296 Original Article
Authors
M. Liu, X. L. Wang, D. Zhang, M. Yang, J. Han, Y. N. Zhang, Z. L. Wang, H. C. Liu
Affiliation
Department of Clinical Pharmacology, Aerospace Center Hospital, Beijing, P. R. China
Key words
Abstract
▶ niacin ● ▶ nicotinuric acid ● ▶ simvastatin ● ▶ simvastatin acid ● ▶ pharmacokinetics ●
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Objective: A fixed dose combination tablet of niacin extended release (ER)/simvastatin was recently developed in China. This study was designed to assess and compare the pharmacokinetics of niacin, simvastatin and their metabolites in healthy Chinese subjects after single and multiple doses administration. Methods: From day 1 to day 7, 12 Chinese subjects were given a tablet every day at approximately 10 p.m. Serial blood samples were collected. Niacin and nicotinuric acid (NUA) in plasma, niacin, NUA, N-methylnicotinamide (MNA) and N-methyl-2pyridone-5-carboxamide (2PY) in urine, simvastatin and simvastatin acid in plasma were determined by LC/MS/MS methods. Pharmacokinetic parameters on days 1 and 7 were compared. Results: The main pharmacokinetic parameters for the single and multiple doses were as follows:
Niacin: Tmax were 3.8 ± 1.5 h and 3.9 ± 2.0 h; Cmax were 2 091 ± 1 315 ng/ml and 2 323 ± 1 542 ng/ml; AUC0-t were 4 123.88 ± 3 138.48 ng ∙ h/ml and 4 385.98 ± 3 127.05 ng ∙ h/ml. NUA: Tmax were 4.7 ± 1.7 h and 3.8 ± 1.5 h; Cmax were 1 057 ± 549 ng/ml and 1 087 ± 470 ng/ml; AUC0-t were 4 012.49 ± 2 168.68 ng ∙ h/ml and 4 040.45 ± 1 886.57 ng ∙ h/ml. Simvastatin: Tmax were 1.8 ± 1.0 h and 2.5 ± 2.5 h; Cmax were 3.15 ± 1.67 ng/ml and 4.87 ± 4.11 ng/ml; AUC0-t were 9.03 ± 5.10 ng ∙ h/ml and 17.63 ± 13.93 ng ∙ h/ml. Simvastatin acid: Tmax were 5.8 ± 1.7 h and 6.5 ± 1.4 h; Cmax were 4.22 ± 2.10 ng/ml and 9.30 ± 8.09 ng/ml; AUC0-t were 34.65 ± 16.89 ng ∙ h/ ml and 61.62 ± 46.41 ng ∙ h/ml. Urine Recovery rate of total niacin: (40.55 ± 7.38) % and (62.87 ± 12.04) %. Conclusion: Compared with those after a single dose, pharmacokinetics of niacin and NUA was similar; total urine recovery of niacin was higher; exposure to simvastatin and simvastatin acid were higher following multiple doses.
received 27.05.2013 accepted 23.09.2013 Bibliography DOI http://dx.doi.org/ 10.1055/s-0033-1357190 Published online: October 23, 2013 Drug Res 2014; 64: 296–300 © Georg Thieme Verlag KG Stuttgart · New York ISSN 2194-9379 Correspondence H. C. Liu, PhD Department of Clinical Pharmacology Aerospace Center Hospital 15 Yuquan Road Haidian District Beijing 100049 P. R. China Tel.: + 86/10/59971 772 Fax: + 86/10/59971 773 [email protected]
Introduction
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Simvastatin is a HMG-CoA reductase inhibitor indicated in the treatment of dyslipidemia and acts primarily by reducing total cholesterol (TCs) and low-density lipoprotein cholesterol (LDL-C) [1, 2]. Niacin is indicated in the treatment of dyslipidemia, and although it reduces TCs and LDL-C, it is primarily used to increase high density lipoprotein cholesterol (HDL-C) [3]. Niacin extended release (ER)/simvastatin (Simcor) is a fixed-dose, combined formulation that incorporates niacin ER with simvastatin [4]. Once-daily niacin ER/ simvastatin is approved in the USA to reduce TCs, LDL-C, apolipoprotein B, non-HDL-C or triglycerides, or to increase HDL-C in patients with primary hypercholesterolaemia and mixed dystients lipidaemia, and to reduce triglycerides in patients with hypertriglyceridaemia when monotherapy with simvastatin or niacin ER is considered inadequate for these purposes [4].
Liu M et al. Pharmacokinetics of Niacin, Simvastatin … Drug Res 2014; 64: 296–300
Niacin is extensively metabolized. Niacin undergoes saturable metabolism via 2 major pathways [5]. One pathway is via glycine conjugation with niacin to form nicotinuric acid (NUA). In the other pathway, N-methylnicotinamide (MNA) and N-methyl-2-pyridone-5-carboxamide (2PY) are found to be the major metabolites. Niacin, NUA, MNA and 2PY are the predominant compounds excreted by the kidneys following oral dosing with niacin [3, 6]. In human, NUA and 2PY were thought to be responsible for the flushing side effect and the increased hepatotoxicity of niacin, respectively. Most immediate release niacin preparations are quickly absorbed and saturate the first pathway, and therefore associated more with flushing, but not hepatotoxicity. On the other hand, longacting niacin preparations are absorbed very slowly and selectively metabolized via the second pathway, thus decreasing flushing, but significantly increasing the risk of serious, dose-related
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Pharmacokinetics of Niacin, Simvastatin and their Metabolites in Healthy Chinese Subjects after Single and Multiple Doses of a Fixed Dose Combination Tablet of Niacin Extended Release/Simvastatin
Original Article 297
Material and Methods
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Chemicals and materials Niacin (99.9 %) was purchased from SUPELCO Analytical (USA); NUA (98.0 %) was purchased from Toronto Research Chemicals (Canada); MNA (100 %) was purchased from Sigma-Aldrich (Product of Japan); 2-Pyr (99.8 %) was purchased from TLC PharmaChem (Canada); simvastatin (99.0 %) was purchased from National Institutes for Food and Drug Control (China); and simvastatin acid (99.2 %) was purchased from TLC PharmaChem (Canada). HPLC grade methanol and acetonitrile were purchased from Fisher Scientific (USA). Distilled water used throughout the study was prepared from deionized water. All other chemicals and solvents were commercially available analytical grade materials used without further purification. Blank (drug free) human plasma was obtained from Aerospace Center Hospital (China).
Subjects Eligible subjects were healthy Chinese male and female subjects within 18–45 years of age and 19–24 kg/m2 of body weight index. Subjects had not donated blood and participated in other drug clinical trials within 3 months prior to dosing. Subjects were in good health as determined by past medical history, physical examination, vital signs, electrocardiogram (ECG) and laboratory tests (e.g., hematology, biochemistry and urinalysis) at screening. Subjects were also screened for drugs of abuse, hepatitis B and C, HIV, and pregnancy in female subjects. The assessment of background and demographic data included medical history, current medical conditions, date of birth, sex, race, weight, height, body weight index. All subjects confirmed abstinence from other medications, alcohol, tobacco and caffeinated products throughout the study.
