A Drug-Drug Interaction Study to Evaluate the Impact of Simvastatin and Itraconazole on Erlotinib Pharmacokinetics in Rats by UPLC-MS/MS.

Aim: The goal of our study was to investigate the effects of single-dose simvastatin and itraconazole application on the pharmacokinetics of erlotinib in rats. Methods: Twenty-one male Sprague-Dawley rats were randomly divided into 3 groups, including erlotinib combined with simvastatin, erlotinib combined with itraconazole and erlotinib alone groups. The rats were given a single dose of 2 mg/kg simvastatin, 15 mg/kg itraconazole or 0.5% sodium carboxymethyl cellulose followed by 12 mg/kg erlotinib. The concentration of erlotinib in rat plasma was determined by UPLC-MS/MS. As internal standard, tinidazole was used for chromatographic analysis on the Kinetex C18 column (100×2.1 mm, 2.6 µm). Results: Erlotinib was validated in the calibration range of 5-1000 ng/mL. The lower limit of quantification (LLOQ) was 5 ng/mL. The inter- and intra-day precisions for erlotinib were less than 10.56%, and the accuracies were in the range of 98.61-104.99%. The validated UPLC-MS/MS method was successfully applied to this study. Compared with the erlotinib alone group, the values of AUC0-t, AUC0-∞, Cmax, Vz/F and t1/2 in the simvastatin group showed no statistical differences among pharmacokinetic parameters (P>0.05). However, the values of AUC0-t, AUC0-∞ and Cmax, in the itraconazole group were approximately 1.32-fold, 1.32-fold and 1.34-fold higher, and the CL/F was lower than those in the erlotinib alone group; the difference was statistically significant (P<0.05). Conclusion: Simvastatin had no significant effect on the pharmacokinetics of erlotinib, whereas co-administration of itraconazole considerably increased the exposure of erlotinib. Therefore, we should pay more attention to the potential drug-drug interaction to ensure safety in cancer patient treatment.

Genomewide Association Study of Simvastatin Pharmacokinetics.

We investigated genetic determinants of single-dose simvastatin pharmacokinetics in a prospective study of 170 subjects and a retrospective cohort of 59 healthy volunteers. In a microarray-based genomewide association study with the prospective data, the SLCO1B1 c.521T>C (p.Val174Ala, rs4149056) single nucleotide variation showed the strongest, genomewide significant association with the area under the plasma simvastatin acid concentration-time curve (AUC; P = 6.0 × 10-10 ). Meta-analysis with the retrospective cohort strengthened the association (P = 1.6 × 10-17 ). In a stepwise linear regression candidate gene analysis among all 229 participants, SLCO1B1 c.521T>C (P = 1.9 × 10-13 ) and CYP3A4 c.664T>C (p.Ser222Pro, rs55785340, CYP3A4*2, P = 0.023) were associated with increased simvastatin acid AUC. Moreover, the SLCO1B1 c.463C>A (p.Pro155Thr, rs11045819, P = 7.2 × 10-6 ) and c.1929A>C (p.Leu643Phe, rs34671512, P = 5.3 × 10-4 ) variants associated with decreased simvastatin acid AUC. Based on these results and the literature, we classified the volunteers into genotype-predicted OATP1B1 and CYP3A4 phenotype groups. Compared with the normal OATP1B1 function group, simvastatin acid AUC was 273% larger in the poor (90% confidence interval (CI), 137%, 488%; P = 3.1 × 10-6 ), 40% larger in the decreased (90% CI, 8%, 83%; P = 0.036), and 67% smaller in the highly increased function group (90% CI, 46%, 80%; P = 2.4 × 10-4 ). Intermediate CYP3A4 metabolizers (i.e., heterozygous carriers of either CYP3A4*2 or CYP3A4*22 (rs35599367)), had 87% (90% CI, 39%, 152%, P = 6.4 × 10-4 ) larger simvastatin acid AUC than normal metabolizers. These data suggest that in addition to no function SLCO1B1 variants, increased function SLCO1B1 variants and reduced function CYP3A4 variants may affect the pharmacokinetics, efficacy, and safety of simvastatin. Care is warranted if simvastatin is prescribed to patients carrying decreased function SLCO1B1 or CYP3A4 alleles.

