Impact of OATP2B1 on Pharmacokinetics of Atorvastatin Investigated in rSlco2b1-Knockout and SLCO2B1-Knockin Rats.

The organic anion transporting polypeptide (OATP) 2B1 is considered an emerging drug transporter that is found expressed in pharmacokinetically relevant organs such as the liver, small intestine, and kidney. Despite its interaction with various substrate drugs, the understanding of its in vivo relevance is still limited. In this study, we first validated the interaction of atorvastatin with rat OATP2B1 using transiently transfected HeLa cells. Moreover, we characterized our rSlco2b1-knockout and SLCO2B1-knockin rats for mRNA, protein expression, and localization of OATP2B1 in the liver, small intestine, and kidney. The transporter showed the highest expression in the liver followed by the small intestine. In humanized rats, human OATP2B1 is localized on the sinusoidal membrane of hepatocytes. In enterocytes of wild-type and humanized rats, the transporter was detected in the luminal membrane with the vast majority being localized subapical. Subsequently, we assessed atorvastatin pharmacokinetics in male wild-type, rSlco2b1-knockout, and SLCO2B1-knockin rats after a single-dose administration (orally and intravenously). Investigating the contribution of rat OATP2B1 or human OATP2B1 to oral atorvastatin pharmacokinetics revealed no differences in concentration-time profiles or pharmacokinetic parameters. However, when comparing the pharmacokinetics of atorvastatin after intravenous administration in SLCO2B1-humanized rats and knockout animals, notable differences were observed. In particular, the systemic exposure (area under the curve) decreased by approximately 40% in humanized animals, whereas the clearance was 57% higher in animals expressing human OATP2B1. These findings indicate that human OATP2B1 influences pharmacokinetics of atorvastatin after intravenous administration, most likely by contributing to the hepatic uptake. SIGNIFICANCE STATEMENT: Wild-type, rSlco2b1-knockout, and SLCO2B1-humanized Wistar rats were characterized for the expression of rat and human SLCO2B1/OATP2B1. Pharmacokinetic studies of atorvastatin over 24 hours were conducted in male wild-type, rSlco2b1-knockout, and SLCO2B1-humanized rats. After a single-dose intravenous administration, a lower systemic exposure and an increase in clearance were observed in SLCO2B1-humanized rats compared with knockout animals indicating a contribution of OATP2B1 to the hepatic clearance.

On sample size calculation in drug interaction trials.

Drug-drug interaction (DDI) trials are an important part of drug development as they provide evidence on the benefits and risks when two or more drugs are taken concomitantly. Sample size calculation is typically recommended to be based on the existence of clinically justified no-effect boundaries but these are challenging to define in practice, while the default no-effect boundaries of 0.8-1.25 are known to be overly conservative requiring a large sample size. In addition, no-effect boundaries are of little use when there is prior pharmacological evidence that a mild or moderate interaction between two drugs may be present, in which case effect boundaries would be more useful. We introduce precision-based sample size calculation that accounts for both the stochastic nature of the pharmacokinetic parameters and the anticipated width of (no-)effect boundaries, should these exist. The methodology is straightforward, requires considerably less sample size and has favorable operating characteristics. A case study on statins is presented to illustrate the ideas.

Statin Drug-Drug Interactions: Pharmacokinetic Basis of FDA Labeling Recommendations and Comparison Across Common Tertiary Clinical Resources.

Statins are widely prescribed and highly susceptible to pharmacokinetic (PK)-based drug-drug interactions (DDIs). To date, there has not been a comprehensive analysis of the basis upon which statin DDI recommendations in US Food and Drug Administration (FDA) prescribing information (PI) are derived. We have conducted such an analysis. We also assessed the degree of concordance of statin DDI recommendations in FDA PI and those provided in common tertiary clinical resources. We catalogued statin DDI information, including PK data and management recommendations, for statin precipitant drugs approved from 2010 to 2021, available from FDA PI and tertiary clinical resource databases. Recommendations were categorized and mapped with associated PK data to assess consistency in the PK basis for labeling recommendations. From the 80 precipitant drugs evaluated, 180 statin DDIs were identified in FDA PI. Dedicated clinical DDI studies were conducted for 54% (n = 97) of these DDIs and 34% (n = 61) of DDI recommendations were extrapolated from clinical data with other statins. Overall, we found that PK-based statin recommendations were consistent across PI. These findings highlight regulatory precedence for translating information across statins without conducting dedicated clinical DDI studies, which may support future efforts toward streamlining the approach to investigation and labeling of statin DDIs. In addition, with the exception of some notable discrepancies, general concordance was observed between FDA and tertiary resources regarding "Dose Adjustment" and "Avoid Coadministration" recommendations. However, further analyses are warranted across other DDI pairs to determine whether discordance can routinely lead to different clinical recommendations depending on the drug information resource.

