Pharmacokinetics Of Simvastatin Research Articles

Decreased exposure of simvastatin and simvastatin acid in a rat model of type 2 diabetes.

Simvastatin is frequently administered to diabetic patients with hypercholesterolemia. The aim of the study was to investigate the pharmacokinetics of simvastatin and its hydrolysate simvastatin acid in a rat model of type 2 diabetes. Diabetes was induced in 4-week-old rats by a treatment of high-fat diet combined with streptozotocin. After the rats received a single dose of simvastatin (20 mg/kg, po, or 2 mg/kg, iv), the plasma concentrations of simvastatin and simvastatin acid were determined. Simvastatin metabolism and cytochrome P4503A (Cyp3a) activity were assessed in hepatic microsomes, and its uptake was studied in freshly isolated hepatocytes. The expression of Cyp3a1, organic anion transporting polypeptide 2 (Oatp2), multidrug resistance-associated protein 2 (Mrp2) and breast cancer resistance protein (Bcrp) in livers was measured using qRT-PCR. After oral or intravenous administration, the plasma concentrations and areas under concentrations of simvastatin and simvastatin acid were markedly decreased in diabetic rats. Both simvastatin metabolism and Cyp3a activity were markedly increased in hepatocytes of diabetic rats, accompanied by increased expression of hepatic Cyp3a1 mRNA. Furthermore, the uptake of simvastatin by hepatocytes of diabetic rats was markedly increased, which was associated with increased expression of the influx transporter Oatp2, and decreased expression of the efflux transporters Mrp2 and Bcrp. Diabetes enhances the metabolism of simvastatin and simvastatin acid in rats via up-regulating hepatic Cyp3a activity and expression and increasing hepatic uptake.

Pharmacokinetic modeling of simvastatin, nelfinavir and their interaction in humans.

Simvastatin, a commonly used HMG-CoA reductase inhibitor, is extensively metabolized by CYP3A4. Therefore, co-administration of simvastatin and CYP3A4 inhibitor can affect simvastatin pharmacokinetics. Nelfinavir, a protease inhibitor, and its major metabolite (M8) are known to be potent CYP3A4 inhibitors. When simvastatin and nelfinavir are co-administered, simvastatin pharmacokinetics is significantly altered and may result in an increased risk of rhabdomyolysis. To develop a mathematical model describing a drug-drug interaction between simvastatin and nelfinavir in humans. Eligible pharmacokinetic studies were selected from Pubmed database and concentration time course data were digitally extracted and used for model development. Compartmental pharmacokinetic models for simvastatin and nelfinavir were developed separately. A drug-drug interaction model of simvastatin and nelfinavir was subsequently developed using the prior information. Finally, the final drug-drug interaction modeled was validated against observed simvastatin concentrations. Three compartmental pharmacokinetic models were successfully developed. Simvastatin pharmacokinetics was best described by a one compartment model for simvastatin linked to its active form, simvastatin hydroxy acid. Nelfinavir pharmacokinetics could be adequately described by a one compartment parent-metabolite model. Our final drug-drug interaction model predicted an increase in simvastatin exposure which is in line with clinical observations linking the simvastatin-nelfinavir combination to an increased risk of rhabdomyolysis. Simvastatin-nelfinavir pharmacokinetic interaction can be explained by our final model. This model framework will be useful in further advanced developing other mechanism based drug-drug interaction model used to predict the risk of rhabdomyolysis occurrence in patients prescribed simvastatin and nelfinavir concurrently.

A pharmacokinetic drug-drug interaction model of simvastatin and verapamil in humans.