Effect of Roxadustat on the Pharmacokinetics of Simvastatin, Rosuvastatin, and Atorvastatin in Healthy Subjects: Results From 3 Phase 1, Open-Label, 1-Sequence, Crossover Studies.

Roxadustat inhibits breast cancer resistance protein and organic anion transporting polypeptide 1B1, which can affect coadministered statin concentrations. Three open-label, 1-sequence crossover phase 1 studies in healthy subjects were conducted to assess effects from steady-state 200-mg roxadustat on pharmacokinetics and tolerability of 40-mg simvastatin (CL-0537 and CL-0541), 40-mg atorvastatin (CL-0538), or 10-mg rosuvastatin (CL-0537). Statins were dosed concomitantly with roxadustat in 28 (CL-0537) and 24 (CL-0538) healthy subjects, resulting in increases of maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve from the time of dosing extrapolated to infinity (AUCinf ) 1.87- and 1.75-fold for simvastatin, 2.76- and 1.85-fold for simvastatin acid, 4.47- and 2.93-fold for rosuvastatin, and 1.34- and 1.96-fold for atorvastatin, respectively. Additionally, simvastatin dosed 2 hours before, and 4 and 10 hours after roxadustat in 28 (CL-0541) healthy subjects, resulted in increases of Cmax and AUCinf 2.32- to 3.10-fold and 1.56- to 1.74-fold for simvastatin and 2.34- to 5.98-fold and 1.89- to 3.42-fold for simvastatin acid, respectively. These increases were not attenuated by time-separated statin dosing. No clinically relevant differences were observed for terminal elimination half-life. Concomitant 200-mg roxadustat and a statin was generally well tolerated during the study period. Roxadustat effects on statin Cmax and AUCinf were statin and administration time dependent. When coadministered with roxadustat, statin-associated adverse reactions and the need for statin dose reduction should be evaluated.

Simvastatin induced ferroptosis for triple-negative breast cancer therapy.

Triple-negative breast cancer (TNBC), a management of aggressive breast cancer, remains an unmet medical challenge. Although a wave of efforts had spurred to design novel therapeutic method of TNBC, unpredictable prognosis with lacking effective therapeutic targets along with the resistance to apoptosis seriously limited survival benefits. Ferroptosis is a non-apoptotic form of cell death that is induced by excessive lipid peroxidation, which provide an innovative way to combat cancer. Emerging evidence suggests that ferroptosis plays an important role in the treatment of TNBC cells. Herein, a novel ferroptosis nanomedicine was prepared by loading simvastatin (SIM), a ferroptosis drug, into zwitterionic polymer coated magnetic nanoparticles (Fe3O4@PCBMA) to improve the therapeutic effect of TNBC. The as-obtained Fe3O4@PCBMA-SIM nanoparticles demonstrated more cytotoxicity against MDA-MB-231 than MCF-7 due to the higher expression of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), which demonstrated that statins could effectively kill TNBC. Further experiments showed that SIM could inhibit the expression of HMGCR to downregulate the mevalonate (MVA) pathway and glutathione peroxidase 4 (GPX4), thereby inducing cancer cell ferroptosis. What's more, PCBMA endows Fe3O4@PCBMA longer blood circulation performance to enhance their accumulation at tumor sites. Given that Fe3O4 have proven for clinical applications by the U.S. Food and Drug Administration (FDA) and SIM could induce cancer cell ferroptosis, the developed Fe3O4@PCBMA-SIM nanosystem would have great potential in clinics for overcoming the drug resistance brought about by apoptotic drugs to cancer cells.

Preparation and characterization of poly (lactic-co-glycolic acid) nanofibers containing simvastatin coated with hyaluronic acid for using in periodontal tissue engineering.

