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

Nencho Nenchev1 | Jiri Skopek2 | Deepa Arora3 | Abdus Samad3 | Sigal Kaplan4 | Mónika Domahidy5 | Hanka de Voogd6 | Stella Böhmert7 | Rita S. Ramos8 | Shashank Jain3

Abstract

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.

KE YWOR DS
age, pharmacokinetics, renal-impairment, safety, tolerability, trimetazidine

1 | INTRODUCTION

Trimetazidine (TMZ) is indicated in adults as an add-on therapy for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled by or intolerant to first-line anti- anginal therapies (European Medicines Agency [EMA], 2012). TMZ exhibits cytoprotective actions leading to the reduction of myocardial cell acidosis and calcium overload, preserves intracellular ATP levels, increases the antioxidant capacity, and protects against oxygen-free radical induced toxicity (Dézsi, 2016). It does not lower heart rate and does not exert unwanted hemodynamic effects (Thadani, 2005). Mod- ified released (MR) formulation of TMZ has been developed for the enhancement of pharmacokinetic effect, specifically to extend the time of peak plasma concentration (tmax), and thus sustain the plasma levels for a longer period (Thadani, 2005). This may lead to prolonged and sustained antianginal and anti-ischemic effect in patients with ischemic heart diseases as well as dosing convenience.
In eight young (age 24.8 ± 8.00 years) healthy volunteers, the mean peak plasma trimetazidine concentration (Cmax; 91.2 μg/L) was reached in 2–6 h in patients receiving TMZ MR 35 mg (BID) for 4 days (Barré et al., 2003). The area under the plasma trimetazidine concentration–time curve (AUC0-12) was 720 ± 110 μg/L•h and t1/2 was ~8 h after repeated administration. Most of the drug is eliminated unchanged (62%) (Jackson et al., 1996). However, 10 metabo- lites have been detected in urine in lower amount. The renal clearance of TMZ was 25.2 L/h after repeated oral administration (Barré et al., 2003). It is primarily excreted in the urine (>80% of an administered dose) within 48 h (Harpey, Clauser, & Labrid, 1989). TMZ have poor affinity (16%) for plasma protein (Harpey et al., 1989).
In the past, TMZ was indicated in cardiology, ophthalmology, and otolaryngology. In April 2012, it was subjected to an Article 31 proce- dure initiated by the French Health Products Agency (AFSSAPS, now ANSM) at the European Medicines Agency (EMA) based on both effi- cacy and safety concerns (predominantly for Parkinson syndrome) (European Medicines Agency (EMA), 2012). As a result, only the cardi- ology indication of TMZ in Summary of Product Characteristics (SmPC) has been retained as an add-on therapy for the symptomatic treatment of subjects with stable angina pectoris who are inade- quately controlled by or intolerant to first-line anti-anginal therapies (European Medicines Agency (EMA), 2012). Stable angina pectoris is more frequent in subjects over 75 year’s age, hence they are an important target population for treatment with TMZ. Moreover, as the primary elimination of TMZ in the body is through renal route (70–90%). Of note, renal function is impaired in subjects with renal impairment which may lead to increased exposure of TMZ in such subjects (Thadani, 2005). Therefore, Committee for Medicinal Prod- ucts for Human Use (CHMP) asked market authorization holders (MAH) to conduct a PK study assessing the effect of age and renal impairment on TMZ PK as data were lacking in these groups.
To fulfill the requirements of CHMP, first we conducted a pre- liminary single-dose study to assess the linearity of the pharmacoki- netics of TMZ in healthy volunteers, TMZ did not show linearity. Based on the results of the single ascending-dose study we designed and conducted this study to assess the effects of age and renal impairment on the PK of a multiple-dose regimen of TMZ 35 mg modified release (MR) tablets and also performed a safety evaluation.