Verapamil is a calcium channel blocker commonly used in treatments of hypertension. Verapamil and its active metabolite, norverapamil, are known to be CYP3A4 inhibitors. Co-administration of verapamil with CYP3A4 substrates can alter the pharmacokinetics of the substrates. Simvastatin, a commonly used HMG-CoA reductase inhibitor for the treatment of hypercholesterolemia is extensively metabolized by CYP3A4. Therefore, concomitant use of simvastatin and verapamil can increase simvastatin plasma concentration levels, resulting in a higher risk of rhabdomyolysis, a serious adverse drug reaction. Even though, pharmacokinetic data regarding the interaction between both drugs have been published, their use is limited to semiquantitative applications. Therefore, we aimed to develop a mathematical model describing drug-drug interaction between simvastatin and verapamil in humans. Eligible pharmacokinetic interaction study between simvastatin and verapamil in humans was selected from PubMed database. The concentration-time courses from this study were digitally extracted and used for model development. The drug-drug interaction between simvastatin and verapamil was modeled simultaneously with a two compartment model for verapamil with its active metabolite, norverapamil and a one compartment model for simvastatin with its active form, simvastatin hydroxy acid. The effects of verapamil and norverapamil on pharmacokinetics of simvastatin and its active form, simvastatin hydroxy acid were described by Michaelis-Menten equation. Simulated simvastatin and simvastatin hydroxy acid concentrations obtained from the final model produced a good fit to the dataset from a literature. The final model adequately describes pharmacokinetic interaction between simvastatin and verapamil which can be helpful in prediction of rhabdomyolysis in patients with concurrent use of these drugs.

Effect of consumption of catechin-rich green tea on pharmacokinetics of simvastatin in healthy volunteers

Effect of consumption of catechin-rich green tea on pharmacokinetics of simvastatin in healthy volunteers

Pharmacokinetic interaction between simvastatin and fenofibrate with staggered and simultaneous dosing: Does it matter?

Simvastatin and fenofibrate are frequently co-prescribed at staggered intervals for the treatment of dyslipidemia. Since a drug-drug interaction has been reported when the two drugs are given simultaneously, it is of clinical interest to know whether the interaction differs between simultaneous and staggered combinations. A study, assessing the impact of both combinations on the interaction, was conducted with 7-day treatment regimens using simvastatin 40 mg and fenofibrate 145 mg: (A) simvastatin only (evening), (B) simvastatin and fenofibrate (both in evening), and (C) simvastatin (evening) and fenofibrate (morning). Eighty-five healthy subjects received the respective treatments in a randomized, 3-way cross-over study. The pharmacokinetics of simvastatin and the active metabolite simvastatin acid were determined. There was a limited reduction in the AUC0-24h of simvastatin acid of 21 and 29% for simultaneous and staggered combination, respectively. The geometric mean AUC0-24h ratio of simvastatin acid for the two combined dosing regimens (B/C) and 90% confidence interval were 111% (102-121). The interaction apparently had no impact on lipid markers. The findings imply that the observed pharmacokinetic interaction is unlikely clinically relevant, and support the combined use of simvastatin and fenofibrate not only given at staggered interval but also given simultaneously.

Identification of the Effect of Multiple Polymorphisms on the Pharmacokinetics of Simvastatin and Simvastatin Acid Using a Population-Modeling Approach

The aim of this work was to develop a joint population pharmacokinetic model for simvastatin (SV) and its active metabolite, simvastatin acid (SVA), that incorporates the effects of multiple genetic polymorphisms and clinical/demographic characteristics. SV/SVA plasma concentrations, demographic/clinical data, and genotypes for 18 genetic variants were collected from 74 individuals (three clinical trials) and analyzed using a nonlinear mixed-effects modeling approach. The structural model that best described the data included a two- and a one-compartment disposition model for SV and SVA, respectively. Age, weight, Japanese ethnicity, and seven genetic polymorphisms-rs4149056 (SLCO1B1), rs776746 (CYP3A5), rs12422149 (SLCO2B1), rs2231142 (ABCG2), rs4148162 (ABCG2), rs4253728 (PPARA), and rs35599367 (CYP3A4)-were identified as significantly affecting model parameters. The developed model was used to assess combinations of these covariates, highlighting specific risk factors associated with altered SV/SVA pharmacokinetics, and consequently myopathy cases that cannot be solely attributed to the rs4149056 CC genotype.