Periodontal diseases can lead to soft tissue defects. Tissue engineering can provide functional replacements for damaged tissues. Recently, electrospun nanofibers have attracted great interest for tissue engineering and drug delivery applications. This has been revealed that statins exhibit positive impacts on the proliferation and regeneration of periodontal tissues. Electrospun simvastatin loaded poly (lactic-co-glycolic acid) (SIM-PLGA-NF) were prepared using electrospinning technique. Optimal conditions for preparation of SIM-PLGA-NF (PLGA concentration of 30 wt%, voltage of 15 kV, and flow rate of 1.5 ml h-1 ) were identified using a 23 factorial design. The optimized SIM-PLGA-NFs (diameter of 640.2 ± 32.5 nm and simvastatin entrapment efficacy of 99.6 ± 1.5%) were surface modified with 1% w/v hyaluronic acid solution (1%HA- SIM-PLGA-NF) to improve their compatibility with fibroblasts and potential application as a periodontal tissue engineering scaffold. HA-SIM-PLGA NFs were analyzed using SEM, FTIR, and XRD. 1%HA-SIM-PLGA-NF had uniform, bead-free and interwoven morphology, which is similar to the extracellular matrix. The mechanical performance of SIM-PLGA-NFs and release profile of simvastatin from these nanofibers have been also greatly improved after coating with HA. In vitro cellular tests showed that the proliferation, adhesion, and differentiation of fibroblast cells positively enhanced on the surface of 1%HA- SIM-PLGA-NF. These results demonstrate the potential application of 1%HA-SIM-PLGA-NFs as a scaffold for periodontal tissue engineering.

Fixed Dose Single Tablet Formulation with Differential Release of Amlodipine Besylate and Simvastatin and Its Pharmacokinetic Profile: QbD and Risk Assessment Approach.

PURPOSE: A differential release fixed dose matrix tablet of amlodipine besylate (AML-B) and simvastatin (SIM) was formulated to enhance patient compliance. MATERIAL AND METHOD: In the first phase, release controlling parameters of AML-B and SIM granules were identified and in the second phase a fixed dose AML-B and SIM tablet formulation was prepared and optimized for a differential release of the drugs using a quality by design (QbD) and risk assessment approach. A validated HPLC method was employed for simultaneous determination of AML-B and SIM for FDC formulation. A pharmacokinetics of the above drugs was studied in healthy dogs in the third phase. RESULTS: In QbD-based optimized formulation, Eudragit® RSPO-dicalcium phosphate (DCP) blend controlled the release of AML-B over 8 h, though this diffusion-controlled release assumed first order kinetics. DCP and Eudragit® RS 100 also retarded release of SIM causing SIM release over 8 h after AML-B release from the optimized FDC tablet formulation. The HPLC retention times of AML-B and SIM were 2.10 and 15.52 min, respectively. Linearity for AML-B was 5.0-50 ng/mL and 0.01-2.0 µg/mL for SIM with percent recoveries of 92.85-101.53% and 94.51-117.75% for AML-B and SIM. AUC0-∞ of AML-B was increased 3 fold, while AUC0-∞ of SIM was decreased 2 fold. The tmax values for AML-B and SIM were 12 and 6 h, respectively. AML-B was absorbed without any lag time (tlag) while tlag was 6.33 ± 0.81 h for SIM, thus met the study objective. CONCLUSION: The pharmacokinetic study showed an immediate absorption of AML-B while that of SIM was withheld for 6 h, close to the desired delay time of 8 h.

Physiologically Based Precision Dosing Approach for Drug-Drug-Gene Interactions: A Simvastatin Network Analysis.

Drug-drug interactions (DDIs) and drug-gene interactions (DGIs) are well known mediators for adverse drug reactions (ADRs), which are among the leading causes of death in many countries. Because physiologically based pharmacokinetic (PBPK) modeling has demonstrated to be a valuable tool to improve pharmacotherapy affected by DDIs or DGIs, it might also be useful for precision dosing in extensive interaction network scenarios. The presented work proposes a novel approach to extend the prediction capabilities of PBPK modeling to complex drug-drug-gene interaction (DDGI) scenarios. Here, a whole-body PBPK network of simvastatin was established, including three polymorphisms (SLCO1B1 (rs4149056), ABCG2 (rs2231142), and CYP3A5 (rs776746)) and four perpetrator drugs (clarithromycin, gemfibrozil, itraconazole, and rifampicin). Exhaustive network simulations were performed and ranked to optimize 10,368 DDGI scenarios based on an exposure marker cost function. The derived dose recommendations were translated in a digital decision support system, which is available at simvastatin.precisiondosing.de. Although the network covers only a fraction of possible simvastatin DDGIs, it provides guidance on how PBPK modeling could be used to individualize pharmacotherapy in the future. Furthermore, the network model is easily extendable to cover additional DDGIs. Overall, the presented work is a first step toward a vision on comprehensive precision dosing based on PBPK models in daily clinical practice, where it could drastically reduce the risk of ADRs.

