Pharmacokinetics and bioequivalence evaluation of two simvastatin 40 mg tablets (<i>Simvast</i> &amp; <i>Zocor</i>) in healthy human volunteers

Najib, Naji M.; Idkaidek, Nasir; Adel, Ayman; Admour, Isra'; Astigarraga, Rafel E. B.; Nucci, Gilberto De; Alam, S. Mahmood; Dham, Ruwayda; Qumaruzaman,

doi:10.1002/bdd.347

Cited by 45 publications

(46 citation statements)

References 5 publications

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“…[5,6] However, in the current study, only simvastatin concentrations were measured and compared between the two formulations. The guidance outlined by the Ministry of Food and Drug Safety of Korea does not require the measurement and comparison of active metabolites, and the European Medicines Agency (EMA) guideline on the investigation of bioequivalence suggests that the assessment of bioequivalence for parent compound is recommended for inactive prodrugs.…”

Section: Transl Clin Pharmacolmentioning

confidence: 99%

“…[5,11] Considering these large inter-subject variabilities, the intra-subject CVs for C max and AUC were assumed to be approximately 30% in the current study. With this information, a sample size of 32 subjects was required to attain the 80% power at a 5% significance level, assuming a mean ratio (test/reference) of C max or AUC of 1 and a 30% intra-subject CV for C max or AUC.…”

Section: Transl Clin Pharmacolmentioning

confidence: 99%

“…[12] Double peaks of the simvastatin concentration were reported in this study, which was consistent with the findings from other bioequivalence studies of simvastatin. [5,6] The individual plots (Fig. 2, 3) show that there are considerable individual variations in the plasma concentrations of simvastatin, and this may have resulted in the double peaks in the mean concentration-time profile in part.…”

Section: Transl Clin Pharmacolmentioning

confidence: 99%

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Comparative pharmacokinetic and tolerability evaluation of two simvastatin 20 mg formulations in healthy Korean male volunteers

Moon

Lee

Jang

et al. 2017

Transl Clin Pharmacol

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Simvastatin is used to reduce plasma cholesterol by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and is primarily used to treat hypercholesterolemia. This study was conducted to assess the bioequivalence between the generic formulation of simvastatin 20 mg and the branded formulation of simvastatin 20 mg. A generic formulation of simvastatin 20 mg tablet was developed and the pharmacokinetics of the generic formulation were compared with those of the branded formulation of simvastatin 20 mg tablet in 33 healthy male volunteers after a single oral dose in a randomized, open-label, two-period, two-sequence, crossover study. The reference (Zocor®, MSD Korea LTD.) and test (Simvarotin®, Korea Arlico Pharm Co., Ltd.) formulations, two 20 mg tablets each, were administered to all subjects in fasting status. The serial blood samples for pharmacokinetic analysis were collected before dosing and up to 24 hours post-dose, and plasma concentrations of simvastatin were determined by liquid chromatography-tandem mass spectrometry. The pharmacokinetic parameters including T max , C max , AUC last , AUC inf and t 1/2 were calculated for both formulations by non-compartmental method, and the log-transformed C max and AUC last were compared statistically. Geometric mean ratios (90% confidence intervals) of the test to the reference formulation in C max and AUC last were 0.9652 (0.8302-1.1223) and 0.9891 (0.8541-1.1455), respectively. No significant differences in tolerability profiles were noted between the two formulations. The two formulations of simvastatin 20 mg tablets exhibited comparable pharmacokinetic profiles and 90% confidence intervals were within the acceptable range of bioequivalence criteria.

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Section: Transl Clin Pharmacolmentioning

confidence: 99%

Section: Transl Clin Pharmacolmentioning

confidence: 99%

Section: Transl Clin Pharmacolmentioning

confidence: 99%

See 1 more Smart Citation

Comparative pharmacokinetic and tolerability evaluation of two simvastatin 20 mg formulations in healthy Korean male volunteers

Moon

Lee

Jang

et al. 2017

Transl Clin Pharmacol

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“…Method by HPLC-UV is not sensitive enough to detect the low concentration of simvastatin and can only detect as low as 20 ng/mL of simvastatin. Since plasma concentrations of simvastatin is expected to be between 0.1 and 15 ng/mL [12]. However, method by HPLC-UV is suitable for determining simvastatin in pharmaceutical formulations and preparations [13], but is not suitable for pharmacokinetic study.…”

Section: Introductionmentioning

confidence: 99%

Method Validation for Analysis of Simvastatin in Human Plasma Using Liquid Chromatography Tandem Mass Spectrometry (LC-MS-MS)

Alakhali¹

2013

JCDR

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Introduction: The Liquid Chromatography Tandem Mass Spectrometry (LC-MS-MS) for determination simvastatin in human plasma has been developed after extraction by by ethyl acetate and hexane (90/10%, v/v) using lovastatin as internal standard. Material and Methods:The mobile phase consisting of mixture of acetonitrile and water (75/25%, v/v) 500μL/min by separated the solutes on a C18 column. discussion:The lower limit of quantitation of 0.25 ng/mL was achieved when the calibration curve was linear from 0.25-50 ng/mL. The entire run time for analysis was only 6 min. The quantitation in the selective reaction monitoring (SRM) in positive ion mode, the daughter ions m/z 325 for simvastatin and m/z 285 for lovastatin were used. The Parent ions in positive ion mode were m/z 441.3 for simvastatin and m/z 405.1 for lovastatin. The intra-day coefficients of variation were less than 14% while the inter-day coefficients of variation were less than 10%. conclusion:The LC-MS-MS detection is sensitive due to its capability to eliminate interferences from endogenous components.

