL-C ≥ 130 mg/dL (3.37 mmol/L) were randomized to receive one of four oral treatments each morning for 14 days: fenofibrate 200 mg + ezetimibe 10 mg, fenofibrate 200 mg, ezetimibe 10 mg, or placebo. Serum lipids were assessed before drug administration on day 1, day 7, and day 14. Pharmacokinetic parameters were assessed on day 14.Main outcome measures: The primary pharmacodynamic parameter was percentage change from baseline in LDL-C concentration following co-administration of ezetimibe and fenofibrate vs either drug alone, or placebo. A secondary outcome was the potential for a pharmacokinetic interaction between ezetimibe and fenofibrate.Results: Ezetimibe and fenofibrate co-administration was well tolerated and produced statistically significant mean percentage reductions from baseline in LDL-C ( p ≤ 0.05 vs either drug alone or placebo), total cholesterol and triglycerides ( p ≤ 0.05 vs either fenofibrate or placebo), apolipoprotein C-III ( p ≤ 0.05 vs placebo), and LDL-III ( p ≤ 0.05 vs either drug alone or placebo). Ezetimibe did not significantly affect the pharmacokinetics of fenofibrate. Concomitant fenofibrate administration significantly increased the mean Cmax and AUC of total ezetimibe approximately 64% and 48%, respectively. However, based on the established safety profile and flat dose-response of ezetimibe, this effect is not considered to be clinically significant.Conclusion: Co-administration of ezetimibe and fenofibrate produced significantly greater reductions in LDL-C than either drug alone and greater reductions in triglycerides than fenofibrate. These effects were accompanied by improvements in the lipid/lipoprotein profile, suggesting that co-administration therapy with ezetimibe and fenofibrate may be an effective therapeutic option for patients with mixed dyslipidemia.