Hyaluronic acid-coated polymeric micelles with hydrogen peroxide scavenging to encapsulate statins for alleviating atherosclerosis.

Inflammation and oxidative stress are two major factors that are involved in the pathogenesis of atherosclerosis. A smart drug delivery system that responds to the oxidative microenvironment of atherosclerotic plaques was constructed in the present study. Simvastatin (SIM)-loaded biodegradable polymeric micelles were constructed from hyaluronic acid (HA)-coated poly(ethylene glycol)-poly(tyrosine-ethyl oxalyl) (PEG-Ptyr-EO) for the purpose of simultaneously inhibiting macrophages and decreasing the level of reactive oxygen species (ROS) to treat atherosclerosis. HA coating endows the micelle system the ability of targeting CD44-positive inflammatory macrophages. Owing to the ROS-responsive nature of PEG-Ptyr-EO, the micelles can not only be degraded by enzymes, but also consumes ROS by itself at the pathologic sites, upon which the accumulation of pro-inflammatory macrophages is effectively suppressed and oxidative stress is alleviated. Consequently, the cellular uptake experiment demonstrated that SIM-loaded HA-coated micelles can be effectively internalized by LPS-induced RAW264.7 cells and showed high cytotoxicity against the cells, but low cytotoxicity against LO2 cells. In mouse models of atherosclerosis, intravenously SIM-loaded HA-coated micelles can effectively reduce plaque content of cholesterol, resulting in remarkable therapeutic effects. In conclusion, the SIM-loaded micelle system provides a promising and innovative option against atherosclerosis.

Simvastatin-Nicotinamide Co-Crystals: Formation, Pharmaceutical Characterization and in vivo Profile.

PURPOSE: To enhance the solubility and dissolution profile of simvastatin (SIM) through co-crystallization with varying ratios of nicotinamide (NIC) using various co-methods. MATERIALS AND METHODS: Twelve SIM:NIC co-crystal formulations (F01-F12) were prepared using dry grinding, slurry, liquid-assisted grinding, and solvent-evaporation methods, and their properties compared. Optimized formulations were selected on the basis of dissolution profiles and solubility for in vivo studies. The angle of repose, Carr Index and Hausner ratio were calculated to evaluate flow properties. Differential light scattering (DLS) was used to estimate particle-size distribution. Scanning electron microscopy (SEM) was employed to evaluate surface morphology. Thermal analyses and Fourier-transform infrared (FTIR) spectroscopy were used to determine the ranges of thermal stability and physical interaction of formulated co-crystals. X-ray powder diffraction (XPD) spectroscopy was used to determine the crystalline nature. Solubility and dissolution studies were undertaken to determine in vitro drug-release behaviors. RESULTS: Micromeritic analyses revealed the good flow properties of formulated co-crystals. DLS showed the particle size of co-crystals to be in the nanometer range. SEM revealed that the co-crystals were regular cubes. Thermal studies showed the stability of co-crystals at >300°C. FTIR spectroscopy revealed minor shifts of various peaks. XPD spectroscopy demonstrated co-crystal formation. The formulations exhibited an improved dissolution profile with marked improvements in solubility. In vivo studies showed a 2.4-fold increase in Cmax whereas total AUC(0-∞) was increased 4.75-fold as compared with that of SIM tablets. CONCLUSION: Co-crystallization with NIC improved the solubility and dissolution profile and, hence, the bioavailability of the poorly water-soluble drug SIM.

Effects of multidose simvastatin co-administration on pharmacokinetic profile of apatinib in rats by UPLC-MS/MS.

Apatinib, a small molecule anti-angiogenic tyrosine kinase inhibitor is used extensively to treat advanced gastric cancer and simvastatin (SV) is often co-prescribed to treat cardiovascular disease in cancer patients. As both apatinib and SV are metabolized primarily by cytochrome P450 variant CYP3A4, they are likely to interact. Therefore, the potential effect of SV co-administration on pharmacokinetics of apatinib in Sprague-Dawley male rats is demonstrated for the first time.Sixteen rats were randomly divided into two groups (n = 8), 2 mg/kg SV orally co-administrated for seven days (group B) and the corresponding control group (group A). Apatinib concentrations of rat plasma samples were detected by ultra-performance liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were calculated using non compartmental methods.Co-administration of SV for seven days significantly increased area under curve (AUC(0-t)), AUC(0-∞) and maximum plasma concentration of apatinib by 2.4-, 2.4-, and 2.7-fold, respectively while decreasing apparent volume of distribution and clearance by 81.7 and 73.9%, respectively.These findings suggest that concomitant administration of SV with 7 days may have inhibited the metabolism of apatinib in rats.