2 | METHODS

2.1 | Study design

This was an open-label, ascending dose study where a total of 73 sub- jects were enrolled in Germany (47), Bulgaria (22), and the Czech Republic (4). Subjects were assigned to their treatment groups according to the age and degree of renal impairment as observed from the baseline serum creatinine data as followed.

2.1.1 | Control

Group 1:12 healthy subjects of 55–65 y of age with normal renal func- tion and estimated glomerular filtration rate of (eGFR) ≥ 90 ml/min.

2.1.2 | Subjects over 65 y age with normal renal function

Group 2:19 subjects of 66–75 y of age (normal renal function; eGFR ≥90 ml/min). Group 3:18 subjects older than 75 y of age (normal renal function, eGFR >60 ml/min, including a sub-group of three or more subjects older than 85 y of age).

2.1.3 | Renally impaired subjects

Group 4:8 subjects of 30–65 y of age with mild renal impairment (eGFR = 60–89 ml/min).
Group 5:8 subjects of 30–65 y of age with moderate renal impair- ment (eGFR = 30–59 ml/min).
Group 6:8 subjects of 30–65 y of age with the severe renal impairment who are not on dialysis (eGFR = 15–29 ml/min).
We excluded subjects with any conditions or laboratory abnormali- ties which would increase the risk associated with study participation or administration of TMZ or interfere with the interpretation of the study results and make the subject ineligible for the study as per the judgment of the investigator. Subjects with HIV, HBsAg, HAV-Ab (determined by IgM testing), HCV-Ab, Parkinson’s disease, Parkinsonian symptoms, tremors, restless leg syndrome, movement disorders, falls related to gait instability or hypotension, on antihypertensive treatment, hypotension, thrombocytopenia, agranulocytosis, impaired liver function, coagulation disorders, neurological symptoms/disorders including disorientation, hallucination, and convulsions were excluded. Breast-feeding/pregnant subjects, subjects hypersensitive to TMZ excipients or any structurally related drugs were excluded from the study as well. In addition, for Groups 2 and 3, subjects with known history or presence of galactose or fructose intolerance, sucrase-isomaltase insufficiency, Lapp lactase insufficiency, galactosemia, or glucose-galactose malabsorption syn- drome were also excluded.
At each study center, the study protocol and the informed consent form (ICF) were reviewed and approved by a duly constituted Indepen- dent Ethics Committee (IEC). This study was designed, monitored, and complied with the ethical principles of Good Clinical Practice (GCP) and conducted in accordance with the Declaration of Helsinki as amended by the 48th World Medical Association General Assembly, Somerset West, Republic of South Africa, October 1996. The study investigators obtained ICF from each subject before the subject was enrolled in the study.

2.2 | Intervention and dosing

Modified release TMZ tablets 35 mg, (Moduxin MR 35 mg, retard tab- let, Gedeon Richter, Romania) were administered orally to subjects at scheduled dosing time in sitting position with 240 ml of drinking water at ambient temperature. The maximal duration was 4 days after screening period for non-renal impaired subjects and 8 days after screening period for renally impaired subjects. The following dosing scheme was employed:
• Groups 1–3: B.D. for 3 days and once on the last day (day 4) of treatment
• Group 4: B.D. for 7 days and once on the last day (day 8) of treatment
• Group 5: O.D. for 8 days
• Group 6: Every 48 h for 8 days

2.4 | Pharmacokinetic evaluation

The following PK parameters were evaluated in blood samples: AUC(0−τ),ss The area under the plasma concentration–time curve within the dosing interval (τ) at steady state. CL/Fss The apparent total body clearance at steady state is calculated as CL/Fss = Dose/AUCss,(0−-τ). was developed and validated before the start of the clinical study. This method could detect trimetazidine in the range of 4.8–28.0 μg/ml which was expected to be present in the plasma samples collected in the clinical study.