Study designs The research followed the tenets of the Declaration of Helsinki and the protocol approved by the Ethics Committee of Aerospace Center Hospital (Beijing, China). Prior to the start of screening, all subjects gave informed consent after the aims and risks of the study were fully explained. During the study, subjects were confined to the clinic. From day 1 to day 7, subjects were given a tablet of niacin ER/simvastatin which contained niacin 1 000 mg and simvastatin 20 mg per tablet. Each dose was administered with 200 ml of water at approximately 10 p.m. after a low-fat snack. Meals controlled for niacin content were administered at about 8 a.m., noon, 6 p.m. and 9:30 p.m. daily. Blood samples were obtained prior to dosing (0 h) on days 1, 4, 5, 6 and 7, and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 16, 24 h after dosing on day 1 and day 7. Plasma was separated by centrifugation and stored frozen at approximately − 80 °C until analysis. Urine samples were collected in the following intervals: 24–16, 16–8, and 8–0 h prior to dosing on day 1, and 0–8, 8–16, 16–24 h after dosing on day 1 and day 7. Urine sample aliquots were stored frozen at approximately − 80 °C until analysis.
Bioanalysis With modification of those adapted from the literatures [5, 9– 11], LC/MS/MS methods were developed and validated to determine niacin and NUA in plasma; niacin, NUA, MNA and 2PY in urine; simvastatin and simvastatin acid in plasma. An API 3200 triple-quadrupole mass spectrometer (Applied Biosystems/MDS SCIEX, Concord, Ontario, Canada) equipped with an electrospray ionization (ESI) source was used for mass analysis and detection. Analyst software (Applied Biosystems/MDS SCIEX, version 1.4.2) was used for data acquisition and processing. Plasma niacin and NUA were determined from the method A. Urine niacin and NUA determinations were obtained from the method B. Determinations of MNA and 2PY required a method, respectively (method C and method D). Plasma simvastatin and simvastatin acid were determined from the method E. Niacin and NUA in plasma (method A). Plasma samples (200 μl) were prepared by deproteinization with acetonitrile (500 μl), then the supernatant after centrifugation was evaporated and reconstituted. Chromatography was performed on a C18 analytical column (Synergi Hydro-RP 80 A, 150 mm × 2.0 mm i. d., 4 μm, Phenomenex, USA) with an isocratic elution of methanol-0.1 % formic acid (20:80, v/v). Multiple-reaction monitoring (MRM) using the fragmentation transitions of m/z 124.1→80.1 and 181.0→79.0 in positive mode was performed to quantify niacin and NUA, respectively. Niacin and NUA in urine (method B). Urine samples (500 μl) were prepared by liquid-liquid extraction (LLE) with ethyl acetate (3 ml), then the supernatant after centrifugation was evaporated and reconstituted. Chromatography was performed on a C18 analytical column (Shim-pack VP-ODS, 150 mm × 2.0 mm i. d., 5 μm, Shimadzu, Japan) with an isocratic elution of methanol-0.1 % formic acid (10:90, v/v). The MS conditions were same as the above method. MNA in urine (method C). Urine samples (10 μl) were directly injected after dilution with methanol-water (10:90, v/v). Chromatography was performed on a C18 analytical column (Shimpack VP-ODS, 150 mm × 2.0 mm i. d., 5 μm, Shimadzu, Japan) with an isocratic elution of methanol-0.2 % formic acid (10:90, v/v). MRM using the fragmentation transitions of m/z 137.1→94.0 in positive mode was performed to quantify MNA.
Liu M et al. Pharmacokinetics of Niacin, Simvastatin … Drug Res 2014; 64: 296–300
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hepatotoxicity. Therefore, a balanced metabolism between the 2 pathways, which may result in less flushing and less risk of hepatotoxicity, is crucial for niacin ER formulation [7]. Simvastatin is a lactone that is readily hydrolyzed in vivo to simvastatin acid, a potent inhibitor of HMG-CoA reductase. Simvastatin is a pro-drug and simvastatin acid is the active metabolite for efficacy, they are primarily metabolized by cytochrome P450 enzymes, specifically CYP3A4 [2]. Simvastatin acid is substrate of the P-glycoprotein efflux transporter. One literature was to compare the effects of 2 common ABCB1 haplotypes, c.1236Cc.2677 G-c.3435C (CGC) and c.1236 T-c.2677 T-c.3435 T (TTT), on the pharmacokinetics of simvastatin. The simvastatin acid AUC0-12 h was 60 % larger in subjects with the ABCB1 TTT/TTT genotype than in those with the CGC/CGC genotype (P < 0.05) [8]. After radiolabelled simvastatin was administered orally, 13 % of the radioactivity was recovered in the urine ( < 0.5 % as active metabolites) and 60 % in the faeces [2]. The pharmacokinetics of niacin and simvastatin from a fixed dose combination tablet of niacin ER/simvastatin have been described in the US manufacturer’s prescribing information [2, 4]. But the pharmacokinetic profile of the drug in Chinese subjects has not been reported. Recently, a fixed dose combination tablet of niacin ER/simvastatin was developed in China and approved by State Food and Drug Administration (SFDA) of China to be put into phase I clinical trial. The goal of the present study was to characterize the pharmacokinetics of niacin, simvastatin and their metabolites in healthy Chinese subjects. The safety and tolerability were also assessed.
298 Original Article
Pharmacokinetic assessments Pharmacokinetic parameters were calculated using non-compartmental method derived in DAS version 3.0.5 (Mathematical Pharmacology Professional Committee, Chinese Pharmacological Society, China). Cmax: maximum concentration observed post dose; Cmin: minimal concentration observed post dose; Tmax: time at which the Cmax occurred; AUC0-t: area under the concentrationtime curve (AUC) from time zero to the last measurable sampling time point (t), calculated by linear trapezoidal method; AUC0-∞: AUC0-t + Ct/λz, where Ct is the concentration at time t, and λz is the terminal elimination rate constant, λz is estimated by linear regression of the terminal portion of the ln(concentration)-time curve; AUCτ: AUC in a dosing interval at steady-state; T1/2: elimination half-life, determined as 0.693/λz; Cav, ss: average concentration at steady-state calculated as AUCτ/τ, where τ is a dosing interval; AF (AUC): accumulation factor based on AUC calculated as AUCτ/ AUC0-t; FI: fluctuation index calculated as (Cmax, ss-Cmin, ss)/Cav, ss. For niacin and its metabolites (NUA, MNA, 2PY) in urine, the urine recovery for each analyte after correction for baseline recovery and molecular weight was calculated and used to compute the total amount of niacin dose excreted in the urine.
Results
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Assay validation This method has been validated in accordance with the US FDA guidelines for bioanalytical method development. The methods were linear in the concentration ranges of 2.00~4 000 ng/ml for niacin and NUA in plasma, 5.00~5 000 ng/ml for niacin in urine, 0.0100~10.0 μg/ml for NUA in urine, 1.00~100 μg/ml for MNA and 2PY in urine and 0.100–15.0 ng/ml for simvastatin and simvastatin acid in plasma. Intra- and inter-batch RSD was < 15.0 %, and RE was within ± 15.0 % at all QC concentrations. The results of extraction recoveries and matrix effects factors were reproducible.