The pharmacokinetics of single-dose oral atorvastatin and its metabolites support therapeutic use in cockatiels (Nymphicus hollandicus).

OBJECTIVE: To evaluate the plasma concentrations and determine the pharmacokinetic parameters of atorvastatin and its primary active metabolites (para- and orthohydroxyatorvastatin) after administration of a single oral dose in cockatiels (Nymphicus hollandicus). ANIMALS: 14 adult cockatiels (7 male, 7 female) around 2 years of age. METHODS: A compounded oral suspension of atorvastatin 10 mg/mL made with an oral suspending agent and an oral sweetener was administered via oral gavage at 20 mg/kg to each bird. Blood samples were collected at 7 different time points from 0.5 to 24 hours postadministration in a balanced incomplete block design with 3 blood samples per bird and 6 replicates per time point. Plasma concentrations of atorvastatin, parahydroxyatorvastatin, and orthohydroxyatorvastatin were determined by liquid chromatography-tandem mass spectrometry. Pharmacokinetic analysis was performed using noncompartmental analysis. RESULTS: The estimated time to maximum concentration (tmax) for atorvastatin, parahydroxyatorvastatin, and orthohydroxyatorvastatin was 3 hours for each. The estimated maximum plasma concentration (Cmax) for atorvastatin, parahydroxyatorvastatin, and orthohydroxyatorvastatin was 152.6, 172.4, and 68.8 ng/mL, respectively. The terminal half-lives were 4, 6.8, and 4.6 hours, respectively. CLINICAL RELEVANCE: These results support the therapeutic use of atorvastatin at the dose evaluated in this species based on human pharmacokinetic data. A starting dose of 20 mg/kg PO every 12 to 24 hours could be used to treat lipid disorders in cockatiels pending more data on multidose use and hypolipidemic efficacy.

Physiologically based pharmacokinetics modeling and transporter proteomics to predict systemic and local liver and muscle disposition of statins.

Statins are used to reduce liver cholesterol levels but also carry a dose-related risk of skeletal muscle toxicity. Concentrations of statins in plasma are often used to assess efficacy and safety, but because statins are substrates of membrane transporters that are present in diverse tissues, local differences in intracellular tissue concentrations cannot be ruled out. Thus, plasma concentration may not be an adequate indicator of efficacy and toxicity. To bridge this gap, we used physiologically based pharmacokinetic (PBPK) modeling to predict intracellular concentrations of statins. Quantitative data on transporter clearance were scaled from in vitro to in vivo conditions by integrating targeted proteomics and transporter kinetics data. The developed PBPK models, informed by proteomics, suggested that organic anion-transporting polypeptide 2B1 (OATP2B1) and multidrug resistance-associated protein 1 (MRP1) play a pivotal role in the distribution of statins in muscle. Using these PBPK models, we were able to predict the impact of alterations in transporter function due to genotype or drug-drug interactions on statin systemic concentrations and exposure in liver and muscle. These results underscore the potential of proteomics-guided PBPK modeling to scale transporter clearance from in vitro data to real-world implications. It is important to evaluate the role of drug transporters when predicting tissue exposure associated with on- and off-target effects.

Drug-drug interactions between pemafibrate and statins on pharmacokinetics in healthy male volunteers: Open-label, randomized, 6-sequence, 3-period crossover studies.