2.5 | Safety evaluation

For safety assessment; physical examination, vital signs measurements (BP, pulse, oral temperature, respiratory rate, and 12-lead ECG in tripli- cate), hematology (red blood cell count, mean corpuscular volume, mean corpuscular hemoglobin, hemoglobin, hematocrit, platelet count, and white blood cell count), differential blood count (neutrophils, eosino- phils, basophils, lymphocytes, and monocytes), biochemistry (magne- sium, sodium, potassium, chloride, creatinine, creatine phosphokinase, glucose, urea, uric acid, calcium, inorganic phosphorus, alkaline phos- phatase [AP], AST, and ALT), gamma-glutamyl transferase, total biliru- bin, total protein, albumin, total cholesterol, and triglycerides), urinalysis (bilirubin, protein, blood, glucose, nitrite, ketone, and pH) were per- formed. Urine samples that were positive for blood or protein were sent for microscopy, if deemed appropriate by the investigator. For renally impaired subjects with positive or strong positive values at baseline, microscopic urine analysis was only performed at baseline and follow- up. ECG, QTc interval, and adverse events (AEs) were recorded. The safety analysis set consisted of a subset of the subjects who received at least one (partial or complete) dose of the investigational product. The grading and reporting of AE were performed according to Common Ter- minology Criteria for Adverse Events (CTCAE).

2.6 | Statistical methods

Pharmacokinetic parameters were analyzed using non-compartmental analysis methods in the software “Phoenix WinNonlin Version 6.3”. Actual sampling times relative to dosing rather than nominal times were used in the calculation of all derived PK parameters and no imputation of missing data was performed. Descriptive statistics (for non-categorical data including hematology and biochemistry) were presented by treat- ment for both actual values (n, mean, standard deviation: SD, median, minimum, and maximum) and change from baseline. Pharmacokinetic concentration data were listed by subject including actual sampling times relative to dosing. Plasma concentrations were summarized by analyte (TMZ), study part, treatment group/cohort, and nominal time point. The following descriptive statistics were presented for plasma concentra- tions obtained at each nominal time point: n, arithmetic mean, SD, geo- metric mean, geometric SD, geometric CV% (calculated as: gCV % = SQRT[exp(SD2)-1] * 100; where SD = standard deviation of the natural-logarithmically transformed data), median, minimum, and maxi- mum values. Mean plasma concentrations versus nominal times were also presented in the linear and semi-logarithmic scale. A linear mixed model was applied to analyze Group 2/Group 1 and Group 3/Group 1 ratio and the corresponding 90% confidence intervals (CI) for AUC(0 −τ),ss and Cmax,ss using log-transformed values to assess the age effect. A linear mixed model was applied to analyze Group 4/Group 1, Group 5/Group 1, and Group 6/Group 1 ratios and the corresponding 90% CI for AUC(0−τ),ss and Cmax,ss using log-transformed values to assess the effect of renal impairment. Analysis of the safety variables were based on the safety analysis set. Numbers of treatment-emergent adverse event (TEAE) were summarized by System Organ Class (SOC) and Pre- ferred Term (PT) and by severity/causality to the study drug. Laboratory values (hematology, biochemistry, and urinalysis) were listed by subject and time point including changes from baseline (exception of urinalysis). The baseline for the laboratory values were the values obtained 1 day prior to first dosing.

3 | RESULTS

3.1 | Subjects demographics

Of the 155 subjects who were screened for the study, 73 subjects met all the study eligibility criteria and were included in the study to receive the TMZ treatment (Figure 1). Approximately 58.9% of sub- jects were male (Table 1). All 73 subjects were Caucasian.