Study population A total of 12 healthy Chinese subjects, 11 Hans and 1 Mongolian, were enrolled in and completed the study. Of the 12 subjects, 6 were males and 6 were females. The mean ± SD age was 27 ± 6 years. The mean ± SD height and weight were 166 ± 9 cm and 59 ± 8 kg, respectively. The mean ± SD body weight index was 21 ± 1 kg/m2.
Pharmacokinetic properties Plasma niacin and NUA Mean plasma concentration vs. time plots for niacin (a) and NUA (b) in healthy Chinese subjects after single and multiple doses of a tablet of niacin ER/simvastatin (1 000 mg/20 mg) are presented ▶ Fig. 1. Steady-state conditions following 7 days of administrain ●
Statistical analysis Statistical analysis was performed using DAS, Version 3.0.5. Pharmacokinetic parameters of single and multiple doses experiments were expressed as mean ± standard deviation (SD) and compared using the paired t-test was except for Tmax where a paired Wilcoxon test was used. A value of p < 0.05 was considered statistically significant.
Safety evaluation During screening and at study termination, a physical examination, laboratory evaluations (clinical chemistry, hematology, and urinalysis) and ECG were conducted on all subjects. Subjects were monitored throughout the study for adverse events through questions from the clinic staff and were encouraged to report any untoward effects. The severity of each adverse event was determined by the clinic staff based on direct observation and interview with the subject. The investigator judged the relationship of the adverse event to the study treatment. Liu M et al. Pharmacokinetics of Niacin, Simvastatin … Drug Res 2014; 64: 296–300
Fig. 1 Plasma concentration vs. time profiles of niacin a and NUA b in healthy Chinese subjects after single (open circle) and multiple (filled square) doses of a tablet of niacin ER/simvastatin (1 000 mg/20 mg). Data are shown as mean ± SD.
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2PY in urine (method D). Urine samples (10 μl) were directly injected after dilution with methanol-water (20:80, v/v). Chromatography was performed on a C18 analytical column (Shimpack VP-ODS, 150 mm × 2.0 mm i. d., 5 μm, Shimadzu, Japan) with an isocratic elution of methanol-0.1 % formic acid (20:80, v/v). MRM using the fragmentation transitions of m/z 153.1 →108.1 in positive mode was performed to quantify 2PY. Simvastatin and simvastatin acid in plasma (method E). Plasma samples (800 μl) were prepared by liquid-liquid extraction (LLE) with ether-dichloromethane (3 ml), then the supernatant after centrifugation was evaporated and reconstituted. Chromatography was performed on a C18 analytical column (Inertsil ODS-SP, 75 mm × 2.1 mm i. d., 3 μm, GL Scinecnces Inc., Japan) with an isocratic elution of acetonitrile-aqueous 1 mM ammonium acetate (pH 4.50, adjusted with glacial acetic acid) (75:25, v/v). The LC-MS/MS data acquisition for simvastatin was conducted in positive mode using the fragmentation transitions of m/z 436.4→199.3 but the data acquisition for simvastatin acid was conducted in negative mode using the fragmentation transitions of m/z 435.3→115.0. The electrode polarity of the mass spectrometer was switched at 2.0 min.
Original Article 299
Niacin Single dose
Tmax or Tmax,ss (h) Cmax or Cmax,ss (ng/ml) Cmin,ss (ng/ml) Cav or Cav,ss (ng/ml) T1/2 (h) AUC0-t or AUCτ (ng ∙ h/ml) AUC0-∞ (ng ∙ h/ml) AF (AUC) FI
3.8 ± 1.5 2 091 ± 1 315
7.29 ± 3.51 4 123.88 ± 3138.48 4 166.19 ± 3 136.81
NUA
Multiple doses 3.9 ± 2.0 2 323 ± 1542 6.56 ± 2.35 182.75 ± 130.29 8.34 ± 2.78 4 385.98 ± 3 127.05 4 465.99 ± 3 108.96 1.41 ± 1.02 14.29 ± 8.03
Table 2 Urine recovery of niacin and its metabolites in healthy Chinese subjects after single and multiple doses of a tablet of niacin ER/simvastatin (1 000 mg/20 mg). Data are shown as mean ± SD. Compound Niacin (mg) NUA (mg) MNA (mg) 2PY (mg) Total recovery of niacin (mg) Recovery rate of niacin ( %)
Single dose 23.96 ± 19.58 93.45 ± 34.46 116.28 ± 34.67 263.11 ± 29.09 405.53 ± 73.77 40.55 ± 7.38
Multiple doses 25.38 ± 18.84 101.75 ± 39.81 286.75 ± 97.56* 340.26 ± 92.58* 628.72 ± 120.38* 62.87 ± 12.04*
*p < 0.05, significantly different compared with single dose
Single dose 4.7 ± 1.7 1 057 ± 549
2.31 ± 1.48 4 012.49 ± 2 168.68 4 023.53 ± 2 172.77
Multiple doses 3.8 ± 1.5 1087 ± 470 1.00 ± 1.19 513.92 ± 258.84 2.37 ± 0.79 4 040.45 ± 1 886.57 4 055.63 ± 1 887.89 0.86 ± 0.43 2.20 ± 0.37
Table 1 Pharmacokinetic parameters of niacin and NUA in healthy Chinese subjects after single and multiple doses of a tablet of niacin ER/simvastatin (1000 mg/20 mg). Data are shown as mean ± SD.
tion of the investigational drug were achieved as assessed by plasma niacin concentrations at predose and at 24 h postdose on day 7. Pharmacokinetic parameters of niacin and NUA are provided ▶ Table 1. Pharmacokinetic parameters of niacin and NUA in ● after multiple doses were identical to those after a single dose.
Urine recovery of niacin and its metabolites Urine recovery of niacin and its metabolites in healthy Chinese subjects after single and multiple doses of a tablet of niacin ER/ ▶ Table 2. Urine simvastatin (1 000mg/20 mg) are provided in ● recovery of MNA, 2PY and total niacin (niacin, NUA, MNA and 2PY) were higher after multiple doses than those after a single dose.
Plasma simvastatin and simvastatin acid Mean plasma concentration vs. time plots for simvastatin (a) and simvastatin acid (b) in healthy Chinese subjects after single and multiple doses of a tablet of niacin ER/simvastatin ▶ Fig. 2. Steady-state condi(1 000 mg/20 mg) are presented in ● tions following 7 days of administration of the investigational drug were achieved as assessed by plasma simvastatin acid concentrations at predose and at 24 h postdose on day 7. Pharmacokinetic parameters of simvastatin and simvastatin acid are ▶ Table 3. Compared with those after a single dose, provided in ● AUC values of simvastatin were about 2-fold higher after multiple doses; AUC values of simvastatin acid were also about 2-fold higher, although the difference was not significant; Cmax and T1/2 values of simvastatin acid were higher after multiple doses.
