Clinical Comparison of Renogen, a Biosimilar Epoetin-a, with the Originator, Eprex, in Chronic Kidney Disease Anemia in Indonesia: A Preliminary Study.

BACKGROUND: treatment of erythropoietin (EPO) is essential in chronic kidney disease (CKD) patients to maintain optimal hemoglobin (Hb) level. Renogen is a biosimilar epoetin-α, and Eprex is the originator epoetin-α. This study aimed to compare the efficacy and tolerance of Renogen with Eprex in CKD anemia. METHODS: Renogen and Eprex were compared in a randomized (2:1), open-label study for 8 weeks, proceeded by 4 weeks adjustment (maintenance) phase, in anemic CKD patients undergoing HD in Cipto Mangunkusumo General Hospital, Jakarta, from June 2017 to October 2018. RESULTS: a total of 45 patients (31 received biosimilar EPO and 14 received originator EPO) were included in the study.  At baseline, mean (SD) Hb levels were 10.9 (0.74) g/dL and 10.9 (0.61) g/dL in biosimilar and originator EPO groups, respectively. At end of study (8 weeks), mean (SD) Hb levels were 10.5 (1.28) g/dL and 11.0 (1.13) g/dL in biosimilar EPO and originator EPO groups, respectively.  The proportion of patients with Hb levels maintained within the target range (>10 g/dL) during 8 weeks randomization phase were 58.1% and 71.4% in biosimilar EPO and originator EPO, respectively (p=0.60; NS). There were no significant difference in epoetin dose between the 2 groups, and there was no drug-related adverse event in either group. CONCLUSION: Hb level at >10 g/dL could be maintained for 8 weeks of treatment with both originator and biosimilar EPO (more consistent with originator EPO and more fluctuations with biosimilar EPO), with similar epoetin dose and no drug-related adverse event.

Safety and Efficacy of NC120 for Improving Lipid Profile: A Double Blind Randomized Controlled Trial.

BACKGROUND: the use of statin to lower blood cholesterol is often associated with bothersome adverse effects such as myopathy and liver dysfunction. NC120 is herbal lipid lowering drug containing red yeast rice (RYR) extract, guggulipid, and chromium picolinate, and expected to have better safety profile. The aim of this study was to evaluate the efficacy and safety profiles of NC120 in lowering blood lipid. METHODS: this was a double blind randomized clinical trial comparing NC120 with placebo in subjects with hypercholesterolemia. Two capsules of NC120 or placebo were administered twice a day for 28 days. Blood total-cholesterol, LDL-cholesterol, and triglyceride were measured on day-0, day-7, and day-28. Unpaired t-test was used to compare study parameter between groups, and one-way ANOVA was used to compare within group. RESULTS: 25 subjects received NC120 and 24 subjects received placebo. Significant decrease of total cholesterol and LDL-cholesterol were observed since day-7 in NC120 group, while the changes in placebo group were not significant at all time of observation. No significant decrease of triglyceride was observed in NC120 group and in placebo group. Side effects were minor and comparable between the two groups. CONCLUSION: NC120 is effective in reducing total cholesterol and LDL-cholesterol, but not triglyceride. This drug shows a good safety profile, and thus can be considered for patients who can not tolerate statin drugs.

Pharmacokinetic equivalence study of nonsteroidal anti-inflammatory drug etoricoxib.