Population Pharmacokinetic Analysis of Simvastatin and its Active Metabolite with the Characterization of Atypical Complex Absorption Kinetics

The pharmacokinetics of simvastatin is complex with multiple peaks in the absorption phase, which cannot be adequately described by a conventional first order absorption model. The biotransformation of simvastatin into simvastatin acid, an active metabolite, is reversible. This study evaluated the pharmacokinetics of simvastatin and simvastatin acid, focusing on the absorption kinetics. Data were collected from three bioequivalence studies, in which subjects were administered 60 mg simvastatin, and from one crossover study, in which subjects were administered two doses randomly selected from 10, 20, 30, 40 to 80 mg simvastatin with washout period. The pharmacokinetics of simvastatin was assessed in 133 healthy males. Plasma concentrations of simvastatin and simvastatin acid were measured in 2,182 and 2,130 samples, respectively, and the pharmacokinetic data were analyzed using NONMEM. The time course of changes in the plasma simvastatin concentration was best described by a two-compartment linear model with three parallel absorption processes, each of which consisted of mixed zero-and first order absorption. Additions of inter-occasional variability to the absorption parameters significantly improved the model's fit. The disposition parameter estimates were significantly different when different absorption models were applied, indicating the importance of the appropriate absorption modeling. Pharmacokinetic modeling preferred the inter-conversion between simvastatin and simvastatin acid. A pharmacokinetic model describing the complex, multiple peak, absorption kinetics of simvastatin was formulated using three parallel, mixed zero and first-order absorptions. This type of absorption model may be applicable to other drugs that show irregular, multiple-peak concentrations during their absorption phase.

Pharmacokinetics of high-dose simvastatin in refractory and relapsed chronic lymphocytic leukemia patients

To evaluate the pharmacokinetics of simvastatin at the maximum tolerated dose (MTD) of 7.5 mg/kg, twice daily, in the context of a pilot trial enrolling patients with recurrent and refractory chronic lymphocytic leukemia. Patients received simvastatin orally at MTD for 7 days during a 21-day cycle for 6 cycles. Blood samples were collected during cycle 1. Simvastatin lactone and carboxylate concentrations were measured in plasma and peripheral blood mononuclear cells (PBMCs) using a validated HPLC-MS/MS assay. Patients accrued to this study showed high variability in their exposure to simvastatin. Exposure was dose proportional (AUC and C max) as compared to those receiving standard hyperlipidemia therapy. Peak plasma concentrations ranged from 0.08 to 2.2 and from 0.03 to 0.6 μM for simvastatin lactone and carboxylate, respectively. Our study shows that when simvastatin is administered at its MTD, only low micro-molar concentrations are achieved in plasma and PBMCs, which is consistent with the results observed in previous studies with lovastatin, but far lower than the concentrations required for anticancer effects in vitro. However, whether simvastatin at its MTD can confer therapeutic benefits to patients still remains to be determined.

Pharmacokinetics of orally administered simvastatin in turkeys

The aim of the present study was to determine the pharmacokinetics of simvastatin (SIM) administered orally in 6-week-old turkeys at a single dose of 2 mg/kg b.w. The SIM concentrations in plasma were determined by validated HPLC-MS/MS method. Mean (+/- SD; n = 10) values of pharmacokinetic parameters evaluated were as follows: Cmax = 0.49 +/- 0.21 ng/ml, t(max) = 1.6 +/- 1.1 h, AUC(0-infinity) = 1.08 +/- 0.57 h x ng/ml, t1/2kel = 2.14 +/-1.3 h and MRT = 3.08 +/- 1.52 h. The results indicate that the SIM is absorbed from the gastrointestinal tract of turkeys; however, achieved plasma level is lower compared to those observed in mammals.

Effect of repeated administration of eslicarbazepine acetate on the pharmacokinetics of simvastatin in healthy subjects