Tolerability No subjects discontinued because of an adverse event. There was no death or serious adverse events during the study. A total of 49 adverse events were reported by 10 of the 12 subjects after administration of the investigational drug. Of the 49 adverse event reported, 42 episodes (85.7 %) were suspected to be related to the investigational drug. Overall, the most common adverse event was flushing (36 episodes), the others were respectively abdominal pain, hyperuricemia, headache, hyperglycemia, elevated alanine aminotransferase and elevated glutamic oxaloacetic transaminase. All adverse events were mild in intensity and relieved without any treatment.
Fig. 2 Plasma concentration vs. time profiles of simvastatin a and simvastatin acid b in healthy Chinese subjects after single (open circle) and multiple (filled square) doses of a tablet of niacin ER/simvastatin (1 000 mg/20 mg). Data are shown as mean ± SD.
Discussion
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Pharmacokinetic parameters of niacin and NUA after multiple doses of a tablet of niacin ER/simvastatin were similar to that observed following a single dose, indicating that the absorption and elimination of niacin were similar following single and mulLiu M et al. Pharmacokinetics of Niacin, Simvastatin … Drug Res 2014; 64: 296–300
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PK parameter
300 Original Article
PK parameter
Simvastatin Single dose
Tmax or Tmax,ss (h) Cmax or Cmax,ss (ng/ml) Cmin,ss (ng/ml) Cav or Cav,ss (ng/ml) T1/2 (h) AUC0-t or AUCτ (ng ∙ h/ml) AUC0-∞ (ng ∙ h/ml) AF (AUC) FI
1.8 ± 1.0 3.15 ± 1.67
3.13 ± 1.01 9.03 ± 5.10 9.67 ± 5.24
Multiple doses
Simvastatin acid Single dose
2.5 ± 2.5 4.87 ± 4.11 0 0.73 ± 0.58 3.64 ± 1.68 17.63 ± 13.93* 18.40 ± 14.22* 1.88 ± 0.54 6.44 ± 2.07
5.8 ± 1.7 4.22 ± 2.10
3.17 ± 0.50 34.65 ± 16.89 35.89 ± 16.60
Multiple doses 6.5 ± 1.4 9.30 ± 8.09* 0.35 ± 0.38 2.74 ± 1.93 4.09 ± 1.08* 61.62 ± 46.41 63.88 ± 48.99 1.82 ± 1.00 3.29 ± 1.06
Table 3 Pharmacokinetic parameters of simvastatin and simvastatin acid in healthy Chinese subjects after single and multiple doses of a tablet of niacin ER/simvastatin (1000 mg/20 mg). Data are shown as mean ± SD.
*p < 0.05, significantly different compared with single dose
Compound
Tmax (h)
Cmax (ng/ml)
AUC0-t (ng•h/ml)
Niacin NUA Simvastatin Simvastatin acid
4.643 ± 1.782 5.095 ± 1.620 1.881 ± 1.041 5.321 ± 2.424
734 ± 959 1 230 ± 741 12.273 ± 7.319 3.469 ± 3.176
1 548 ± 1 860 5 121 ± 3 268 42.622 ± 18.719 31.209 ± 25.922
In conclusion, compared with those after a single dose of a tablet of niacin ER/simvastatin, which has been developed in China, pharmacokinetics of niacin and NUA was similar, total urine recovery of niacin was higher, exposure to simvastatin and simvastatin acid were higher following multiple doses.
Conflict of Interest
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We declare that we have no conflict of interest. tiple doses. Compared with that after a single dose, the urine recovery of MNA, 2PY and total niacin were higher after multiple doses. The reason might be due to the slower elimination of MNA and 2PY [12]. AUC value of simvastatin, Cmax and T1/2 values of simvastatin acid after multiple doses of a tablet of niacin ER/simvastatin were higher than that observed following a single dose, indicating that there was some accumulation of simvastatin and simvastatin acid after multiple doses. The accumulation factor might be higher than that after only administration simvastatin, since coadministration of niacin ER/simvastatin increased exposure to simvastatin and simvastatin acid [2, 13]. Pharmacokinetic parameters of a single dose of 2 tablets of niacin ER/simvastatin (500 mg/20 mg) in the USA study are pro▶ Table 4. By comparison with the T vided in ● max values of niacin and NUA of the similar product developed in USA [2], it was known that the niacin absorption rate of the investigational drug might be a little faster. After a single dose at the same level, exposure (AUC and Cmax) to niacin observed in the present study was much higher than that found with the similar product developed in USA. After oral administration of simvastatin in healthy volunteers, linear pharmacokinetics was found at doses from 5 to 120 mg. Compared with those of the similar product developed in USA, Cmax and AUC values of simvastatin after a single dose in the present study were lower when the doses were judged to the same level [2]. However, Cmax and AUC values of simvastatin acid were higher than those in the USA study, even the dose of simvastatin in that study was 40 mg [2]. These differences observed might be attributed to the differences in trial subjects and the drug formulations. However, the subject population in the study in USA was not showed out in the literature [2]. In the USA study, 38 (88.4 %) out of the 43 subjects reported at least one adverse event. 75.7 % adverse events were classified as probably related to the study medications. 15.5 % adverse events were classified as possibly related to the study medications. The most common adverse event was flushing, experienced by 37 (86.0 %) subjects following the treatment. All the reported adverse events were mild in intensity. Liu M et al. Pharmacokinetics of Niacin, Simvastatin … Drug Res 2014; 64: 296–300
References 1 Hess DC, Fagan S. Pharmacology and clinical experience with simvastatin. Exp Opin Pharmacother 2001; 2: 153–163 2 Abbott. Simcor: clinical pharmacology and biopharmaceutics review(s) [Online] Available at http://www.accessdata.fda.gov/scripts/ cder/drugsatfda/index.cfm?fuseaction = Search.DrugDetails Accessed on 9 April 2012 3 Mccormack PL, Keating GM. Prolonged-release nicotinic acid: a review of its use in the treatment of dyslipidaemia. Drugs 2005; 65: 2719– 2740 4 Abbott. Simcor: prescribing information [online] Available at: http:// www.fda.gov/cder/foi/label/2008/022078lbl Accessed on 9 Sep 2008 5 Mullangi R, Srinivas NR. Niacin and its metabolites: role of LC-MS/ MS bioanalytical methods and update on clinical pharmacology. An overview. Biomed Chromatogr 2011; 25: 218–237 6 Felsted R, Chaykin S. N-Methylnicotinamide oxidation in a number of mammals. J Biol Chem 1967; 242: 1274–1279 7 Piepho RW. The pharmacokinetics and pharmacodynamics of agents proven to raise high-density lipoprotein cholesterol. Am J Cardiol 2000; 86: 35L–40L 8 Keskitalo JE, Kurkinen KJ, Neuvonen PJ et al. ABCB1 haplotypes differentially affect the pharmacokinetics of the acid and lactone forms of simvastatin and atorvastatin. Clin Pharmacol Ther 2008; 84: 457–461 9 Szafarz M, Lomnicka M, Sternak M et al. Simultaneous determination of nicotinic acid and its four metabolites in rat plasma using high performance liquid chromatography with tandem mass spectrometric detection (LC/MS/MS). J Chromatogr B 2010; 878: 895–902 10 Apostolou C, Kousoulos C, Dotsikas Y et al. An improved and fully validated LC-MS/MS method for the simultaneous quantification of simvastatin and simvastatin acid in human plasma. J Pharm Biomed Anal 2008; 46: 771–779 11 Patel BN, Sharma N, Sanyal M et al. Simultaneous determination of simvastatin and simvastatin acid in human plasma by LC-MS/MS without polarity switch: Application to a bioequivalence study. J Sep Sci 2008; 31: 301–313 12 Menon R, Tolbert D, Cefali E. The comparative bioavailability of an extended-release niacin and lovastatin fixed dose combination tablet versus extended-release niacin tablet, lovastatin tablet and a combination of extended-release niacin tablet and lovastatin tablet. Biopharm Drug Dispos 2007; 28: 297–306 13 Jang SB, Lee YJ, Lim LA et al. Pharmacokinetic comparison of controlled-release and immediate-release oral formulations of simvastatin in healthy Korean subjects: a randomized, open-label, parallel-group, single- and multiple-dose study. Clinical Therapeutics 2010; 32: 206–216
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Table 4 Pharmacokinetic parameters of a single dose of 2 tablets of niacin ER/simvastatin (500mg/20 mg) in the USA study. Data are shown as mean ± SD.