PURPOSE: The current study aimed to evaluate whether a generic product of etoricoxib 120 mg film-coated tablet (the test drug) was bioequivalent to the reference product (Arcoxia® film-coated tablet 120 mg). METHODS: This was a randomized, open-label, two-sequence, crossover study under fasting condition, with a 14-day washout period, involving 26 healthy adult male and female subjects. Blood samples were taken and analyzed for plasma concentrations of etoricoxib (Chemical Abstracts Service [CAS] 202409-33-4) using a high-pressure liquid chromatography-ultraviolet detector (HPLC-UV) system capable of measuring etoricoxib concentrations ranging from 5.00 to 5002.90 ng/mL, with the lowest limit of quantitation of 5.00 ng/mL. A noncompartmental method was used to determine the pharmacokinetic parameters of a single-dose administration of the drug, including the area under plasma concentration-time curve from time zero to the time of last observed concentration (AUC0-t ), the area under plasma concentration-time curve from time zero to infinity (AUC0-∞), the maximum plasma concentration (Cmax), the time to reach the maximum plasma concentration (tmax), and the terminal half-life (t½). RESULTS: After a single-dose administration of etoricoxib 120 mg film-coated tablet, the mean (SD) values for the AUC0-72h and Cmax of the test drug were 45913.42 (13142.19) ng·h/mL and 3155.93 (752.81) ng/mL, respectively; the values for the reference drug were 44577.20 (13541.85) ng·h/mL and 2915.13 (772.81) ng/mL, respectively. The geometric mean ratios (90% CIs) of the test drug/reference drug were 103.40% (98.70%-108.32%) for AUC0-72h and 109.26% (100.18%-119.18%) for Cmax. No clinically significant differences in tmax and t½values were found between the test drug and the reference drug. No adverse events were experienced by the subjects during this study. CONCLUSION: The present study demonstrated that the evaluated generic etoricoxib 120 mg film-coated tablets were bioequivalent to the reference drug.

Clinical Effectiveness, Safety and Tolerability of Amlodipine/Valsartan in Hypertensive Patients: the Indonesian Subset of the EXCITE Study.

AIM: to assess the effectiveness, safety and tolerability of amlodipine/valsartan (Aml/Val) single-pill combination (SPC) in hypertensive patients in a real-world setting. METHODS: the Indonesian subset of the EXCITE (clinical EXperience of amlodIpine and valsarTan in hypErtension) study, which was a multinational, prospective, observational, open study in hypertensive patients treated with Aml/Val SPC for 26 weeks. Aml/Val SPCs (5/80, 5/160, 10/160 mg) were administered as monotherapy or as add-on therapy to other antihypertensive medications in patients not controlled by prior monotherapy. The effectiveness outcomes were (1) mean decrease in sitting systolic blood pressure and diastolic blood pressure (msSBP and msDBP) from baseline to week 26; (2) proportion of patients achieving BP goal (<140/90 mmHg for nondiabetics, or <130/80 mmHg for diabetics); (3) proportion of patients who were responders (achieving BP goal or BP reduction of >20/10 mmHg). The safety variables were the incidence of AEs and SAEs, and the incidence of edema. RESULTS: a total of 500 patients from Indonesia received Aml/Val SPC, 487 patients were analyzed for efficacy (by LOCF), and 464 patients completed the study. At study end (week 26), the overall msSBP and msDBP(95% CI) reductions from baseline were -33.7 (-35.2, -32.1) mmHg and -14.8 (-15.7, -13.8) mmHg, respectively. Among the 487 patients, 52.4% achieved BP goal and 80.5% were responders (LOCF). Among 464 patients who completed the study, 53.7% achieved BP goal and 84.5% were responders. Aml/Val SPC was effective in decreasing BP in Indonesian patients. AEs, including SAEs, were reported in 11.4% patients, with SAEs in 1% of patients, and death in 0.8% of patients. SAEs and deaths were considered unrelated to the study drug. Edema was reported by 9.4% of patients at baseline, and in 3.7% patients at end of study. Effectiveness, tolerability and compliance were rated good and very good in 90.8%, 92.2%, and 89.2% of patients, respectively, according to the investigators. CONCLUSION: Aml/Val SPC was effective for BP reductions and well tolerated in hypertensive patients, not adequately controlled by monotherapy, in a daily clinical setting in Indonesia.

Underutilization of anticoagulant for venous thromboembolism prophylaxis in three hospitals in Jakarta.