To investigate the effect of eslicarbazepine acetate (ESL) on the pharmacokinetics of simvastatin (SMV), a known CYP3A4 substrate, in healthy subjects. Single centre, two-way cross-over, randomized, open-label study in 24 healthy volunteers. The volunteers received an oral single-dose of SMV 80mg on two occasions (once administered alone and once after treatment with an oral once-daily dose of 800mg of ESL for 14 days), separated by a wash-out period of 3 weeks or more. The analysis of variance (ANOVA) was used to test for differences between Test (SMV under co-administration with ESL) and Reference (SMV administered alone) treatments for AUC0-∞, AUC0-t and Cmax of SMV and SMV-acid. Mean systemic exposure (AUC) measurements for both SMV and SMV-β-hydroxyacid (SMV-acid) were up to 54% lower during ESL use. The Test/Reference geometric mean ratios (GMR) (90% CI) for the AUC0-t of SMV and SMV-acid were 46% (38%; 55%) and 49% (44%; 55%), respectively. Mean peak concentrations (Cmax) of both SMV and SMV-acid were reduced by 60% and 41%, respectively, when SMV was administered with ESL. A significant effect of repeated ESL administration on the pharmacokinetics of SMV and its metabolite SMV-acid was observed. Therefore, dose adjustment of SMV may be required when used concomitantly with ESL, if a clinically significant change in lipids is noted.

Impact of Tesamorelin, a Growth Hormone-Releasing Factor (GRF) Analogue, on the Pharmacokinetics of Simvastatin and Ritonavir in Healthy Volunteers.

The potential impact of tesamorelin on CYP3A activity was investigated by examining its effect on the pharmacokinetics of simvastatin and ritonavir. In two randomized, two-way crossover studies, subjects were administered 2 mg tesamorelin on Days 1-7 with 80 mg simvastatin or 100 mg ritonavir co-administered on Day 6 (Treatment A), and a single dose of simvastatin or ritonavir alone on Day 6 (Treatment B). Pharmacokinetic samples were collected on Day 6 to measure simvastatin, ritonavir and tesamorelin plasma concentrations. For simvastatin, A/B ratios of least squares geometric means and corresponding 90% confidence intervals (CIs) for AUC0-t , AUC0-inf and Cmax were contained within the usual no effect range of 80-125%. For ritonavir, ratios and 90% CIs for AUCs were within this acceptance range, but the lower CI for Cmax was 74.8%, suggesting a decreased rate of exposure. However, since the A/B ratios for AUCs and Cmax parameters were approximately 90%, these were minor decreases and no dose adjustment of ritonavir is required in the presence of tesamorelin. These studies showed that the impact of tesamorelin on CYP3A activity appears to be minimal, if any. Either medication may be co-administered with tesamorelin in patients without changing their original dosing regimen.

Green Tea Extract Affects the Cytochrome P450 3A Activity and Pharmacokinetics of Simvastatin in Rats

Effects of green tea extract (GTE) on the activity of cytochrome P450 (CYP) enzymes and pharmacokinetics of simvastatin (SIM) were investigated in rats. Inhibitory effects of GTE on CYP3A activity were investigated in rat hepatic microsomes (RHM) using midazolam (MDZ) 1'-hydroxylation as a probe reaction. SD female rats received a single oral dose of GTE (400 mg/kg) or troleandomycin (TAO, a CYP3A selective inhibitor, 500 mg/kg), followed 30 min later by SIM (20 mg/kg). Plasma concentrations of SIM and its active metabolite, simvastatin acid, were determined up to 6 h after the SIM administration using LC/MS/MS. In RHM, GTE inhibited MDZ 1'-hydroxylation with IC₅₀ and K(i)(app) values of 12.5 and 18.8 µg/mL, respectively, in a noncompetitive manner. Area under plasma concentration-time curves for SIM in the GTE and TAO groups were increased by 3.4- and 10.2-fold, respectively, compared with the control. The maximum concentrations of SIM were higher in the GTE (3.3-fold) and TAO (9.5-fold) groups. GTE alters the pharmacokinetics of SIM, probably by inhibiting intestinal CYP3A.