Authors
M. Liu, X. L. Wang, D. Zhang, M. Yang, J. Han, Y. N. Zhang, Z. L. Wang, H. C. Liu
Affiliation
Department of Clinical Pharmacology, Aerospace Center Hospital, Beijing, P. R. China
Key words
Abstract
▶ niacin ● ▶ nicotinuric acid ● ▶ simvastatin ● ▶ simvastatin acid ● ▶ pharmacokinetics ●
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Objective: A fixed dose combination tablet of niacin extended release (ER)/simvastatin was recently developed in China. This study was designed to assess and compare the pharmacokinetics of niacin, simvastatin and their metabolites in healthy Chinese subjects after single and multiple doses administration. Methods: From day 1 to day 7, 12 Chinese subjects were given a tablet every day at approximately 10 p.m. Serial blood samples were collected. Niacin and nicotinuric acid (NUA) in plasma, niacin, NUA, N-methylnicotinamide (MNA) and N-methyl-2pyridone-5-carboxamide (2PY) in urine, simvastatin and simvastatin acid in plasma were determined by LC/MS/MS methods. Pharmacokinetic parameters on days 1 and 7 were compared. Results: The main pharmacokinetic parameters for the single and multiple doses were as follows:
Niacin: Tmax were 3.8 ± 1.5 h and 3.9 ± 2.0 h; Cmax were 2 091 ± 1 315 ng/ml and 2 323 ± 1 542 ng/ml; AUC0-t were 4 123.88 ± 3 138.48 ng ∙ h/ml and 4 385.98 ± 3 127.05 ng ∙ h/ml. NUA: Tmax were 4.7 ± 1.7 h and 3.8 ± 1.5 h; Cmax were 1 057 ± 549 ng/ml and 1 087 ± 470 ng/ml; AUC0-t were 4 012.49 ± 2 168.68 ng ∙ h/ml and 4 040.45 ± 1 886.57 ng ∙ h/ml. Simvastatin: Tmax were 1.8 ± 1.0 h and 2.5 ± 2.5 h; Cmax were 3.15 ± 1.67 ng/ml and 4.87 ± 4.11 ng/ml; AUC0-t were 9.03 ± 5.10 ng ∙ h/ml and 17.63 ± 13.93 ng ∙ h/ml. Simvastatin acid: Tmax were 5.8 ± 1.7 h and 6.5 ± 1.4 h; Cmax were 4.22 ± 2.10 ng/ml and 9.30 ± 8.09 ng/ml; AUC0-t were 34.65 ± 16.89 ng ∙ h/ ml and 61.62 ± 46.41 ng ∙ h/ml. Urine Recovery rate of total niacin: (40.55 ± 7.38) % and (62.87 ± 12.04) %. Conclusion: Compared with those after a single dose, pharmacokinetics of niacin and NUA was similar; total urine recovery of niacin was higher; exposure to simvastatin and simvastatin acid were higher following multiple doses.
received 27.05.2013 accepted 23.09.2013 Bibliography DOI http://dx.doi.org/ 10.1055/s-0033-1357190 Published online: October 23, 2013 Drug Res 2014; 64: 296–300 © Georg Thieme Verlag KG Stuttgart · New York ISSN 2194-9379 Correspondence H. C. Liu, PhD Department of Clinical Pharmacology Aerospace Center Hospital 15 Yuquan Road Haidian District Beijing 100049 P. R. China Tel.: + 86/10/59971 772 Fax: + 86/10/59971 773 [email protected]
Introduction
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Simvastatin is a HMG-CoA reductase inhibitor indicated in the treatment of dyslipidemia and acts primarily by reducing total cholesterol (TCs) and low-density lipoprotein cholesterol (LDL-C) [1, 2]. Niacin is indicated in the treatment of dyslipidemia, and although it reduces TCs and LDL-C, it is primarily used to increase high density lipoprotein cholesterol (HDL-C) [3]. Niacin extended release (ER)/simvastatin (Simcor) is a fixed-dose, combined formulation that incorporates niacin ER with simvastatin [4]. Once-daily niacin ER/ simvastatin is approved in the USA to reduce TCs, LDL-C, apolipoprotein B, non-HDL-C or triglycerides, or to increase HDL-C in patients with primary hypercholesterolaemia and mixed dystients lipidaemia, and to reduce triglycerides in patients with hypertriglyceridaemia when monotherapy with simvastatin or niacin ER is considered inadequate for these purposes [4].
Liu M et al. Pharmacokinetics of Niacin, Simvastatin … Drug Res 2014; 64: 296–300
Niacin is extensively metabolized. Niacin undergoes saturable metabolism via 2 major pathways [5]. One pathway is via glycine conjugation with niacin to form nicotinuric acid (NUA). In the other pathway, N-methylnicotinamide (MNA) and N-methyl-2-pyridone-5-carboxamide (2PY) are found to be the major metabolites. Niacin, NUA, MNA and 2PY are the predominant compounds excreted by the kidneys following oral dosing with niacin [3, 6]. In human, NUA and 2PY were thought to be responsible for the flushing side effect and the increased hepatotoxicity of niacin, respectively. Most immediate release niacin preparations are quickly absorbed and saturate the first pathway, and therefore associated more with flushing, but not hepatotoxicity. On the other hand, longacting niacin preparations are absorbed very slowly and selectively metabolized via the second pathway, thus decreasing flushing, but significantly increasing the risk of serious, dose-related
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Pharmacokinetics of Niacin, Simvastatin and their Metabolites in Healthy Chinese Subjects after Single and Multiple Doses of a Fixed Dose Combination Tablet of Niacin Extended Release/Simvastatin
Original Article 297
Material and Methods
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Chemicals and materials Niacin (99.9 %) was purchased from SUPELCO Analytical (USA); NUA (98.0 %) was purchased from Toronto Research Chemicals (Canada); MNA (100 %) was purchased from Sigma-Aldrich (Product of Japan); 2-Pyr (99.8 %) was purchased from TLC PharmaChem (Canada); simvastatin (99.0 %) was purchased from National Institutes for Food and Drug Control (China); and simvastatin acid (99.2 %) was purchased from TLC PharmaChem (Canada). HPLC grade methanol and acetonitrile were purchased from Fisher Scientific (USA). Distilled water used throughout the study was prepared from deionized water. All other chemicals and solvents were commercially available analytical grade materials used without further purification. Blank (drug free) human plasma was obtained from Aerospace Center Hospital (China).