Elevated triglyceride levels are associated with an increased risk of cardiovascular events despite guideline-based statin treatment of low-density lipoprotein cholesterol. Peroxisome proliferator-activated receptor α (PPARα) agonists exert a significant triglyceride-lowering effect. However, combination therapy of PPARα agonists with statins poses an increased risk of rhabdomyolysis, which is rare but a major concern of the combination therapy. Pharmacokinetic interaction is suspected to be a contributing factor to the risk. To examine the potential for combination therapy with the selective PPARα modulator (SPPARMα) pemafibrate and statins, drug-drug interaction studies were conducted with open-label, randomized, 6-sequence, 3-period crossover designs for the combination of pemafibrate 0.2 mg twice daily and each of 6 statins once daily: pitavastatin 4 mg/day (n = 18), atorvastatin 20 mg/day (n = 18), rosuvastatin 20 mg/day (n = 29), pravastatin 20 mg/day (n = 18), simvastatin 20 mg/day (n = 20), and fluvastatin 60 mg/day (n = 19), involving healthy male volunteers. The pharmacokinetic parameters of pemafibrate and each of the statins were similar regardless of coadministration. There was neither an effect on the systemic exposure of pemafibrate nor a clinically important increase in the systemic exposure of any of the statins on the coadministration although the systemic exposure of simvastatin was reduced by about 15% and its open acid form by about 60%. The HMG-CoA reductase inhibitory activity in plasma samples from the simvastatin and pemafibrate combination group was about 70% of that in the simvastatin alone group. In conclusion, pemafibrate did not increase the systemic exposure of statins, and vice versa, in healthy male volunteers.

Pharmacokinetic and Safety Comparison of Fixed-Dose Combination of Cilostazol/Rosuvastatin (200 + 20 mg) Versus Concurrent Administration of the Separate Components in Healthy Adults.

The combined cilostazol and rosuvastatin therapy is frequently used for coronary artery disease treatment. This open-label, 3 × 3 crossover clinical trial evaluated the pharmacokinetics and safety of a fixed-dose combination (FDC) of cilostazol/rosuvastatin (200 + 20 mg) versus a concurrent administration of the separate components (SCs) under both fasted and fed conditions. Among 48 enrolled healthy adults, 38 completed the study. Participants were administered a single oral dose of cilostazol/rosuvastatin (200 + 20 mg), either as an FDC or SCs in a fasted state, or FDC in a fed state, in each period of the trial. Blood samples were taken up to 48 hours after dosing, and plasma concentrations were analyzed using validated liquid chromatography-tandem mass spectrometry. The geometric mean ratios of FDC to SCs for area under the plasma concentration-time curve from time zero to the last quantifiable concentration (AUClast) and maximum plasma concentration (Cmax) were 0.94/1.05 and 1.06/1.15 for cilostazol and rosuvastatin, respectively (AUClast/Cmax). Compared with that during fasting, fed-state administration increased the AUClast and Cmax for cilostazol by approximately 72% and 160% and decreased these parameters for rosuvastatin by approximately 39% and 43%, respectively. To conclude, the FDC is bioequivalent to the SCs, with notable differences in pharmacokinetics when administered in a fed state. No significant safety differences were observed between the treatments.

Clinical Evaluation of the Effect of Encorafenib on Bupropion, Rosuvastatin, and Coproporphyrin I and Considerations for Statin Coadministration.

BACKGROUND AND OBJECTIVES: Encorafenib is a kinase inhibitor indicated for the treatment of patients with unresectable or metastatic melanoma or metastatic colorectal cancer, respectively, with selected BRAF V600 mutations. A clinical drug-drug interaction (DDI) study was designed to evaluate the effect of encorafenib on rosuvastatin, a sensitive substrate of OATP1B1/3 and breast cancer resistance protein (BCRP), and bupropion, a sensitive CYP2B6 substrate. Coproporphyrin I (CP-I), an endogenous substrate for OATP1B1, was measured in a separate study to deconvolute the mechanism of transporter DDI. METHODS: DDI study participants received a single oral dose of rosuvastatin (10 mg) and bupropion (75 mg) on days - 7, 1, and 14 and continuous doses of encorafenib (450 mg QD) and binimetinib (45 mg BID) starting on day 1. The CP-I data were collected from participants in a phase 3 study who received encorafenib (300 mg QD) and cetuximab (400 mg/m2 initial dose, then 250 mg/m2 QW). Pharmacokinetic and pharmacodynamic analysis was performed using noncompartmental and compartmental methods. RESULTS: Bupropion exposure was not increased, whereas rosuvastatin Cmax and area under the receiver operating characteristic curve (AUC) increased approximately 2.7 and 1.6-fold, respectively, following repeated doses of encorafenib and binimetinib. Increase in CP-I was minimal, suggesting that the primary effect of encorafenib on rosuvastatin is through BCRP. Categorization of statins on the basis of their metabolic and transporter profile suggests pravastatin would have the least potential for interaction when coadministered with encorafenib. CONCLUSION: The results from these clinical studies suggest that encorafenib does not cause clinically relevant CYP2B6 induction or inhibition but is an inhibitor of BCRP and may also inhibit OATP1B1/3 to a lesser extent. Based on these results, it may be necessary to consider switching statins or reducing statin dosage accordingly for coadministration with encorafenib. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03864042, registered 6 March 2019.