Food–drug interactions: Effect of capsaicin on the pharmacokinetics of simvastatin and its active metabolite in rats

Capsaicin (trans-8-methy-N-vanilly-6-nonenamide, CAP), the main ingredient responsible for the hot pungent taste of chilli peppers. However, little is known about the metabolic interactions between CAP and clinically used drugs. This study attempted to investigate the effect of CAP on the pharmacokinetics of simvastatin (SV), a cytochrome P450 (CYP) 3A substrate and an important cholesterol-lowering agent. CAP (3, 8 or 25 mg/kg), ketoconazole, dexamethasone or 5% CMC-Na was given to rats for seven consecutive days and on the seventh day SV (80 mg/kg) was administered orally. The results showed that when a single dose of SV was administered to rats fed with CAP over one week, AUC(0→∞), C(max) of SV and its acid metabolite was significantly decreased in comparison to the control treatment. Pretreatment of rats with CAP resulted in an decrease in the AUC(0-∞) of SV of about 67.06% (CAP 3 mg/kg, P<0.05), 73.21% (CAP 8 mg/kg, P<0.01) and 77.49% (CAP 25 mg/kg, P<0.01) compared with the control group. The results demonstrate that chronic ingestion of high doses of CAP will decrease the bioavailability of SV to a significant extent in rats.

Disposition of Atorvastatin, Rosuvastatin, and Simvastatin in Oatp1b2‐/‐ Mice and Intraindividual Variability in Human Subjects

Response to statin therapy is often unpredictable because of variability in metabolism and transport. In the recently created organic anion transporting-polypeptide 1b2 (Oatp1b2/Slco1b2)-null mice, the investigators found significantly lower liver-to-plasma ratios compared with controls for atorvastatin (16.0 ± 5.1 vs 43.5 ± 13.7, P = .002) and rosuvastatin (15.2 ± 3.3 vs 28.4 ± 9.3, P = .03), but not simvastatin (5.2 ± 1.1 vs 6.3 ± 2.9, P = .49), following tail vein injection of 1 mg/kg of each drug. In addition, the investigators examined intraindividual variation in atorvastatin, rosuvastatin, and simvastatin pharmacokinetics in healthy human subjects in a crossover study design. Areas under the plasma concentration-time curve of atorvastatin and simvastatin acid were significantly related (Spearman r = 0.68; P = .035), whereas rosuvastatin profile was not related to atorvastatin or simvastatin exposure. Together, these results in mice and humans demonstrate that predictability of exposure to one statin based on another is dependent on the specific statin pairs and the context in which they are compared.

Pharmacokinetics and Safety of Ezetimibe/Simvastatin Combination Tablet

Ezetimibe/simvastatin combination tablet has been approved for the treatment of high low-density lipoprotein cholesterol (LDL-C) levels in patients with primary hypercholesterolaemia or mixed hypercholesterolaemia as adjunctive therapy to diet, when diet alone is insufficient in lowering cholesterol. The aims of this study were to assess the pharmacokinetics and safety of an ezetimibe/simvastatin combination tablet after oral single-dose administration in healthy Chinese subjects including sex-related differences in pharmacokinetics. This was an open-label, single-dose study. Twelve healthy subjects (six males and six females) received a single dose of an ezetimibe/simvastatin combination tablet (ezetimibe 10mg and simvastatin 40mg). The pharmacokinetic parameters for ezetimibe and simvastatin were assessed by determining total ezetimibe, free ezetimibe, simvastatin and simvastatin acid concentrations using a validated liquid chromatography-tandem mass spectrometry method. Safety was evaluated by monitoring adverse events, laboratory assays, vital signs, physical examinations and 12-lead electrocardiograms. The pharmacokinetic parameters (mean±SD) for total ezetimibe and free ezetimibe following a single dose were: maximum plasma drug concentration (C(max)) 81.56±26.62 and 9.40±6.17ng/mL; time to reach C(max) (t(max)) 0.93±0.30 and 1.25±1.27h; elimination half-life (t(½)) 24.32±13.27 and 18.90±9.66h, and mean area under the plasma concentration-time curve from time zero to the time of the last measurable concentration (AUC(last)) 579.06±241.45 and 126.01±69.01ng·h/mL, respectively. The pharmacokinetic parameters (mean±SD) for simvastatin and simvastatin acid following a single dose were: C(max) 11.92±5.50 and 3.37±1.78ng/mL, t(max) 0.98±0.28 and 3.73±1.68h, t(½) 4.19±1.81 and 7.65±7.96h, and mean AUC(last) 33.63±20.41 and 32.50±18.79ng·h/mL. Higher AUC(last) and AUC from time zero to infinity (AUC(∞)), and lower apparent total body clearance of drug from plasma after oral administration (CL/F) for total ezetimibe and free ezetimibe were observed in female subjects compared with those in male subjects. There were no differences between the pharmacokinetic parameters of simvastatin and simvastatin acid for female and male subjects in the study. Ezetimibe/simvastatin combination tablet has a generally favourable safety and tolerability profile in healthy Chinese subjects. A statistically significant difference with regard to sex in the pharmacokinetics of ezetimibe was observed. Sex had no effect on the pharmacokinetics of simvastatin and simvastatin acid.