AIM: to assess the current use of anticoagulants and implementation of International Guidelines in venous thromboembolism (VTE) prophylaxis in hospitalized patients with acute medical illnesses in Jakarta, Indonesia. METHODS: a multicenter, prospective, disease registry, recruiting patients diagnosed as acutely ill medical diseases and other medical conditions at risk of VTE, with in-hospital immobilization for at least 3 days. RESULTS: of 401 patients, 46.9% received anticoagulants which included unfractionated heparin (64.4%), fondaparinux (11.7%), enoxaparin (9.6%), warfarin (3.7%), and combination of anticoagulants (10.6%). VTE prophylaxis using physical and mechanical method was used in 81.3% of patients, either as a single modality or in combination with anticoagulants. During hospitalization, VTE were found in 3.2% patients; 10 patients (2.5%) had lower limb events and 3 patients (0.75%) had a suspected pulmonary embolism. The main reference international guidelines used were AHA/ASA 2007 (47.4%), followed by ACCP 2008 (21.7%). CONCLUSION: the study showed underutilization of prophylaxis anticoagulants in which mechanical thromboprophylaxis either alone or combination with anticoagulants was the most commonly used. Unfractionated heparin was the preferable choice. The most commonly used guideline was AHA/ASA 2007. VTE thromboprophylaxis in medically ill patients needs to be encouraged.

QT interval prolongation associated with amiodarone use in Cipto Mangunkusumo Hospital, Jakarta.

AIM: To evaluate the incidence of QTc interval prolongation associated with the use of amiodarone, as well as factors that influence its occurrence. METHODS: This was a descriptive retrospective study conducted from November 2010 until December 2011 using medical record of patients at ICCU Cipto Mangunkusumo Hospital from 2004-2011. Four groups of patients were included: (1) patients receiving amiodarone and other drugs causing which can cause QTc prolongation, (2) patients receiving amiodarone and other drug not causing QTc prolongation, (3) patients receiving drugs which can cause causing QTc prolongation, (4) patients not receiving amiodarone, nor other drugs which can cause causing QTc prolongation (served as control group). Difference of QTc interval within the same group was analyzed with paired t-test or Wilcoxon matched-pairs test. Between groups comparison were performed with Kruskal Wallis test. The influence of other factors (sex, age, heart failure, liver disorder, electrolyte imbalance) on QTc prolongation was analyzed using multiple regression. RESULTS: QTc interval prolongation in groups 1, 2, and 3 were respectively 65.5%, 63.3%, 56.6%, which were significantly different from control group (24.4%); Hypernatremia and hypertension were revealed as significant risk factor for QTc prolongation. Mortality occurred in 3, 4, and 4 patients in group 1, 2, and 3 respectively, and none in group 4. CONCLUSION: QTc interval prolongation occurred in association with amiodarone and other drugs known to prolong QTc interval. Hypernatremia and hypertension were shown as significant influencing factor of QTc interval prolongation.

Safety and effectiveness of candesartan and candesartan/HCT fixed dose combination in patients with hypertension.

AIM: to assess the safety and effectiveness of candesartan and candesartan/HCT fixed-dose combination (FDC) in patients with hypertension in daily clinical practice. METHODS: an open observational study with a 12-week period of treatment. Candesartan tablets of 4 mg, 8 mg, or 16 mg, or candesartan/HCT FDC tablets (16/12.5 mg) were prescribed to adult hypertensive subjects, both treatment-naive patients and previously treated but uncontrolled patients, depending on the physicians' discretion based on his/her judgment on the clinical condition. RESULTS: from a total of 112 treatment-naive patients and 381 previously treated patients eligible for safety analysis, there were only 3 patients with adverse events, and 2 of which were considered possibly related to candesartan (0.41%) and there were no serious adverse events. Both patients were previously treated patients, one patient experienced nausea and the other patient experienced paresthesia. Candesartan and candesartan/HCT were effective in lowering systolic blood pressure (SBP) and diastolic blood pressure (DBP) from baseline at weeks 4, 8, and 12, in both groups, with 26-27 mm Hg decreases in SBP at week 12 and a trend toward a larger reduction in treatment-naive patients than in previously treated patients, although not statistically significant. However, in terms of patients achieving a BP of <140/90 mm Hg between groups were significantly superior in treatment-naive patients than in previously treated patients at week 8 (56% vs 40%; p=0.003) and week 12 (69% vs 53%; p=0.004). Candesartan and candesartan/HCT were also effective for patients with long-standing (>4 years) uncontrolled hypertension with previous antihypertensive therapy, which was most commonly calcium channel blockers (became controlled in >50% of all uncontrolled patients). CONCLUSION: results of this open observational study showed that candesartan and candesartan/HCT were well tolerated and effective in both treatment-naive patients and uncontrolled hypertensive patients with previous antihypertensive treatment.