Genome-Wide Association Study of Atorvastatin Pharmacokinetics: Associations With SLCO1B1, UGT1A3, and LPP.

In a genome-wide association study of atorvastatin pharmacokinetics in 158 healthy volunteers, the SLCO1B1 c.521T>C (rs4149056) variant associated with increased area under the plasma concentration-time curve from time zero to infinity (AUC0-∞) of atorvastatin (P = 1.2 × 10-10), 2-hydroxy atorvastatin (P = 4.0 × 10-8), and 4-hydroxy atorvastatin (P = 2.9 × 10-8). An intronic LPP variant, rs1975991, associated with reduced atorvastatin lactone AUC0-∞ (P = 3.8 × 10-8). Three UGT1A variants linked with UGT1A3*2 associated with increased 2-hydroxy atorvastatin lactone AUC0-∞ (P = 3.9 × 10-8). Furthermore, a candidate gene analysis including 243 participants suggested that increased function SLCO1B1 variants and decreased activity CYP3A4 variants affect atorvastatin pharmacokinetics. Compared with individuals with normal function SLCO1B1 genotype, atorvastatin AUC0-∞ was 145% (90% confidence interval: 98-203%; P = 5.6 × 10-11) larger in individuals with poor function, 24% (9-41%; P = 0.0053) larger in those with decreased function, and 41% (16-59%; P = 0.016) smaller in those with highly increased function SLCO1B1 genotype. Individuals with intermediate metabolizer CYP3A4 genotype (CYP3A4*2 or CYP3A4*22 heterozygotes) had 33% (14-55%; P = 0.022) larger atorvastatin AUC0-∞ than those with normal metabolizer genotype. UGT1A3*2 heterozygotes had 16% (5-25%; P = 0.017) smaller and LPP rs1975991 homozygotes had 34% (22-44%; P = 4.8 × 10-5) smaller atorvastatin AUC0-∞ than noncarriers. These data demonstrate that genetic variation in SLCO1B1, UGT1A3, LPP, and CYP3A4 affects atorvastatin pharmacokinetics. This is the first study to suggest that LPP rs1975991 may reduce atorvastatin exposure. [Correction added on 6 April, after first online publication: An incomplete sentence ("= 0.017) smaller in heterozygotes for UGT1A3*2 and 34% (22%, 44%; P × 10-5) smaller in homozygotes for LPP noncarriers.") has been corrected in this version.].

Validation of a novel direct method to determine reduced adherence to atorvastatin therapy.

AIMS: Objective methods to determine statin adherence are requested to improve lipid management. We have recently established a method to detect reduced adherence to atorvastatin therapy with cut-off values based on the sum of atorvastatin and its major metabolites in the blood. We aimed to validate this method in patients with and without cardiovascular disease, and optimize previous cut-off values. METHODS AND RESULTS: The pharmacokinetic study included 60 participants treated with atorvastatin 20 mg (N = 20), 40 mg (N = 20), and 80 mg (N = 20). Atorvastatin was then stopped and blood samples collected from day zero to day four. Quantification of the parent drug and its metabolites in blood plasma was performed with a liquid chromatography-tandem mass spectrometry assay. The cut-off values for reduced adherence were validated and optimized by calculating diagnostic sensitivity and specificity. Our candidate cut-off value of dose-normalized six-component sum of atorvastatin plus metabolites <0.10 nM/mg provided a sensitivity of 97% and a specificity of 93% for detecting ≥2 omitted doses. An optimized cut-off <0.062 nM/mg provided a sensitivity of 90% and a specificity of 100%. An alternative simplified two-component metabolite sum with a cut-off value <0.05 nM/mg provided a sensitivity of 98% and a specificity of 76%. An optimized cut-off <0.02 nM/mg provided a sensitivity of 97% and a specificity of 98%. CONCLUSION: This validation study confirms that our direct method discriminates reduced adherence from adherence to atorvastatin therapy with high diagnostic accuracy. The method may improve lipid management in clinical practice and serve as a useful tool in future studies.

