Effect of age and renal impairment on the pharmacokinetics and safety of trimetazidine: An open-label multiple-dose study.

This study evaluated the effect of age and renal impairment on pharmacokinetics of trimetazidine (TMZ) in healthy elderly and renally impaired subjects and assess safety and tolerability. In this open-label, multi-dose study, 73 subjects were divided into six treatment groups: (1) 55-65 years; (2) 66-75 years; (3) >75 years (dosing for groups 1-3 [healthy]: B.D. for 4 days), (4) mild renally impaired (dosed B.D. for 8 days); (5) moderate renally impaired (dosed O.D. for 8 days); and (6) severe renally impaired-no dialysis (dosed once every 48 h for 8 days). Blood and urine samples were collected and analyzed. The geometric least squares mean ratios for; Group 2 and 1 of AUC(0-τ)ss was 112.2 (90% CI; 92.0-136.8) and Cmax,ss was 109.9 (89.6-134.8), Group 3 and 1 of AUC(0-τ),ss was 140.5 (115.9-170.3) and Cmax,ss was 137.8 (112.9-168.2), Group 4 and 1 of AUC(0-τ),ss was 114.2 (90.3-144.4) and Cmax,ss was 120.8 (92.5-157.8), Group 5 and 1 of; AUC(0-τ),ss was 213.0 (153.1-296.3) and Cmax,ss was 123.3 (92.2-164.7) and Group 6 and 1 of AUC(0-τ),ss was 247.4 (197.8-309.6) and Cmax,ss was 95.6 (73.0-125.1). Significant increase in systemic exposure of TMZ was observed in subjects; over 75 year's age and renally impaired compared to healthy subjects. TMZ was safe and well-tolerated.

A drug utilization study to evaluate effectiveness of risk minimization measures for trimetazidine in France, Hungary, Romania and Spain.

WHAT IS KNOWN AND OBJECTIVE: The approved indication for trimetazidine (TMZ) was restricted to "add-on therapy for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled by or intolerant to first-line antianginal therapies" in 2012 by the Committee for Medicinal Products for Human Use (CHMP). TMZ was no longer indicated for ophthalmology and otolaryngology (ENT) indications. This drug utilization study analysed actual utilization of TMZ before and after the restriction on its indications to evaluate the effectiveness of risk minimization measures (RMM). METHODS: This was a multi-national, cross-sectional, non-interventional drug utilization study using European databases: IMS Prescribing Insights (PI) for France and Spain, National Diagnostic Index (NDI) for Romania and National Prescription Audit (NPA) for Hungary. TMZ prescriptions issued by Ear-Nose-Throat (ENT) specialists, ophthalmologists, cardiologists and General Physicians (GPs)/others were analysed during the 24-month period before (reference period) and after RMM implementation (assessment period). RESULTS AND DISCUSSION: During the assessment period, most of the TMZ prescriptions for ENT and ophthalmology indications (un-authorized indications) were made by GPs/others followed by ENT specialists, ophthalmologists and cardiologists in most of the countries. The proportion of TMZ prescriptions for ENT or ophthalmological indications after the restrictions on indication was reduced in Hungary (by 0.4%) and Spain (by 11.8%), remained the same in Romania and increased in France (by 3.7%). WHAT IS NEW AND CONCLUSION: This study showed that a significant proportion of TMZ prescriptions was off-label for ENT or ophthalmological indications following the RMM implementation. More effective RMM strategies are required to reduce off-label prescriptions of TMZ.

Evaluation of the effectiveness of risk minimization measures for trimetazidine: A cross sectional joint PASS survey among physicians in selected European countries.

PURPOSE: In 2012, the Committee for Medicinal Products for Human Use (CHMP) restricted prescription of trimetazidine (TMZ) to "add-on therapy for patients with stable angina pectoris who are inadequately controlled by or intolerant to first-line therapies." TMZ was no longer indicated for ophthalmology and otolaryngology. Risk minimization measure (RMM) was communicated to physicians. The survey presented here evaluated effectiveness of the RMM and assessed physicians knowledge and compliance with RMM. It also analyzed actual prescribing pattern of TMZ. METHODS: A cross sectional, web-based survey was developed and conducted among prescribing physicians of TMZ across 12 European countries. Physicians' samples were weighted to account for the actual proportion of specialties within and across countries. RESULTS: Using weighted samples, data from 1123 physicians and 8332 prescriptions were analyzed. Most (74.0%) of the physicians assumed stable angina pectoris to be an indication for TMZ. Three quarter of (75.7%) of these physicians were aware of the approved indication. Vertigo (62.1%), tinnitus (42.5%), declined visual acuity, and visual field disturbances (45.1%) were also presumed to be approved indications for TMZ, and physicians actually prescribed for these indications. Only 29.8% of the physicians remembered receiving RMM communications regarding TMZ. Most (90.5%) of the physicians expressed their interest to know and comply with the safety communications. Of all prescriptions, 33.9% were issued for add-on therapy for patients with stable angina pectoris. CONCLUSIONS: RMM for TMZ prescription have been moderately effective. Improvement in physician's compliance with safety information of TMZ is necessary for patient's safety.