Safety and efficacy of lansoprazole injection in upper gastrointestinal bleeding: a postmarketing surveillance conducted in Indonesia.

AIM: to assess the safety and effectiveness of lansoprazole injection (Prosogan®) in patients with upper gastrointestinal bleeding due to peptic ulcers or erosive gastritis. METHODS: this study was a multicenter observational postmarketing study of lansoprazole (Prosogan®) injection. Patients with upper gastrointestinal bleeding due to peptic ulcers or erosive gastritis were given intravenous lansoprazole for a maximum of 7 days or until the bleeding stopped and the patients were able to take oral doses of lansoprazole. Primary outcome of the study was cessation of bleeding. Some laboratory parameters were also measured. RESULTS: among a total of 204 patients evaluable for safety, there was no adverse event reported during the study. A total of 200 patients were eligible for efficacy evaluation, 125 patients (62.5%) were males. Among these patients, upper GI bleeding stopped in 20 patients (10.0%) on day 1, in 71 patients (35.5%) on day 2, 75 patients (37.5%) on day 3, 24 patients (12.0%) on day 4, and 7 patients (3.5%) on day 5, making a cumulative of 197 patients (98.5%) on day 5. The hemostatic effect was rated as 'excellent' if the bleeding stopped within 3 days, and 'good' if the bleeding stopped within 5 days. Thus, the results were 'excellent' in 166 patients (83.0%) and 'good' in 31 patients (15.5%). These results were not different between males and females, between age below 60 years and 60 years and above, and between baseline Hb below 10 g/dL and 10 g/dL and above. CONCLUSION: the results of this observational postmarketing study in 200 patients with upper gastrointestinal bleeding due to peptic ulcers or erosive gastritis demonstrated that intravenous lansoprazole twice a day was well tolerated and highly effective.

VICTORY project: a study of counterfeit PDE5 inhibitor (sildenafil) in Indonesia.

AIM: to quantify the extent of counterfeit sildenafil in Indonesia. METHODS: the study was conducted in 4 big areas: Jakarta, Bandung, East Java (Surabaya and Malang), and Medan. Sildenafil 100 mg tablets were purchased from pharmacies, drugstores, street peddlers, and 3 Indonesian websites. The outlets were chosen by random sampling in each stratum (type of outlet). Sildenafil tablets purchased were sent to Pfizer Quality Operations Division, Dalian, China, for authenticity evaluations (by infra red spectral analysis). All counterfeit tablets were then sent to Pfizer Counterfeit Medicines Laboratory, Sandwich, UK, a portion of which were analyzed quantitatively for sildenafil concentration per tablet (by HPLC). RESULTS: a total of 518 sildenafil 100 mg tablets were collected and sent to Dalian. Of these tablets, 284 tablets (55%) were genuine sildenafil and 234 tablets (45%) were counterfeit sildenafil. Counterfeit sildenafil were mostly found in street peddlers (100%), in drugstores (56%), and from internet (33%), but pharmacies also had (13%) counterfeit sildenafil. The sildenafil content of 106 counterfeit tablets analyzed varied from 24 to 157 mg per 100 mg tablet. No analysis was done to determine other active ingredient. CONCLUSION: 45% sildenafil 100 mg tablets in Indonesia were found counterfeit and widely distributed in street peddlers, drugstores, and pharmacies. This report is aimed to alert the potential consumers, health professionals and regulators of this problem.

Bioequivalence study of two formulations of bisoprolol fumarate film-coated tablets in healthy subjects.