Subjects Eligible subjects were healthy Chinese male and female subjects within 18–45 years of age and 19–24 kg/m2 of body weight index. Subjects had not donated blood and participated in other drug clinical trials within 3 months prior to dosing. Subjects were in good health as determined by past medical history, physical examination, vital signs, electrocardiogram (ECG) and laboratory tests (e.g., hematology, biochemistry and urinalysis) at screening. Subjects were also screened for drugs of abuse, hepatitis B and C, HIV, and pregnancy in female subjects. The assessment of background and demographic data included medical history, current medical conditions, date of birth, sex, race, weight, height, body weight index. All subjects confirmed abstinence from other medications, alcohol, tobacco and caffeinated products throughout the study.
Study designs The research followed the tenets of the Declaration of Helsinki and the protocol approved by the Ethics Committee of Aerospace Center Hospital (Beijing, China). Prior to the start of screening, all subjects gave informed consent after the aims and risks of the study were fully explained. During the study, subjects were confined to the clinic. From day 1 to day 7, subjects were given a tablet of niacin ER/simvastatin which contained niacin 1 000 mg and simvastatin 20 mg per tablet. Each dose was administered with 200 ml of water at approximately 10 p.m. after a low-fat snack. Meals controlled for niacin content were administered at about 8 a.m., noon, 6 p.m. and 9:30 p.m. daily. Blood samples were obtained prior to dosing (0 h) on days 1, 4, 5, 6 and 7, and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 16, 24 h after dosing on day 1 and day 7. Plasma was separated by centrifugation and stored frozen at approximately − 80 °C until analysis. Urine samples were collected in the following intervals: 24–16, 16–8, and 8–0 h prior to dosing on day 1, and 0–8, 8–16, 16–24 h after dosing on day 1 and day 7. Urine sample aliquots were stored frozen at approximately − 80 °C until analysis.
Bioanalysis With modification of those adapted from the literatures [5, 9– 11], LC/MS/MS methods were developed and validated to determine niacin and NUA in plasma; niacin, NUA, MNA and 2PY in urine; simvastatin and simvastatin acid in plasma. An API 3200 triple-quadrupole mass spectrometer (Applied Biosystems/MDS SCIEX, Concord, Ontario, Canada) equipped with an electrospray ionization (ESI) source was used for mass analysis and detection. Analyst software (Applied Biosystems/MDS SCIEX, version 1.4.2) was used for data acquisition and processing. Plasma niacin and NUA were determined from the method A. Urine niacin and NUA determinations were obtained from the method B. Determinations of MNA and 2PY required a method, respectively (method C and method D). Plasma simvastatin and simvastatin acid were determined from the method E. Niacin and NUA in plasma (method A). Plasma samples (200 μl) were prepared by deproteinization with acetonitrile (500 μl), then the supernatant after centrifugation was evaporated and reconstituted. Chromatography was performed on a C18 analytical column (Synergi Hydro-RP 80 A, 150 mm × 2.0 mm i. d., 4 μm, Phenomenex, USA) with an isocratic elution of methanol-0.1 % formic acid (20:80, v/v). Multiple-reaction monitoring (MRM) using the fragmentation transitions of m/z 124.1→80.1 and 181.0→79.0 in positive mode was performed to quantify niacin and NUA, respectively. Niacin and NUA in urine (method B). Urine samples (500 μl) were prepared by liquid-liquid extraction (LLE) with ethyl acetate (3 ml), then the supernatant after centrifugation was evaporated and reconstituted. Chromatography was performed on a C18 analytical column (Shim-pack VP-ODS, 150 mm × 2.0 mm i. d., 5 μm, Shimadzu, Japan) with an isocratic elution of methanol-0.1 % formic acid (10:90, v/v). The MS conditions were same as the above method. MNA in urine (method C). Urine samples (10 μl) were directly injected after dilution with methanol-water (10:90, v/v). Chromatography was performed on a C18 analytical column (Shimpack VP-ODS, 150 mm × 2.0 mm i. d., 5 μm, Shimadzu, Japan) with an isocratic elution of methanol-0.2 % formic acid (10:90, v/v). MRM using the fragmentation transitions of m/z 137.1→94.0 in positive mode was performed to quantify MNA.
Liu M et al. Pharmacokinetics of Niacin, Simvastatin … Drug Res 2014; 64: 296–300
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hepatotoxicity. Therefore, a balanced metabolism between the 2 pathways, which may result in less flushing and less risk of hepatotoxicity, is crucial for niacin ER formulation [7]. Simvastatin is a lactone that is readily hydrolyzed in vivo to simvastatin acid, a potent inhibitor of HMG-CoA reductase. Simvastatin is a pro-drug and simvastatin acid is the active metabolite for efficacy, they are primarily metabolized by cytochrome P450 enzymes, specifically CYP3A4 [2]. Simvastatin acid is substrate of the P-glycoprotein efflux transporter. One literature was to compare the effects of 2 common ABCB1 haplotypes, c.1236Cc.2677 G-c.3435C (CGC) and c.1236 T-c.2677 T-c.3435 T (TTT), on the pharmacokinetics of simvastatin. The simvastatin acid AUC0-12 h was 60 % larger in subjects with the ABCB1 TTT/TTT genotype than in those with the CGC/CGC genotype (P < 0.05) [8]. After radiolabelled simvastatin was administered orally, 13 % of the radioactivity was recovered in the urine ( < 0.5 % as active metabolites) and 60 % in the faeces [2]. The pharmacokinetics of niacin and simvastatin from a fixed dose combination tablet of niacin ER/simvastatin have been described in the US manufacturer’s prescribing information [2, 4]. But the pharmacokinetic profile of the drug in Chinese subjects has not been reported. Recently, a fixed dose combination tablet of niacin ER/simvastatin was developed in China and approved by State Food and Drug Administration (SFDA) of China to be put into phase I clinical trial. The goal of the present study was to characterize the pharmacokinetics of niacin, simvastatin and their metabolites in healthy Chinese subjects. The safety and tolerability were also assessed.