Single Ascending Dose Study to Assess Pharmacokinetic Linearity, Safety, and Tolerability of Trimetazidine - Modified Release in Healthy Human Subjects.

AIM: This study assessed the linearity of pharmacokinetics (PK) of trimetazidine (TMZ) modified-release tablets (indicated in adults as an add-on therapy for stable angina pectoris) and measured its renal elimination, safety, and tolerability in healthy subjects. METHODS: This was a randomized, open-label, single-ascending dose study in healthy subjects. Subjects were administered with a single dose of 35, 70, or 105 mg TMZ-modified release tablets (six subjects each). Pharmacokinetic evaluations and safety analysis were performed before the first dose and till 48 h post-first dose. RESULTS: Following administration of 35, 70, and 105 mg TMZ-modified release; the Cmax (mean±SD) was 79.32 (±23.08), 153.17 (±23.08), and 199.67 (±23.08) ng/mL, the Tmax was 5.42 (±0.49), 4.51 (±1.27), and 4.57 (±0.96) h, t1/2 was 7.75 (±1.62), 6.40 (±1.23), and 6.50 (±1.18) h, AUC(0-inf) was 1116.89 (±378.35), 1838.39 (±284.50), and 2504.84 (±348.35) ng.h/mL, CLR was 13.70 (±2.24), 14.80 (±5.91), and 19.58 (±6.24) L·h-1 and CL/F was 33.69 (±8.51), 38.85 (±6.15), and 42.74 (±7.10) L·h-1, respectively. Slope estimates for AUC(0-inf), AUC(0-t), and Cmax were less than 1. Corresponding 95% CI of the slope for the AUC parameters excluded 1, indicating that the deviation from dose-proportionality was statistically significant. Corresponding 95% CI of the slope for Cmax included 1, indicating that the less than dose-proportional increase in Cmax was not statistically significant. No significant adverse events were observed. CONCLUSION: Substantial deviation from a dose-proportional increase in AUC(0-inf) and AUC(0-t) suggested a non-linear PK for TMZ-modified release. Single dose of TMZ-modified release was well tolerated and safe.

Use of antibiotic-impregnated bone grafts in a rabbit osteomyelitis model.

BACKGROUND: Both osteomyelitis and prosthetic joint infection can be treated surgically with the use of antibiotic loaded bone grafts, as part of local antimicrobial therapy. OBJECTIVE: The purpose of the study was to evaluate and to report on a novel, biodegradable, long-acting (4-6 weeks) antibiotic-impregnated bone graft (AIBG). A novel drug delivery system, containing vancomycin, was utilized in a rabbit osteomyelitis model in order to evaluate the antimicrobial efficacy of the antibiotic bone graft. METHODS: Forty adult New Zealand rabbits were used. The animals were randomized into three Groups: healthy animals without osteomyelitis, where AIBG was used to fill a defect (Group I); osteomyelitis caused with a methicillin-resistant S.aureus strain (MRSA) treated with AIBG (Group II); osteomyelitis caused with MRSA and treated with bone grafts without local antibiotics (Group III). At six weeks post-operation, the animals were sacrificed and histological, laboratory and radiologic evaluations were performed. RESULTS: Of the 24 operated rabbits, osteomyelitis was confirmed in 18 animals. In groups with osteomyelitis, only minor radiological changes were observed on day 21 post-op. Radiographs taken on day 42 post-op showed radiological signs of chronic osteomyelitis in Group III, whereas in Group II, bone healing was observed. Bacterial cultures taken on day 42 post-op revealed the original MRSA strain in Group III, whereas no bacteria were detected in Group II. Histological examinations showed the presence of macrophage cells which slowly break down the DDS matrix. The presence of DDS did not inhibit re-ossification. CONCLUSIONS: The drug delivery system was effective against MRSA-induced osteomyelitis without negative effect on osteointegration. This biodegradable technology has the potential to be a powerful tool in fighting bone infections.

In vitro efficiency of vancomycin containing experimental drug delivery systems.

Biofilm-forming Staphylococcus epidermidis strains are common cause of the periprosthetic infection. The treatment of the periprosthetic infection is very problematic, so the prevention of these infections by an antibiotic containing prothesis could be an option for prevention.The purpose of the present study was to examine the in vitro effects of drug delivery systems (DDSs), namely Wax 1 and Wax 2 with different vancomycin content: 0.5, 1, 2 and 4 mg. In order to control the antibacterial activity of DDSs killing curve study was performed and in order to determine the antibiotic release and the antibiotic peak concentration from the DDSs biological assay was carried out.The time kill curve studies showed, that both DDSs with all vancomycin concentration decreased significantly the bacterial counts, however, Wax 2 with 4 mg vancomycin significantly decreased the bacterial count than all the other groups.The vancomycin release was the best with the highest peak concentration from DDSs with 4 mg vancomycin contain; it was significantly better than in the other groups, however, no significant difference was observed between Wax 1 and Wax 2 in this respect.These findings suggest that Wax 2 with 4 mg vancomycin content could be a potential agent for clinical use.