Understanding the impact of ABCG2 polymorphisms on drug pharmacokinetics: focus on rosuvastatin and allopurinol.

INTRODUCTION: In addition to the well-established understanding of the pharmacogenetics of drug-metabolizing enzymes, there is growing data on the effects of genetic variation in drug transporters, particularly ATP-binding cassette (ABC) transporters. However, the evidence that these genetic variants can be used to predict drug effects and to adjust individual dosing to avoid adverse events is still limited. AREAS COVERED: This review presents a summary of the current literature from the PubMed database as of February 2024 regarding the impact of genetic variants on ABCG2 function and their relevance to the clinical use of the HMG-CoA reductase inhibitor rosuvastatin and the xanthine oxidase inhibitor allopurinol. EXPERT OPINION: Although there are pharmacogenetic guidelines for the ABCG2 missense variant Q141K, there is still some conflicting data regarding the clinical benefits of these recommendations. Some caution appears to be warranted in homozygous ABCG2 Q141K carriers when rosuvastatin is administered at higher doses and such information is already included in the drug label. The benefit of dose adaption to lower possible side effects needs to be evaluated in prospective clinical studies.

Del concepto de estatinas de alta potencia a los efectos extralipídicos de las estatinas / Statins: from high potency to extralipid effects

Las estatinas son fármacos que reducen la concentración plasmática de colesterol unido a lipoproteínas de baja densidad, con demostrada eficacia en la prevención cardiovascular primaria y secundaria. Pueden clasificarse según su capacidad hipolipemiante; se consideran de alta potencia o intensidad las que logran una reducción aproximada del 50%. También ejercen acciones que no parecen explicarse únicamente por la reducción de colesterol y se cree que están relacionadas con otras propiedades (antioxidantes, antiinflamatorias, antitrombóticas...) asociadas a su acción sobre las proteínas G. Se han estudiado estos posibles efectos extralipídicos en diferentes enfermedades cardiovasculares y otras enfermedades, como sepsis, cáncer, demencia, etc., pero aún no hay datos definitivos que justifiquen la ampliación de las indicaciones terapéuticas de las estatinas más allá de la reducción del colesterol (AU)

Statins are drugs that reduce the plasma low-density lipoprotein cholesterol level. They have been shown to be effective for both primary and secondary cardiovascular prevention. These drugs can be classified according to their lipid-lowering capacity and are considered to have a high potency or high intensity if they can reduce levels by approximately 50%. In addition, they have other effects that do not appear to be explained solely by their ability to reduce the cholesterol level. It is thought these effects are related to other properties of the drugs (e.g. their antioxidant, anti-inflammatory or antithrombotic properties) which are associated with their actions on G proteins. These extralipid effects have been studied in various cardiovascular diseases and in other conditions, such as sepsis, cancer and dementia. However, existing data are not clear enough to justify extending the therapeutic indications of statins beyond cholesterol reduction (AU)

¿Modifica la ingesta calórica y el consumo de grasas la utilización de estatinas? / Does the use of statins modify calorie intake and fat consumption?