Effect of posaconazole on the pharmacokinetics of simvastatin and midazolam in healthy volunteers

Objectives: The aim of the study is to determine the effect of posaconazole, an extended-spectrum triazole, on the pharmacokinetics of the HMG-CoA reductase inhibitor, simvastatin.Methods: This randomized, fixed-sequence, parallel-group, single-center, open-label study was conducted in 35 healthy volunteers randomly assigned to receive one of three doses of oral posaconazole: 50, 100 or 200 mg. All subjects received single doses of the reference drug midazolam (2 mg oral) alone on day -9; simvastatin (40 mg oral) alone on day -6; posaconazole (50, 100 or 200 mg) on days 1 – 7 once daily (q.d.); posaconazole plus midazolam (day 8); posaconazole alone (days 9 – 10); posaconazole plus simvastatin (day 11) and posaconazole alone (days 12 – 13).Results: Relative to simvastatin alone, posaconazole (50, 100 and 200 mg q.d.) significantly increased the Cmax and AUC of simvastatin (5- to 11-fold increase in AUC) and simvastatin acid (5- to 8-fold increase in AUC) during co-administration. Relative to midazolam alone, posaconazole (50, 100 and 200 mg q.d.) significantly inhibited CYP3A4-mediated metabolism of midazolam (three to sixfold increase in AUC).Conclusion: These findings support the classification of posaconazole as a strong CYP3A4 inhibitor. Simvastatin, or other statins predominantly metabolized by CYP3A4, should not be co-administered with posaconazole. Other statins, whose metabolism/elimination is not affected by CYP3A4 inhibition, should be considered for co-administration.

Evaluation of Pharmacokinetics of Simvastatin and Its Pharmacologically Active Metabolite from Controlled-Release Tablets of Simvastatin in Rodent and Canine Animal Models

Biotransformation of pharmacologically inactive lactone prodrug simvastatin (SV) into pharmacologically active simvastatin βhydroxy acid (SVA) exhibits inter-species differences due to variations in amount and activity of esterase enzymes. In this study, we investigated the pharmacokinetics (PK) of SV and its metabolite SVA following oral doses of SV from controlled-release (CR) tablets and immediate-release (IR) tablets in rodent and canine animal models that features different esterase activity. In rat PK study, no SV was detected in plasma for both formulations due to rapid hydrolysis of SV into SVA by plasma esterase. Besides, no signifi cant differences in PK parameters of SV or SVA were observed between both species. In dog PK study, the relative oral bioavailability of CR tablets in terms of SV was 72.3% compared to IR tablets. Regarding formulation differences in dogs, CR tablets exhibited signifi cantly lower C max (p<0.05), and higher T max (p<0.01) and MRT (p<0.01) for both SV and SVA compared to IR tablets. Accordingly, CR tablets of SV with prolonged drug release profi les in both species might be a potential candidate for a more effective delivery of SV with reduced side effects. Besides, similar PK parameters of SV and SVA in both species despite variation in enzyme activities suggested involvement of equally potent biotransformation pathways in these animal species.