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“…Bioequivalence is assumed if the 90% confidence interval of the ratio of the area under the plasma simvastatin acid concentration-time curve (AUC) for a generic and 'reference' product is between 80% and 125% [25]. A published bioequivalence study for simvastatin found that the lower limit of the ratio of the AUC (generic ⁄ reference) could be 0.85 while still meeting bioequivalence criteria [26]. We used this ratio to create a hypothetical simvastatin generic product by modifying the clearance of simvastatin acid.…”

Section: Methodsmentioning

confidence: 99%

The Influence of Dosing Time, Variable Compliance and Circadian Low-Density Lipoprotein Production on the Effect of Simvastatin: Simulations from a Pharmacokinetic-Pharmacodynamic Model

Wright

Kumar

Al‐Sallami

et al. 2011

Basic &Amp; Clinical Pharmacology &Amp; Toxicology

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The aim of this study was to explore the influence of simvastatin dosing time, variable compliance and circadian cholesterol production on the reduction of low-density lipoprotein (LDL). A published pharmacokinetic-pharmacodynamic (PKPD) model for simvastatin was identified and evaluated. A model for circadian LDL production was incorporated into the PKPD model. Reduction in LDL from baseline was simulated stochastically from the full model at dose levels of 10, 20, 40 and 80 mg daily for 30 days. Simulated dosing times for each data set were morning (8.00 a.m.), evening (22.00 p.m.), evening with reduced compliance and evening for a hypothetical bioequivalent generic. Differences in LDL reduction from baseline between evening (33-43%) and morning dosing (31-43%) were negligible across a range of doses. Any differences were negated when variable compliance was considered. In addition, differences in simvastatin effect between morning and evening dosing were found to be within the range of LDL concentrations that would be permissible for a bioequivalent generic (at the lower limit) and hence are not likely to be important clinically. The results of this study suggest that taking simvastatin in the evening is not superior to morning dosing.Elevated plasma low-density-lipoprotein (LDL) concentrations have been linked to an increased risk of cardiovascular and cerebrovascular morbidity and mortality [1,2]. It has been proposed that a reduction in plasma LDL by 1 mmol ⁄ L will result in about a 20% reduction in adverse vascular events, regardless of the baseline concentration [3]. This would represent a 25-35% reduction in LDL concentration from a baseline of 3-4 mmol ⁄ L. Simvastatin reduces serum LDL concentrations by inhibiting HMG-CoA reductase, the rate-limiting enzyme for cholesterol production in the liver.Cholesterol synthesis follows a circadian pattern, with peak production occurring between midnight and 6.00 a.m. [4,5]. It is usually recommended that daily doses of simvastatin be taken in the evening on the grounds that this will allow peak simvastatin concentrations to occur at the same time as peak circadian cholesterol production [6][7][8][9]. Hence, it is generally assumed that evening dosing will result in a greater reduction in plasma LDL compared with morning dosing. However, the rate-limiting step in the time course of simvastatin effect on cholesterol is not the half-life of simvastatin but the relatively slow turnover of cholesterol itself. The estimated half-life of cholesterol in the plasma is in the order of 3-4 days [9]. As a result, the peak effect of simvastatin on LDL reduction has been found to be substantially delayed with respect to the peak plasma concentration of the drug [10,11]. This suggests that dosing simvastatin in the evening and measuring LDL in the morning may not necessarily reflect the greatest effect on plasma cholesterol concentrations.Compliance with evening dosing has been found to be 5-25% lower compared with morning dosing for a variety of cardiovascular dru...

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Pharmacokinetics and bioequivalence evaluation of two simvastatin 40 mg tablets (Simvast & Zocor) in healthy human volunteers

Cited by 45 publications

References 5 publications

Comparative pharmacokinetic and tolerability evaluation of two simvastatin 20 mg formulations in healthy Korean male volunteers

Comparative pharmacokinetic and tolerability evaluation of two simvastatin 20 mg formulations in healthy Korean male volunteers

Method Validation for Analysis of Simvastatin in Human Plasma Using Liquid Chromatography Tandem Mass Spectrometry (LC-MS-MS)

The Influence of Dosing Time, Variable Compliance and Circadian Low-Density Lipoprotein Production on the Effect of Simvastatin: Simulations from a Pharmacokinetic-Pharmacodynamic Model

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