3.2 | Pharmacokinetic analysis of TMZ in elderly and renal-impaired

The mean steady-state plasma Cmax,ss of TMZ in Group 1, 2, and 3 was observed at 108.96 (±44.74), 116.11 (±28.54), and 144.63 (±31.72) ng/ml, respectively, suggesting a moderate increase in Cmax,ss with increasing age (Table 2). The corresponding mean Tmax,ss was similar among all the Groups 1, 2, and 3 [4.70 (±2.70), 4.42 (±1.99), and 4.41 (±1.67) h, respectively]. A reduction in mean CL/Fss in Groups 2 [33.58 (±8.50) L/h] and group 3 [26.59 (±5.47) L/h] in com- parison with Group 1 [38.28 (±11.06) L/h] suggesting that an age- related reduction in CL/Fss. Mean CLRss was 12.45 (±3.19), 15.62 (±5.50), and 9.65 (±2.24) L/h in Groups 1, 2, and 3, respectively.
The mean steady-state plasma Cmax,ss was comparable in Groups 4 and 5 [(129.21 (±36.11) and 131.46 (±40.11) ng/ml, respectively] but less in Group 6 [100.84 (±25.95) ng/ml] (Table 2). However, as the frequency of administration was not the same in each of these Groups (every 12, 24, and 48 h in group 4, 5, and 6, respectively). Thus, these data do not demonstrate the intrinsic impact of renal function on TMZ Cmax,ss following an equivalent dosing regimen.

3.3 | Effect of age on the pharmacokinetics of TMZ

Table 3 presents the impact of age on the steady-state TMZ phar- macokinetic parameters AUC(0−τ),ss and Cmax,ss. The geometric least squares mean ratio for Group 2 vs. Group 1 (90% confidence inter- val) for AUC(0−τ),ss [112.2 (92.2–136.8) and Cmax,ss [109.9 (89.6–134.8)] indicate that the steady-state systemic exposure was increased in subjects aged 66–75 y in comparison with subjects aged 55–65 y (Figure 2). However, the corresponding 90% CIs indi- cated that the increase was not statistically significant. A greater increase was noted in the geometric least squares mean ratio for Group 3 versus Group 1 [140.5 (115.9–170.3) and 137.8 (112.9–168.2)] for AUC(0−τ),ss and Cmax,ss, respectively. The corresponding 90% CIs indicated that the difference in systemic exposure between Group 1 and Group 3 was statistically significant. In summary, an age-related increase in systemic exposure was observed in the subjects over 75 y age in comparison with healthy volunteers. This increase was statistically significant in those sub- jects who were older than 75 y.

3.4 | Effect of renal impairment on the pharmacokinetics of TMZ

The impact of renal impairment on the steady-state TMZ pharmaco- kinetic parameters AUC(0−τ),ss and Cmax,ss is presented in Table 4. The geometric least squares mean ratios (90% confidence interval) for AUC(0−τ),ss were 114.2 (90.3–144.4), 213.0 (153.1–296.3), and 247.4 (197.8–309.6) when comparing Group 4, 5, and 6, respectively, to Group 1, indicating that renal impairment has increased the total exposure to TMZ during the dosing interval at steady-state (Figure 2). The corresponding 90% CI included 100 when comparing tGroup 4 and Group 1, indicating that the increase in AUC(0−τ),ss was not significant for subjects who have mild renal impairment, in com- parison with healthy volunteers. In contrast, the 90% CIs excluded 100 when comparing Group 5 or Group 6 to Group 1 indicating that the increase in AUC(0−τ),ss was significant for subjects who have a moderate or severe renal impairment, in comparison with healthyvolunteers with normal renal function. In summary, an increase in systemic TMZ exposure was observed in subjects with impaired renal function, in comparison with healthy volunteers with normal renal function.