Clinical Controversy in Transplantation: Tacrolimus Versus Cyclosporine in Statin Drug Interactions.

Objective: To review the available literature that provides evidence for the absence of statin interactions with tacrolimus compared with cyclosporine. Data Sources: A literature search of PubMed was performed (1990 to June 2019) using the following search terms: calcineurin inhibitors, tacrolimus, cyclosporine, statins, atorvastatin, simvastatin, and drug interactions. Clinical practice guidelines, article bibliographies, drug interaction database references, and product monographs were also reviewed. Study Selection and Data Extraction: Relevant English-language studies describing the mechanism of interaction, the magnitude of pharmacokinetic alterations, and safety were evaluated. In vitro data and studies conducted in adult humans were considered. Data Synthesis: Studies demonstrate pharmacokinetic differences between cyclosporine and tacrolimus, particularly with regard to inhibition of 2 hepatic transporters: P-glycoprotein and organic anion transporting polypeptide (OATP). Compared with cyclosporine, tacrolimus does not affect these transporters, does not enhance statin exposure, and does not increase statin-associated safety events. Relevance to Patient Care and Clinical Practice: Clinical practice guidelines allude to the need to reduce statin doses in the setting of tacrolimus. Some providers have adopted this practice, and doing so may prevent transplant recipients from attaining cardiovascular benefit, especially when increased or high-intensity doses are required. The pharmacokinetic differences between tacrolimus and cyclosporine highlight different interaction potential with statins. Conclusions: Clinicians need to be aware that tacrolimus and cyclosporine are not the same with regard to causing drug interactions with statins. Tacrolimus can be used with statins without the need for dose adjustments because of lack of an interaction.

Complex DDI by Fenebrutinib and the Use of Transporter Endogenous Biomarkers to Elucidate the Mechanism of DDI.

Mechanistic understanding of complex clinical drug-drug interactions (DDIs) with potential involvement of multiple elimination pathways has been challenging, especially given the general lack of specific probe substrates for transporters. Here, we conducted a clinical DDI study to evaluate the interaction potential of fenebrutinib using midazolam (MDZ; CYP3A), simvastatin (CYP3A and OATP1B), and rosuvastatin (BCRP and OATP1B) as probe substrates. Fenebrutinib (200 mg) increased the area under the curve (AUC) of these probe substrates twofold to threefold. To evaluate the mechanism of the observed DDIs, we measured the concentration of coproporphyrin I (CP-I) and coproporphyrin III (CP-III), endogenous biomarkers of OATP1B. There was no change in CP-I or CP-III levels with fenebrutinib, suggesting that the observed DDIs were caused by inhibition of CYP3A and BCRP rather than OATP1B, likely due to increased bioavailability. This is the first published account using an endogenous transporter biomarker to understand the mechanism of complex DDIs involving multiple elimination pathways.

Impact of Disease and Treatment Response in Drug-Drug Interaction Studies: Osimertinib and Simvastatin in Advanced Non-Small Cell Lung Cancer.

A phase I, open-label study (NCT02197234) assessed the effects of osimertinib on simvastatin exposure in patients with advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer and disease progression post-EGFR tyrosine kinase inhibitor treatment. Here, we report on a retrospective analysis of two patients (patients 1 and 2) who had liver metastases and high simvastatin exposure prior to osimertinib treatment, which changed following treatment. Patients received single oral doses of simvastatin 40 mg on day (D) 1 and D31, and osimertinib 80 mg once daily on D3-32. At baseline, both patients had abnormal liver function tests (LFTs; Child-Pugh scores of 6 and 8, respectively), significant liver metastasis, and, after a single simvastatin dose, had higher (~ 10-fold) exposure compared with all other patients. Following 31 days of continuous osimertinib treatment, simvastatin exposures (area under the plasma concentration-time curve from zero to infinity (AUC) and maximum plasma concentration (Cmax )) and LFTs, such as alanine transaminase, aspartate aminotransferase, and bilirubin normalized to population mean values. Additionally, ~ 50% and ~ 80% reductions in liver metastases were observed on computed tomography scans in patients 1 and 2, respectively. High simvastatin exposure on D1 likely resulted from impairment of hepatic first pass metabolism due to liver metastases. Reduction in hepatic disease burden due to osimertinib treatment likely resulted in liver function returning to normal levels.