BACKGROUND: The present study was conducted to compare the bioavailability of two bisoprolol fumarate 5 mg film-coated tablet formulations (test and reference formulations). PATIENTS AND METHODS: This study was a randomized, single-blind, two-period, two-sequence crossover study that included 18 healthy adult male and female subjects under fasting condition. The pharmacokinetic parameters were determined based on the concentrations of bisoprolol (CAS 66722-44-9), using ultraperformance liquid chromatography with a tandem mass spectrometer detector. In each of the two study periods (separated by a washout of 1 week) a single dose of test or reference product was administered. The pharmacokinetic parameters assessed were area under the plasma concentration-time curve from time zero to 48 hours (AUC(t)), AUC from time zero to infinity (AUC(inf)), the peak plasma concentration of the drug (C(max)), time needed to achieve C(max) (t(max)), and the elimination half-life (t(1/2)). RESULTS: The geometric mean ratios (90% confidence intervals) of the test drug/reference drug for bisoprolol were 101.61% (96.14%-107.38%) for AUC(t), 101.31% (95.66%-107.29%) for AUC(inf), and 100.28% (93.90%-107.09%) for C(max). The differences between the test and reference drug products for bisoprolol t(max) and t(1/2) values were not statistically significant (P > 0.05). There was no adverse event encountered during this bioequivalence test. The 90% confidence intervals of the test/reference AUC ratio and C(max) ratio of bisoprolol were within the acceptance range for bioequivalence. CONCLUSION: It was concluded that the two bisoprolol film-coated tablet formulations (the test and reference products) were bioequivalent in terms of the rate and extent of absorption.

Urinary 11-dehydro-thromboxane B2 and 2,3-dinor-6-keto-prostaglandin-F1α in healthy post-menopausal and pre-menopausal women receiving aspirin 100 mg.

The prevalence of cardiovascular diseases in women increases sharply after menopause. In postmenopausal women, thromboxane production increases while prostacyclin decreases. Low dose aspirin reduces the production of both thromboxane and prostacyclin. The present study was an open-label clinical trial with two parallel groups of 15 premenopausal women and 15 postmenopausal women. Twenty-four hours urine was collected from each subject before and after aspirin 100 mg daily for 7 days. The concentration of thromboxane and prostacyclin was measured as their metabolites (11-dehydro-thromboxane B(2) and 2,3-dinor-6-keto-prostaglandin-F(1α)) in urine using enzyme immunoassay methods. This study showed that aspirin significantly reduced thromboxane in both groups with significantly larger percentage reduction in postmenopausal women compared to premenopausal women (73.32 vs. 61.13%, p = 0.021). This study also showed that aspirin reduced prostacyclin significantly in both groups, but the percentage reduction between the groups was not significantly different. The decrease in the ratio of 11-dTXB(2)/2,3-dinor-6-keto-PGF(1α) should be compared to assess aspirin efficacy as an antithrombotic. Calculation of the ratio of 11-dTXB(2)/2,3-dinor-6-keto-PGF(1α) before aspirin consumption was higher in postmenopausal women than in premenopausal women. The decrease in 11-dTXB(2)/2,3-dinor-6-keto-PGF(1α) ratio by aspirin was greater in postmenopausal women than in premenopausal women (1.91 vs. 0.17; p = 0.022). It was concluded that aspirin reduced thromboxane and prostacyclin significantly in each group with significant 11-dTXB(2) percentage reduction between groups and non-significant 2,3-dinor-6-keto-PGF(1α) percentage reduction between groups, but reduced the 11-dTXB(2)/2,3-dinor-6-keto-PGF(1α) ratio much larger in postmenopausal women compared to that in premenopausal women.

Bioequivalence study of two perindopril erbumine tablet formulations in healthy volunteers.