Importancia del problema: Tanto la modificación de la dieta como la utilización de estatinas disminuyen los niveles de colesterol en la sangre. El incremento de la ingesta calórica entre la población general se señala que se ha estancado en la pasada década, sin embargo, no existe ningún estudio que evalúe las relaciones que pudieran existir entre las tendencias de la ingesta calórica y la utilización de estatinas. Objetivo: Examinar las diferencias temporales entre las tendencias de ingesta calórica y de ingesta grasa entre los tratados con estatinas y los no tratados en la población norteamericana. Material y métodos: Se trata de un estudio transversal con muestra nacional representativa con 27.886 ciudadanos estadounidenses de más de 20 años de edad en tratamiento. o no con estatinas extraídos de la encuesta National Health and Nutrition Examination Survey entre 1999 y 2010. Se evaluó la ingesta calórica y de grasas según un registro de 24 h. Se aplicó un modelo lineal generalizado que midiera la tendencia temporal entre la interacción entre la ingesta dietética, por calorías e ingesta de grasas, y la utilización o no de estatinas tras ajustarlo según diversas variables confusoras. El índice de masa corporal (IMC) también se comparó entre ambos grupos. Resultados: Según el estudio, entre los años 1999 y 2000 la ingesta calórica disminuyó significativamente entre los pacientes en tratamiento con estatinas frente a aquellos que no las utilizaban (2.000 frente a 2.179 kcal/d; p = 0,007). Estas diferencias se acortaron con el tiempo, no existiendo cambios significativos en el período 2005-2006. Entre los que tenían prescritas las estatinas en el período 2009-2010 hubo una ingesta calórica un 9,6% (IC 95% 1,8- 18,1; p = 0,02) mayor que en el período 1999-2000, que contrastó con la falta de cambios en este sentido entre los que no ingerían estatinas en el mismo período. En relación con la ingesta grasa, los que estaban en tratamiento con estatinas también consumieron menos en el período 1999- 2000 (71,7 frente a 81,2 g/d, p = 0,003), pero esta ingesta se incrementó tras este período hasta un 14,4% (IC 95% 3,8- 26,1; p = 0,007), al tiempo que no variaba entre los que no consumían estatinas. En cuanto al IMC, se incrementó más entre los que utilizaban las estatinas (+ 1,3) que entre los que no las utilizaban (+ 0,4), según el modelo aplicado (p = 0,02). Conclusiones: La ingesta calórica y de grasas se incrementó entre los pacientes a los que se les habían prescrito estatinas a lo largo del tiempo, algo que no ocurrió entre los que no ingerían esta medicación. El incremento del IMC fue más rápido entre los del grupo de estatinas que entre los que no las consumían. Todo ello lleva a hacer hincapié en el control de la dieta en los pacientes que utilizan estatinas (AU)

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The effect of some medications given to CKD patients on vitamin D levels / Efectos de algunos fármacos administrados a los pacientes de ERC sobre los niveles de vitamina D

Background: Vitamin D deficiency and polypharmacy is a common problem over chronic kidney disease (CKD) population. Objectives: To assess the clinical and analytical characteristics of CKD patients with 25-OH-D3 deficiency (<15 ng/mL), including the possible role of associated drugs. Methods: A single center observational review of 137 incident patients referred to our outpatient clinic with different stages of CKD and 25-OH-D3<15ng/mL (male gender 53.3%, mean age 70.8 [±16.1] years, mean GFR (MDRD-4) 43.6 [±25.5] ml/min/1.73 m2). 25-OH-D3 levels were collected in spring. Clinical and biochemical data and associated medications were recorded. Results: Mean 25-OH-D3 levels were 8.23 [±4.03] ng/ml. Eighty-eight patients (64.7%) had 3 or more concomitant drugs. Only 7 patients (5.1%) were not receiving any medication. Patients were divided in three groups according the therapies into none (n=26), RAS inhibitors or allopurinol (n=81), and RAS inhibitors plus allopurinol (n=30); with the aim to study the influence of statin therapy. Patients under renin angiotensin (RAS) inhibitors or Allopurinol treatment presented significantly higher 25-OH-D3 levels (p=0.001 and p=0.01 respectively), however patients with Statins treatment had lower 25-OH-D3 level (p=0.039). Personal history of diabetes, cardiovascular events or other therapies did not modify 25-OH-D3 levels, adjusted by age and eGFR. Conclusions: CKD patients with vitamin D deficiency who received RAS inhibitors or Allopurinol treatment had higher 25-OH-D3 levels, however those with statins treatment had lower vitamin D levels. Randomized controlled trials are required to confirm these findings (AU)