Disease–Drug–Drug Interaction Involving Tocilizumab and Simvastatin in Patients With Rheumatoid Arthritis

In rheumatoid arthritis (RA), interleukin-6 (IL-6) concentration is elevated, which may cause reduced cytochrome P450 (CYP) activity and increased exposure (peak plasma concentration and area under the plasma concentration-vs.-time curve (AUC)) to certain drugs. Tocilizumab may reverse IL-6-induced suppression of CYP3A4 activity. In this study, exposure to simvastatin was significantly reduced at 1 and 5 weeks after tocilizumab infusion in 12 patients with RA. The mean effect ratio for simvastatin AUC(last) was 43% (90% confidence interval (CI), 34-55%) at 1 week after tocilizumab infusion (day 15) and 61% (90% CI, 47-78%) at 5 weeks after tocilizumab infusion, as compared with baseline (day 1); both ratios were significantly lower than the bioequivalence boundary (80-125%). Mean plasma C-reactive protein (CRP) levels normalized within 1 week after tocilizumab was initiated; the time course of tocilizumab's CRP-reducing effect paralleled that of simvastatin pharmacokinetics. The study findings suggest that caution should be exercised when starting tocilizumab in RA patients who are taking simvastatin.

Effect of linagliptin (BI 1356) on the steady-state pharmacokinetics of simvastatin

This study was conducted to investigate any potential effect of the dipeptidyl peptidase-4 inhibitor linagliptin (which is being developed to improve glycemic control in patients with Type 2 diabetes) on the pharmacokinetics of simvastatin (a lipid-lowering, HMG-CoA reductase inhibitor). This open-label, multiple-dose study was conducted in 20 healthy male Caucasian subjects. Simvastatin (40 mg/day) was administered alone for 6 days, followed by co-administration with linagliptin (10 mg/ day) for 6 days, followed by simvastatin single administration for a further 8 days. Plasma concentrations of simvastatin and its active metabolite simvastatin beta-hydroxy acid were determined on Day 6 (before co-administration of linagliptin) and Days 12, 16 and 20 (after co-administration of linagliptin). The geometric mean ratio (GMR) (90% confidence interval (CI)) following co-administration of linagliptin with simvastatin (Day 12) compared with administration of simvastatin alone (Day 6) for simvastatin AUC was 134.2% (119.4, 150.7) and for simvastatin acid AUC was 133.3% (118.1, 150.3). The GMR (90% CI) for simvastatin Cmax,ss was 110.0% (89.3, 135.6) and for simvastatin acid Cmax,ss was 120.7% (101.5, 143.6). 20 adverse events were reported by 11 subjects. Both simvastatin and linagliptin were well tolerated. Linagliptin-mediated effects on simvastatin exposure are not considered to be clinically relevant in terms of patient tolerability or safety. Therefore, a dose adjustment of linagliptin is not necessary when these two agents are administered together and linagliptin co-administration is not expected to exert a clinically relevant effect on the pharmacokinetics of other CYP3A4 substrates.

Different Effects of the ABCG2 C.421C&gt;A SNP on the Pharmacokinetics of Fluvastatin, Pravastatin and Simvastatin

This study aimed to investigate possible effects of the ABCG2 c.421C>A (p.Gln141Lys; rs2231142) genotype on fluvastatin, pravastatin and simvastatin pharmacokinetics. In a crossover study, five healthy volunteers with the ABCG2 c.421A/A genotype, four with the c.421C/A genotype and 23 with the c.421C/C genotype ingested a single 40-mg dose of fluvastatin, pravastatin and simvastatin, with a washout period of 1 week. Plasma statin concentrations were measured up to 12 h. The estimated marginal mean area under the plasma concentration-time curve from 0 h to infinity (AUC(0-infinity)) of fluvastatin was 97% (p = 0.015) or 72% (p = 0.009) larger in participants with the A/A genotype than in those with the C/A or C/C genotype. The AUC(0-infinity) of simvastatin lactone was 111% (p = 0.005) larger in participants with the A/A genotype than in participants with the C/C genotype. The simvastatin acid:lactone AUC(0-infinity) ratio was 46% (p = 0.017) smaller in individuals with the A/A genotype than in those with the C/C genotype. The ABCG2 genotype had no significant effect on simvastatin acid or pravastatin pharmacokinetics. Genetic variability in ABCG2 markedly affects the pharmacokinetics of fluvastatin and simvastatin lactone, but has no significant effect on pravastatin or active simvastatin acid. Genotyping for ABCG2 in addition to SLCO1B1 and ABCB1 polymorphisms could help in predicting statin pharmacokinetics when selecting a statin and its dose for an individual patient.