298 Original Article
Pharmacokinetic assessments Pharmacokinetic parameters were calculated using non-compartmental method derived in DAS version 3.0.5 (Mathematical Pharmacology Professional Committee, Chinese Pharmacological Society, China). Cmax: maximum concentration observed post dose; Cmin: minimal concentration observed post dose; Tmax: time at which the Cmax occurred; AUC0-t: area under the concentrationtime curve (AUC) from time zero to the last measurable sampling time point (t), calculated by linear trapezoidal method; AUC0-∞: AUC0-t + Ct/λz, where Ct is the concentration at time t, and λz is the terminal elimination rate constant, λz is estimated by linear regression of the terminal portion of the ln(concentration)-time curve; AUCτ: AUC in a dosing interval at steady-state; T1/2: elimination half-life, determined as 0.693/λz; Cav, ss: average concentration at steady-state calculated as AUCτ/τ, where τ is a dosing interval; AF (AUC): accumulation factor based on AUC calculated as AUCτ/ AUC0-t; FI: fluctuation index calculated as (Cmax, ss-Cmin, ss)/Cav, ss. For niacin and its metabolites (NUA, MNA, 2PY) in urine, the urine recovery for each analyte after correction for baseline recovery and molecular weight was calculated and used to compute the total amount of niacin dose excreted in the urine.
Results
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Assay validation This method has been validated in accordance with the US FDA guidelines for bioanalytical method development. The methods were linear in the concentration ranges of 2.00~4 000 ng/ml for niacin and NUA in plasma, 5.00~5 000 ng/ml for niacin in urine, 0.0100~10.0 μg/ml for NUA in urine, 1.00~100 μg/ml for MNA and 2PY in urine and 0.100–15.0 ng/ml for simvastatin and simvastatin acid in plasma. Intra- and inter-batch RSD was < 15.0 %, and RE was within ± 15.0 % at all QC concentrations. The results of extraction recoveries and matrix effects factors were reproducible.
Study population A total of 12 healthy Chinese subjects, 11 Hans and 1 Mongolian, were enrolled in and completed the study. Of the 12 subjects, 6 were males and 6 were females. The mean ± SD age was 27 ± 6 years. The mean ± SD height and weight were 166 ± 9 cm and 59 ± 8 kg, respectively. The mean ± SD body weight index was 21 ± 1 kg/m2.
Pharmacokinetic properties Plasma niacin and NUA Mean plasma concentration vs. time plots for niacin (a) and NUA (b) in healthy Chinese subjects after single and multiple doses of a tablet of niacin ER/simvastatin (1 000 mg/20 mg) are presented ▶ Fig. 1. Steady-state conditions following 7 days of administrain ●
Statistical analysis Statistical analysis was performed using DAS, Version 3.0.5. Pharmacokinetic parameters of single and multiple doses experiments were expressed as mean ± standard deviation (SD) and compared using the paired t-test was except for Tmax where a paired Wilcoxon test was used. A value of p < 0.05 was considered statistically significant.
Safety evaluation During screening and at study termination, a physical examination, laboratory evaluations (clinical chemistry, hematology, and urinalysis) and ECG were conducted on all subjects. Subjects were monitored throughout the study for adverse events through questions from the clinic staff and were encouraged to report any untoward effects. The severity of each adverse event was determined by the clinic staff based on direct observation and interview with the subject. The investigator judged the relationship of the adverse event to the study treatment. Liu M et al. Pharmacokinetics of Niacin, Simvastatin … Drug Res 2014; 64: 296–300
Fig. 1 Plasma concentration vs. time profiles of niacin a and NUA b in healthy Chinese subjects after single (open circle) and multiple (filled square) doses of a tablet of niacin ER/simvastatin (1 000 mg/20 mg). Data are shown as mean ± SD.
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2PY in urine (method D). Urine samples (10 μl) were directly injected after dilution with methanol-water (20:80, v/v). Chromatography was performed on a C18 analytical column (Shimpack VP-ODS, 150 mm × 2.0 mm i. d., 5 μm, Shimadzu, Japan) with an isocratic elution of methanol-0.1 % formic acid (20:80, v/v). MRM using the fragmentation transitions of m/z 153.1 →108.1 in positive mode was performed to quantify 2PY. Simvastatin and simvastatin acid in plasma (method E). Plasma samples (800 μl) were prepared by liquid-liquid extraction (LLE) with ether-dichloromethane (3 ml), then the supernatant after centrifugation was evaporated and reconstituted. Chromatography was performed on a C18 analytical column (Inertsil ODS-SP, 75 mm × 2.1 mm i. d., 3 μm, GL Scinecnces Inc., Japan) with an isocratic elution of acetonitrile-aqueous 1 mM ammonium acetate (pH 4.50, adjusted with glacial acetic acid) (75:25, v/v). The LC-MS/MS data acquisition for simvastatin was conducted in positive mode using the fragmentation transitions of m/z 436.4→199.3 but the data acquisition for simvastatin acid was conducted in negative mode using the fragmentation transitions of m/z 435.3→115.0. The electrode polarity of the mass spectrometer was switched at 2.0 min.
Original Article 299
Niacin Single dose
Tmax or Tmax,ss (h) Cmax or Cmax,ss (ng/ml) Cmin,ss (ng/ml) Cav or Cav,ss (ng/ml) T1/2 (h) AUC0-t or AUCτ (ng ∙ h/ml) AUC0-∞ (ng ∙ h/ml) AF (AUC) FI
3.8 ± 1.5 2 091 ± 1 315
7.29 ± 3.51 4 123.88 ± 3138.48 4 166.19 ± 3 136.81
NUA
Multiple doses 3.9 ± 2.0 2 323 ± 1542 6.56 ± 2.35 182.75 ± 130.29 8.34 ± 2.78 4 385.98 ± 3 127.05 4 465.99 ± 3 108.96 1.41 ± 1.02 14.29 ± 8.03
Table 2 Urine recovery of niacin and its metabolites in healthy Chinese subjects after single and multiple doses of a tablet of niacin ER/simvastatin (1 000 mg/20 mg). Data are shown as mean ± SD. Compound Niacin (mg) NUA (mg) MNA (mg) 2PY (mg) Total recovery of niacin (mg) Recovery rate of niacin ( %)
Single dose 23.96 ± 19.58 93.45 ± 34.46 116.28 ± 34.67 263.11 ± 29.09 405.53 ± 73.77 40.55 ± 7.38
Multiple doses 25.38 ± 18.84 101.75 ± 39.81 286.75 ± 97.56* 340.26 ± 92.58* 628.72 ± 120.38* 62.87 ± 12.04*
*p < 0.05, significantly different compared with single dose
Single dose 4.7 ± 1.7 1 057 ± 549
2.31 ± 1.48 4 012.49 ± 2 168.68 4 023.53 ± 2 172.77
Multiple doses 3.8 ± 1.5 1087 ± 470 1.00 ± 1.19 513.92 ± 258.84 2.37 ± 0.79 4 040.45 ± 1 886.57 4 055.63 ± 1 887.89 0.86 ± 0.43 2.20 ± 0.37
Table 1 Pharmacokinetic parameters of niacin and NUA in healthy Chinese subjects after single and multiple doses of a tablet of niacin ER/simvastatin (1000 mg/20 mg). Data are shown as mean ± SD.
tion of the investigational drug were achieved as assessed by plasma niacin concentrations at predose and at 24 h postdose on day 7. Pharmacokinetic parameters of niacin and NUA are provided ▶ Table 1. Pharmacokinetic parameters of niacin and NUA in ● after multiple doses were identical to those after a single dose.