Antecedentes: La deficiencia de vitamina D y la polifarmacia constituyen un problema común en la población con enfermedad renal crónica (ERC). Objetivos: Evaluar las características clínicas y analíticas de los pacientes de ERC con deficiencia de 25-OH-D3 (<15 ng/mL), incluyendo la función posible de los fármacos asociados. Métodos: Se realizó una revisión observacional en un único centro, de 137 pacientes incidentes remitidos a nuestra clínica ambulatoria con diferentes estadios de ERC y 25-OH-D3<15 ng/mL (varones 53,3%, edad media 70,8 [±16,1] año, GFR medio (MDRD-4) 43,6 [±25,5] ml/min/1,73 m2). Los valores de 25-OH-D3 se recolectaron en primavera. Se registraron los datos bioquímicos y los fármacos asociados. Resultados: Los niveles medios de 25-OH-D3 fueron de 8,23 [±4,03] ng/ml. Ochenta y ocho pacientes (64,7%) tomaban tres o más fármacos concomitantes. Únicamente siete pacientes (5,1%) no recibían medicación alguna. Los pacientes fueron divididos en tres grupos, conforme a las terapias: ninguna (n = 26), inhibidores RAS o Alopurinol (n = 81), e inhibidores RAS más alopurinol (n = 30), a fin de estudiar la influencia de la terapia de estatinas. Los pacientes sometidos a tratamiento de inhibidores de la renina-angiotensina (RAS) o Alopurinol presentaron unos niveles considerablemente superiores de 25-OH-D3 (p = 0,001 y p = 0,01 respectivamente), y sin embargo los pacientes con tratamiento de estatinas presentaron unos menores niveles de 25-OH-D3 (p = 0,039). La presencia de diabetes, episodios cardiovasculares u otras terapias no modificaron los niveles de 25-OH-D3, ajustados por edad y eGFR. Conclusiones: Los pacientes de ERC con deficiencia de vitamina D, sometidos a tratamiento de inhibidores RAS o Alopurinol reflejaron unos niveles superiores de 25-OH-D3, y sin embargo aquellos sometidos a tratamiento de estatinas reflejaron unos menores niveles de vitamina D. Se precisan ensayos aleatorizados controlados para confirmar estos hallazgos (AU)

Pitavastatina: otra estatina a emplear y vigilar / Pitavastatin: other statin to be used and monitored

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Estratificación del riesgo cardiovascular en pacientes con sobrepeso u obesidad en prevención primaria. Implicaciones en la utilización de estatinas / Cardiovascular risk stratification in overweight or obese patients in primary prevention. Implications for use of statins

ANTECEDENTES Y OBJETIVOS: La estimación del riesgo cardiovascular en pacientes con sobrepeso/obesidad no está estandarizada. Nuestros objetivos fueron: estratificar el riesgo cardiovascular mediante distintos puntajes, analizar la indicación de estatinas, describir la prevalencia de placa aterosclerótica carotídea (PAC) y determinar el punto de corte óptimo (PCO) de los puntajes que discriminen entre sujetos con o sin PAC. Material y métodos Incluimos a pacientes no diabéticos con sobrepeso u obesidad en prevención primaria. Calculamos los puntajes de Framingham (PF) y europeo (PE), y el propuesto por las nuevas guías norteamericanas (NP), evaluando la indicación de estatinas. Determinamos la prevalencia de PAC mediante ultrasonido. Realizamos un análisis ROC. RESULTADOS: Se incluyó a 474 pacientes (67% con sobrepeso y 33% obesos). El PF fue el que más sujetos clasificó como «bajo riesgo». La prevalencia de PAC fue mayor en los obesos en comparación con los sujetos con sobrepeso (44.8% vs. 36.1%, p = 0,04). Basándose en el PF, PE y NP, el 26,7, el 39,1 y el 39,1% de los sujetos con sobrepeso y el 28,6, el 39,0 y el 39,0% de los obesos tenían indicación absoluta de estatinas. Los 3 puntajes mostraron discriminar aceptablemente entre sujetos con o sin PAC (área bajo la curva > 0,7). Los PCO evaluados no necesariamente coincidieron con los valores que determinan las categorías de riesgo. CONCLUSIONES: En esta población con sobrepeso/obesidad, la estratificación de riesgo y la indicación de estatinas variaron según la función utilizada. Conocer la relación entre los puntajes y la presencia de PAC podría optimizar la estimación de riesgo

BACKGROUND AND OBJECTIVES: Cardiovascular risk estimation in patients with overweight/obesity is not standardized. Our objectives were to stratify cardiovascular risk using different scores, to analyze use of statins, to report the prevalence of carotid atherosclerotic plaque (CAP), and to determine the optimal cut-off point (OCP) of scores that discriminate between subjects with or without CAP. MATERIAL AND METHODS: Non-diabetic patients with overweight or obesity in primary prevention were enrolled. The Framingham score (FS), the European score (ES), and the score proposed by the new American guidelines (NS) were calculated, and statin indication was evaluated. Prevalence of CAP was determined by ultrasound examination. A ROC analysis was performed. RESULTS: A total of 474 patients (67% with overweight and 33% obese) were enrolled into the study. The FS classified the largest number of subjects as low risk. PAC prevalence was higher in obese as compared to overweight subjects (44.8% vs. 36.1%, P = .04). According to the FS, ES, and NS respectively, 26.7%, 39.1%, and 39.1% of overweight subjects and 28.6%, 39.0%, and 39.0% of obese subjects had an absolute indication for statins. All three scores were shown to acceptably discriminate between subjects with and without CAP (area under the curve > 0.7). The OCPs evaluated did not agree with the risk category values. CONCLUSIONS: Risk stratification and use of statins varied in the overweight/obese population depending on the function used. Understanding of the relationship between scores and presence of CAP may optimize risk estimate