The present study was performed to compare the bioavailability of two perindopril erbumine (CAS 107133-36-8) 4 mg tablet formulations (test formulation and reference formulation). This study was a randomized, single-blind, two-period, two-sequence cross-over study which included 20 healthy adult male and female subjects under fasting conditions. In this study, one subject withdrew from the study and one reserve subject did not appear at both periods. The pharmacokinetic parameters were assessed based on the concentrations of perindopril (CAS 82834-16-0) and perindoprilat (CAS 95153-31-4) because perindopril has litte pharmacologic activity until hydrolized in the liver into its active metabolite, perindoprilat. The blood samples from 18 subjects were analyzed for plasma concentrations of perindopril and perindoprilat. In each of the two study periods (separated by a washout of three weeks) a single dose of test or reference drug was administered. Plasma concentrations of the drug were determined by LC-MS/MS method. The pharmacokinetic parameters assessed in this study were area under the plasma concentration-time curve from time zero to 192 h (AUC), area under the plasma concentration-time curve from time zero to infinity (AUCinf), the peak plasma concentration of the drug (Cmax time needed to achieve the peak plasma concentration (tmax), and the elimination half-life (t(1/2)). The geometric mean ratios (90% CI) of the test drug/reference drug for perindopril and perindoprilat were 106.59% (92.97-122.20%) and 100.56% (94.11-107.46%) for AUC,, 106.64% (93.39-121.77%) and 100.88% (95.30-106.80%) for AUCinfo, and 101.23% (87.39-117.27%) and 99.30% (90.42-109.05%) for Cmax, respectively. The 90% confidence intervals calculated for AUCt and Cmax of perindopril and perindoprilat were within the standard bioequivalence range (80-125% for AUC and Cmax). It was concluded that the two perindopril erbumine tablets (test and reference drug) were bioequivalent in terms of the rate and extent of absorption.

Bioequivalence study of two clopidogrel film-coated tablet formulations in healthy volunteers.

The present study was performed to compare the bioavailability of two clopidogrel 75 mg film-coated tablet formulations (test formulation and reference formulation). This study was a randomized, single-blind, two-period, two-sequence cross-over study which included 24 healthy adult male and female subjects under fasting condition. The pharmacokinetic parameters were assessed based on the concentrations of clopidogrel (CAS 120202-66-6) parent compound. In each of the two study periods (separated by a washout of one week) a single dose of test or reference drug was administered. Plasma concentrations of the drug were determined by LC-MS/MS method. The pharmacokinetic parameters assessed in this study were area under the plasma concentration-time curve from time zero to 24 h (AUCt), area under the plasma concentration-time curve from time zero to infinity (AUCinf), the peak plasma concentration of the drug (Cmax), time needed to achieve the peak plasma concentration (t(max)), and the elimination half life (t1/2). The geometric mean ratios (90% CI) of the test drug/reference drug for clopidogrel parent compound were 95.19% (81.63-110.90%) for AUCt, 95.55% (80.50-113.42%) for AUCinf, and 100.18% (80.87-124.09%) for Cmax. The 90% confidence intervals calculated for AUCt and Cmax of clopidogrel parent compound were within the standard bioequivalence range (80-125% for AUC and Cmax). It was concluded that the two clopidogrel film-coated tablets (test and reference drug) were bioequivalent in terms of the rate and extent of absorption.

The role of SOCS-3 protein in leptin resistance and obesity.

Obesity is one of the risk factors in various chronic diseases and malignancy. It may result from excess accumulation of body fat. This condition may be caused by dysfunction of appetite-regulating pathways and energy balance due to leptin resistance. Leptin, a 16 kDa hormone, is the most important regulator of appetite and energy balance in the body. Most individuals with obesity have leptin resistance characterized by increased leptin blood levels. Some possibilities of mechanism involved in leptin resistance have been proposed by researchers despite the fact that it is still being studied hitherto. One of the mechanisms considered to have a role in leptin resistance is disruption in signal transduction process through Janus-activating kinase2-signal transducer and activator of transcription 3 (JAK2-STAT3) pathway on leptin receptors by suppressor of cytokine signaling-3 (SOCS-3). SOCS-3 is a protein that inhibits the signal transduction process of various cytokines in the body, including leptin. SOCS-3 expression is induced by leptin and SOCS-3 activation will inhibit STAT3 phosphorylation which is important in signal transmission on leptin receptors. Such inhibition will consequently cause leptin resistance characterized by dysfunction of leptin biological function.