3.5 | Evaluation of safety after TMZ administration

The study drug was well tolerated, with a low incidence of TEAEs (Table 5). Overall, 19 AEs were reported by 17 (23.3%) subjects in the study. Fifteen TEAEs were experienced by 14 subjects in the study. The most frequently reported TEAEs in the study were headache (Nervous System Disorders SOC, four subjects) and hypertension (Vascular Disorders SOC, three subjects) (Table 6). Three out of four TEAEs of headache reported in the study were considered related to the study drug. All TEAEs reported were mild in severity. Two severe TEAEs (increased Gamma-Glutamyl transferase and metastatic esoph- ageal cancer) were reported and both were experienced by Group 1 subjects in the study. None of these TEAEs were related to the study drug. Two of the three TEAEs of hypertension were experienced by group six subjects and were moderate in severity; one TEAE of hypertension was experienced by Group 4 subject in the study and was mild in severity.
All three TEAEs of hypertension were not related to the study drug. No subjects died during the study. One subject experienced one SAE (PT = Esophageal Cancer Metastatic) in the study. One subject discontinued due to a TEAE (PT = ventricular extrasystoles). There were no AEs of special interest reported in the study. There were no notable shifts in biochemistry and hematology values in the study. Changes in vital signs from screening were small and there were no consistent differences among different groups in the study with respect to vital signs. There were no clinically significant changes in ECG recording from screening for any subject in the study. Taken together, these observations suggest that TMZ was well tolerated in the subjects over 75 year’s age as well as in renally impaired subjects.

4 | DISCUSSION

This PK study was conducted according to the requirements by CHMP and the protocol agreed with CHMP and evaluated the effect of age and renal impairment on TMZ pharmacokinetics. An increase in systemic exposure of TMZ and a decrease in renal clearance were observed in subjects over 75 year’s age and in subjects with impaired- renal function. However, TMZ did not affect laboratory parameters and ECG recording and was well-tolerated among all dose groups. No new or unexpected safety concerns were observed, even though In 2003, Barre et al evaluated PK of TMZ in two studies with 41 subjects (Barré et al., 2003). The study reported a two-fold increase in exposure of TMZ in subjects >72 y of age. Similarly, in this study, we observed an increase in exposure of TMZ by 1.4-fold in subjects >79 y of age. Moreover, in severe renally impaired subjects (eGFR = 17 ± 5 ml/min) and moderately renal-impaired subjects (eGFR = 39 ± 6 ml/min), systemic exposure (AUC0–24) of TMZ was significantly increased by 2.5- and 5-folds, respectively, in the study by Barre et al. On the same lines, we observed a significant increase by 2.2- and 2.4-fold in systemic exposure of TMZ in moderately and severe renally impaired subjects. However, we have used modified dose schedule for severe renally impaired subjects (35 mg in every 48 h) and for moderately renally impaired subjects (35 mg every 24 h) as compared to standard dose of TMZ used in the study (35 mg in every 12 h) by Barre et al which may have resulted in a high sys- temic exposure of fivefolds. In our study, we observed a higher than expected exposure of TMZ in severe renal impaired subjects due to non-linear PK of TMZ. As trimetazidine is primarily excreted by kid- ney, it’s elimination may be modified in patients with lower eGFR. Decreased elimination may have led to increased exposure of TMZ in renal-impaired patients and elderly. Moreover, we collected the blood and urine samples for analysis at shorter time intervals and included a larger number of subjects which increased the sample size and power.
Barre and colleagues did not suggest any dose modification for TMZ in elderly and renally impaired subjects since TMZ has a wide safety margin (Barré et al., 2003). Impaired renal function frequently modifies the PK of drugs that are predominantly eliminated via the renal route. A reduction in renal function is associated with increasing age (Klotz, 2009). SmPC for TMZ considered dose modification for subjects over 75 year’s age (eGFR = 30–60 ml/min) and renally impaired subjects (eGFR = 30–60 ml/min) and recommended once a day (35 mg) dosing for them compared to twice a day (70 mg) for patients with normal renal function (Les Laboratoiros Servier France, 2012). Of note, we did not observe any serious adverse events any of the treatment groups of normal, subjects over 75 y age, and renal- impaired subjects suggesting that TMZ is well-tolerated in all these patient’s populations and may be safe for such patients.
In summary, increased systemic exposure of TMZ and decreased renal clearance was observed in subjects over 75 year’s age and in subjects with impaired renal function. Notably, TMZ MR was well tol- erated in subjects over 75 year’s age and renally impaired subjects and did not cause any significant safety concern in such patients.

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