Urine recovery of niacin and its metabolites Urine recovery of niacin and its metabolites in healthy Chinese subjects after single and multiple doses of a tablet of niacin ER/ ▶ Table 2. Urine simvastatin (1 000mg/20 mg) are provided in ● recovery of MNA, 2PY and total niacin (niacin, NUA, MNA and 2PY) were higher after multiple doses than those after a single dose.
Plasma simvastatin and simvastatin acid Mean plasma concentration vs. time plots for simvastatin (a) and simvastatin acid (b) in healthy Chinese subjects after single and multiple doses of a tablet of niacin ER/simvastatin ▶ Fig. 2. Steady-state condi(1 000 mg/20 mg) are presented in ● tions following 7 days of administration of the investigational drug were achieved as assessed by plasma simvastatin acid concentrations at predose and at 24 h postdose on day 7. Pharmacokinetic parameters of simvastatin and simvastatin acid are ▶ Table 3. Compared with those after a single dose, provided in ● AUC values of simvastatin were about 2-fold higher after multiple doses; AUC values of simvastatin acid were also about 2-fold higher, although the difference was not significant; Cmax and T1/2 values of simvastatin acid were higher after multiple doses.
Tolerability No subjects discontinued because of an adverse event. There was no death or serious adverse events during the study. A total of 49 adverse events were reported by 10 of the 12 subjects after administration of the investigational drug. Of the 49 adverse event reported, 42 episodes (85.7 %) were suspected to be related to the investigational drug. Overall, the most common adverse event was flushing (36 episodes), the others were respectively abdominal pain, hyperuricemia, headache, hyperglycemia, elevated alanine aminotransferase and elevated glutamic oxaloacetic transaminase. All adverse events were mild in intensity and relieved without any treatment.
Fig. 2 Plasma concentration vs. time profiles of simvastatin a and simvastatin acid b in healthy Chinese subjects after single (open circle) and multiple (filled square) doses of a tablet of niacin ER/simvastatin (1 000 mg/20 mg). Data are shown as mean ± SD.
Discussion
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Pharmacokinetic parameters of niacin and NUA after multiple doses of a tablet of niacin ER/simvastatin were similar to that observed following a single dose, indicating that the absorption and elimination of niacin were similar following single and mulLiu M et al. Pharmacokinetics of Niacin, Simvastatin … Drug Res 2014; 64: 296–300
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PK parameter
300 Original Article
PK parameter
Simvastatin Single dose
Tmax or Tmax,ss (h) Cmax or Cmax,ss (ng/ml) Cmin,ss (ng/ml) Cav or Cav,ss (ng/ml) T1/2 (h) AUC0-t or AUCτ (ng ∙ h/ml) AUC0-∞ (ng ∙ h/ml) AF (AUC) FI
1.8 ± 1.0 3.15 ± 1.67
3.13 ± 1.01 9.03 ± 5.10 9.67 ± 5.24
Multiple doses
Simvastatin acid Single dose
2.5 ± 2.5 4.87 ± 4.11 0 0.73 ± 0.58 3.64 ± 1.68 17.63 ± 13.93* 18.40 ± 14.22* 1.88 ± 0.54 6.44 ± 2.07
5.8 ± 1.7 4.22 ± 2.10
3.17 ± 0.50 34.65 ± 16.89 35.89 ± 16.60
Multiple doses 6.5 ± 1.4 9.30 ± 8.09* 0.35 ± 0.38 2.74 ± 1.93 4.09 ± 1.08* 61.62 ± 46.41 63.88 ± 48.99 1.82 ± 1.00 3.29 ± 1.06
Table 3 Pharmacokinetic parameters of simvastatin and simvastatin acid in healthy Chinese subjects after single and multiple doses of a tablet of niacin ER/simvastatin (1000 mg/20 mg). Data are shown as mean ± SD.
*p < 0.05, significantly different compared with single dose
Compound
Tmax (h)
Cmax (ng/ml)
AUC0-t (ng•h/ml)
Niacin NUA Simvastatin Simvastatin acid
4.643 ± 1.782 5.095 ± 1.620 1.881 ± 1.041 5.321 ± 2.424
734 ± 959 1 230 ± 741 12.273 ± 7.319 3.469 ± 3.176
1 548 ± 1 860 5 121 ± 3 268 42.622 ± 18.719 31.209 ± 25.922
In conclusion, compared with those after a single dose of a tablet of niacin ER/simvastatin, which has been developed in China, pharmacokinetics of niacin and NUA was similar, total urine recovery of niacin was higher, exposure to simvastatin and simvastatin acid were higher following multiple doses.
Conflict of Interest
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We declare that we have no conflict of interest. tiple doses. Compared with that after a single dose, the urine recovery of MNA, 2PY and total niacin were higher after multiple doses. The reason might be due to the slower elimination of MNA and 2PY [12]. AUC value of simvastatin, Cmax and T1/2 values of simvastatin acid after multiple doses of a tablet of niacin ER/simvastatin were higher than that observed following a single dose, indicating that there was some accumulation of simvastatin and simvastatin acid after multiple doses. The accumulation factor might be higher than that after only administration simvastatin, since coadministration of niacin ER/simvastatin increased exposure to simvastatin and simvastatin acid [2, 13]. Pharmacokinetic parameters of a single dose of 2 tablets of niacin ER/simvastatin (500 mg/20 mg) in the USA study are pro▶ Table 4. By comparison with the T vided in ● max values of niacin and NUA of the similar product developed in USA [2], it was known that the niacin absorption rate of the investigational drug might be a little faster. After a single dose at the same level, exposure (AUC and Cmax) to niacin observed in the present study was much higher than that found with the similar product developed in USA. After oral administration of simvastatin in healthy volunteers, linear pharmacokinetics was found at doses from 5 to 120 mg. Compared with those of the similar product developed in USA, Cmax and AUC values of simvastatin after a single dose in the present study were lower when the doses were judged to the same level [2]. However, Cmax and AUC values of simvastatin acid were higher than those in the USA study, even the dose of simvastatin in that study was 40 mg [2]. These differences observed might be attributed to the differences in trial subjects and the drug formulations. However, the subject population in the study in USA was not showed out in the literature [2]. In the USA study, 38 (88.4 %) out of the 43 subjects reported at least one adverse event. 75.7 % adverse events were classified as probably related to the study medications. 15.5 % adverse events were classified as possibly related to the study medications. The most common adverse event was flushing, experienced by 37 (86.0 %) subjects following the treatment. All the reported adverse events were mild in intensity. Liu M et al. Pharmacokinetics of Niacin, Simvastatin … Drug Res 2014; 64: 296–300
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Table 4 Pharmacokinetic parameters of a single dose of 2 tablets of niacin ER/simvastatin (500mg/20 mg) in the USA study. Data are shown as mean ± SD.