Analysis of secondary care data to evaluate the clinical relevance of the drug-drug interaction between amlodipine and simvastatin.

BACKGROUND: Pharmacokinetic analyses revealed an increase in the bioavailability of simvastatin when co-administered with amlodipine [Nishio S et al. Hypertensin research 2005; Son H et al. Drug metabolism and pharmacokinetics 2014]. This may induce an increased risk of muscle toxicity for patients who receive this combination. So far, no in vivo data on the clinical relevance of this interaction exist. The objective of the present analysis was to determine the number of patients with concomitant treatment of amlodipine and simvastatin. Subsequently, the data was analyzed for the indication of muscular discomfort. Patients with combined prescription of amlodipine and another hydroxymethylglutaryl-CoA-reductase inhibitor except simvastatin or patients receiving simvastatin without amlodipine served as control groups. METHODS: The present analysis used secondary data from the health insurance company AOK PLUS including information regarding diagnosis and drug prescriptions. RESULTS: In total, 67.081 patients corresponding to 4.93% of the analyzed collective received a combined prescription of amlodipine and simvastatin. The absolute frequency increased continuously over time. Muscular discomfort was detected in a) 6.20% of the patients receiving amlodipine and simvastatin, b) 6.60% of the patients receiving amlodipine and another hydroxymethylglutaryl-CoA- reductase inhibitor and c) 8.04% of the patients with simvastatin only. CONCLUSIONS: The present analysis shows an increasing trend of combined prescriptions of amlodipine and simvastatin. Evidence for simvastatin dose adaptation or therapy switch to another hydroxymethylglutaryl-CoA-reductase inhibitor, however, was not found. Muscular discomfort does not occur more often in patients with amlodipine and simvastatin compared to the two control groups. The results of the present analysis reveal no evidence for a clinically relevant interaction between amlodipine and simvastatin.

A population pharmacokinetic model for simvastatin and its metabolites in children and adolescents.

PURPOSE: Poor adherence to dietary/behaviour modifications as interventions for hypercholesterolemia in paediatric patients often necessitates the initiation of statin therapy. The aim of this study was to develop a joint population pharmacokinetic model for simvastatin and four metabolites in children and adolescents to investigate sources of variability in simvastatin acid exposure in this patient population, in addition to SLCO1B1 genotype status. METHODS: Plasma concentrations of simvastatin and its four metabolites, demographic and polymorphism data for OATP1B1 and CYP3A5 were analysed utilising a population pharmacokinetic modelling approach from an existing single oral dose (10 mg < 17 years and 20 mg ≥ 18 years) pharmacokinetic dataset of 32 children and adolescents. RESULTS: The population PK model included a one compartment disposition model for simvastatin with irregular oral absorption described by two parallel absorption processes each consisting of sequential zero and first-order processes. The data for each metabolite were described by a one-compartment disposition model with the formation and elimination apparent parameters estimated. The model confirmed the statistically significant effect of c.521T>C (rs4149056) on the pharmacokinetics of the active metabolite simvastatin acid in children/adolescents, consistent with adult data. In addition, age was identified as a covariate affecting elimination clearances of 6-hydroxymethyl simvastatin acid and 3, 5 dihydrodiol simvastatin metabolites. CONCLUSION: The model developed describes the pharmacokinetics of simvastatin and its metabolites in children/adolescents capturing the effects of both c.521T>C and age on variability in exposure in this patient population. This joint simvastatin metabolite model is envisaged to facilitate optimisation of simvastatin dosing in children/adolescents.

Fevipiprant has a low risk of influencing co-medication pharmacokinetics: Impact on simvastatin and rosuvastatin in different SLCO1B1 genotypes.

Fevipiprant, a prostaglandin D2 receptor 2 antagonist, is in clinical development as a treatment for asthma. The goal of this study was to assess the potential of fevipiprant to cause drug-drug interactions (DDI) as a perpetrator, that is, by altering the pharmacokinetics (PK) of co-medications. In vitro drug interaction studies of clinically relevant drug metabolizing enzymes and transporters were conducted for fevipiprant and its acyl glucuronide (AG) metabolite. Comparison of Ki values with unbound systemic or portal vein steady-state plasma exposure of fevipiprant and its AG metabolite revealed the potential for inhibition of organic anion transporting polypeptide 1B1 (OATP1B1) transporters (R-value of 5.99), while other targets including cytochrome P450 enzymes were not, or only marginally, inhibited. Consequently, an open-label, two-part, two-period, single-sequence clinical study assessed the effect of fevipiprant 450 mg QD on the pharmacokinetics of simvastatin 20 mg and rosuvastatin 20 mg, two statins with different dependency in OATP1B1-mediated hepatic uptake, in healthy adult volunteers. The study also assessed the pharmacogenetics of the SLCO1B1 gene, which encodes OATP1B1. Clinically, fevipiprant 450 mg QD showed a low potential for interaction and increased the peak concentrations of simvastatin acid and rosuvastatin by 2.23- and 1.87-fold, respectively, with little or no impact on total exposure. Genotype analysis confirmed that SLCO1B1 genotype influences statin pharmacokinetics to a similar extent either with or without fevipiprant co-administration. In summary, fevipiprant at 450 mg QD has only minor liabilities as a perpetrator for DDI.

Assessment of Drug-Drug Interactions between Taspoglutide, a Glucagon-Like Peptide-1 Agonist, and Drugs Commonly Used in Type 2 Diabetes Mellitus: Results of Five Phase I Trials.

BACKGROUND AND OBJECTIVE: Taspoglutide, a glucagon-like peptide-1 agonist, like native glucagon-like peptide-1, delays gastric emptying time and prolongs intestinal transit time, which may alter the pharmacokinetics of concomitantly administered oral drugs. The effect of taspoglutide on the pharmacokinetics of five oral drugs commonly used in patients with type 2 diabetes mellitus was assessed in healthy subjects. METHODS: Five clinical pharmacology studies evaluated the potential drug-drug interaction between multiple subcutaneous taspoglutide doses and a single dose of lisinopril, warfarin, and simvastatin and multiple doses of digoxin and an oral contraceptive containing ethinylestradiol and levonorgestrel. The extent of interaction was quantified using geometric mean ratios and 90% confidence intervals for the maximum plasma concentration and area under the plasma concentration-time curve. In addition to pharmacokinetics, pharmacodynamic effects were assessed for warfarin and the oral contraceptive. RESULTS: Among the tested drugs, the effect of taspoglutide on the pharmacokinetics of simvastatin was most pronounced, on the day of taspoglutide administration, the average exposure to simvastatin was decreased by - 26% and - 58% for the area under the plasma concentration-time curve and maximum plasma concentration, respectively, accompanied by an increase in average exposure to its active metabolite, simvastatin ß-hydroxy acid (+ 74% and + 23% for area under the plasma concentration-time curve and maximum plasma concentration, respectively). Although statistically significant changes in exposure were observed for other test drugs, the 90% confidence intervals for the geometric mean ratio for maximum plasma concentration and area under the plasma concentration-time curve were within the 0.7-1.3 interval. No clinically relevant changes on coagulation (for warfarin) and ovulation-suppressing activity (for the oral contraceptive) were apparent. CONCLUSION: Overall, multiple doses of taspoglutide did not result in changes in the pharmacokinetics of digoxin, an oral contraceptive containing ethinylestradiol and levonorgestrel, lisinopril, warfarin, and simvastatin that would be considered of clinical relevance. Therefore, no dose adjustments are warranted upon co-administration.

Simulating the Impact of Elevated Levels of Interleukin-6 on the Pharmacokinetics of Various CYP450 Substrates in Patients with Neuromyelitis Optica or Neuromyelitis Optica Spectrum Disorders in Different Ethnic Populations.

A physiologically based pharmacokinetic (PBPK) model was used to simulate the impact of elevated levels of interleukin (IL)-6 on the exposure of several orally administered cytochrome P450 (CYP) probe substrates (caffeine, S-warfarin, omeprazole, dextromethorphan, midazolam, and simvastatin). The changes in exposure of these substrates in subjects with rheumatoid arthritis (and hence elevated IL-6 levels) compared with healthy subjects were predicted with a reasonable degree of accuracy. The PBPK model was then used to simulate the change in oral exposure of the probe substrates in North European Caucasian, Chinese, and Japanese population of patients with neuromyelitis optica (NMO) or NMO spectrum disorder with elevated plasma IL-6 levels (up to 100 pg/mL). Moderate interactions [mean AUC fold change, ≤ 2.08 (midazolam) or 2.36 (simvastatin)] was predicted for CYP3A4 probe substrates and weak interactions (mean AUC fold change, ≤ 1.29-1.97) were predicted for CYP2C19, CYP2C9, and CYP2D6 substrates. No notable interaction was predicted with CYP1A2. Although ethnic differences led to differences in simulated exposure for some of the probe substrates, there were no marked differences in the predicted magnitude of the change in exposure following IL-6-mediated suppression of CYPs. Decreased levels of serum albumin (as reported in NMO patients) had little impact on the magnitude of the simulated IL-6-mediated drug interactions. This PBPK modeling approach allowed us to leverage knowledge from different disease and ethnic populations to make predictions of cytokine-related DDIs in a rare disease population where actual clinical studies would otherwise be difficult to conduct.

Co-delivery of gemcitabine and simvastatin through PLGA polymeric nanoparticles for the treatment of pancreatic cancer: in-vitro characterization, cellular uptake, and pharmacokinetic studies.

Despite the ongoing extensive research, cancer therapeutics still remains an area with unmet needs which is hampered by shortfall in the development of newer medicines. The present study discusses a nano-based combinational approach for treating solid tumor. Dual-loaded nanoparticles encapsulating gemcitabine HCl (GM) and simvastatin (SV) were fabricated by double emulsion solvent evaporation method and optimized. Optimized nanoparticles showed a particle size of 258 ± 2.4 nm, polydispersity index of 0.32 ± 0.052, and zeta potential of -12.5 mV. The size and the morphology of the particles wee further confirmed by transmission electron microscopy (TEM) and scanning electron microscopy, respectively of the particles. The entrapment efficiency of GM and SV in the nanoparticles was 38.5 ± 4.5% and 72.2 ± 5.6%, respectively. The in vitro release profile was studied for 60 h and showed Higuchi release pattern. The cell toxicity was done using MTT assay and lower IC50 was obtained with the nanoparticles as compared to the pure drug. The bioavailability of GM and SV in PLGA nanoparticles was enhanced by 1.4-fold and 1.3-fold respectively, compared to drug solution. The results revealed that co-delivery of GM and SV could be used for its oral delivery for the effective treatment of pancreatic cancer.

Hybrid nanocarrier system for guiding and augmenting simvastatin cytotoxic activity against prostate cancer.

Prostate cancer is the most common non-skin cancer among men. Though statins are mainly used as antihyperlipidemic drugs, many studies have reported their proapoptotic and antimetastatic activities on prostate cancer. However, the poor solubility and insufficient delivery of statins in tumor site limit their anticancer activity. The present study introduces an efficient hybrid drug delivery system for the treatment of prostate cancer. The system involves the chemical conjugation of Simvastatin (SMV), a statin compound, to acid-terminated poly(D, L-lactic-co-glycolic acid), PLGA chains followed by its conversion into nanoparticles (NPs), with in situ physical incorporation of more SMV and superparamagnetic iron oxide nanoparticles (SPIONS) into the PLGA NPs. The PLGA-based hybrid nanocarrier system has been designed in such a way to evade the low bioavailability of SMV, confer sustained release of both encapsulated and chemically conjugated SMV, as well as enhancing the anti-cancer effect of the formula via the magnetic targeting with the aid of the encapsulated SPIONS. Magnetism, morphological and physicochemical characterizations, as well as in-vitro release studies were performed. Besides, cytotoxicity on human prostate cancer cell line (PC-3) was evaluated using MTT assay, cell cycle arrest analysis, annexin V/propidium iodide apoptosis assay and ELISA immunoassay for apoptotic enzyme. Optimum PLGA-based hybrid nanocarrier significantly improved the SMV anticancer activity against human prostate cancer cell line through both apoptosis mechanism and retardation of G2-M phase of cell cycle. Also, the up-regulation of the Caspase 3 was aligned with cytotoxicity study's findings.