Farmacogenómica: aplicaciones cardiovasculares / Pharmacogenomics: cardiovascular applications

Las enfermedades cardiovasculares constituyen un importante problema de salud pública al ser la principal causa de morbilidad y mortalidad en el mundo. Por ello, existe la creciente necesidad de tratamientos farmacoterapéuticos más eficaces y seguros. Sin embargo, a pesar de que los médicos prescriben fármacos sobre la base de las características farmacológicas del medicamento y la probabilidad de obtener resultados clínicamente reproducibles, muchos de los fármacos son eficaces sólo entre 25-60% de los pacientes. En este sentido es que la Farmacogenómica, a través del estudio de variantes genéticas de proteínas involucradas en la farmacocinética y farmacodinamia de los medicamentos, persigue maximizar su eficacia y seguridad, Este trabajo pretende dar una visión general acerca de farmacogenómica cardiovascular y la posibilidad de utilizar, en la consulta clínica, herramientas genéticas para apoyar la decisión farmacoterapéutica, con el objeto de mejorar la respuesta al tratamiento de enfermedades cardiovasculares, un paso hacia la medicina personalizada en Chile.

Cardiovascular disease is a major public health problem being the leading cause of morbidity and mortality worldwide. Therefore, there is a growing need for safer and more effective pharmacotherapeutic treatments. However, although physicians prescribe drugs based on pharmacological properties of each drug and the probability of obtaining clinically reproducible results, many drugs are effective only in 25-60% of patients. In this respect, pharmacogenomics, through the study of genetic variants of proteins involved in the pharmacokinetics and pharmacodynamics of drugs, pursues to maximize their efficacy and safety, This paper aims to give an overview of cardiovascular pharmacogenomics and the possibility to use, in clinical practice, genetic tools to support pharmacotherapeutical decisions, in order to improve the response to treatment of cardiovascular diseases, a step toward personalized medicine in Chile.

¿Es posible la regresión de la placa aterosclerótica? / Is regression of atherosclerotic plaque possible?

La patogenia de los síndromes coronarios agudos está relacionada con la rotura o erosión de una placa aterosclerótica vulnerable. La estabilización de dicha placa, por reducción del núcleo lipídico y/o aumento de la capa fibrosa, sería uno de los mecanismos potencialmente beneficiosos observados con agentes antiateroscleróticos. El concepto de estabilización de la placa de ateroma se desarrolló para explicar el efecto beneficioso del tratamiento hipolipemiante, sin cambios apreciables en el tamaño y la morfología de la lesión aterosclerótica («paradoja angiográfica»). En la actualidad, el desarrollo de nuevas técnicas de imagen no invasivas (ultrasonido vascular e histología virtual, resonancia magnética, tomografía de coherencia óptica, etc.) permite determinar el volumen, el tamaño y la composición de la placa, con lo que es posible caracterizar las placas más vulnerables y, por consiguiente, más susceptibles de rotura. Una estrategia hipolipemiante «agresiva» puede estabilizar e incluso reducir de forma significativa la carga aterosclerótica y la incidencia de episodios vasculares, al menos en parte, a través de un efecto estabilizador de la placa

As it is well-known, a thrombus evolving into a disrupted/eroded atherosclerotic plaque causes most acute coronary syndromes. Plaque stabilization via reduction of the lipid core and/or thickening of the fibrous cap is one of the possible mechanisms accounted for the clinical benefits displayed by different anti-atherosclerotic strategies. The concept of plaque stabilization was developed to explain how lipid-lowering agents could decrease adverse coronary events without substantial modifications of the atherosclerotic lesion ("angiographic paradox"). A number of imaging modalities (vascular ultrasound and virtual histology, MRI, optical coherence tomography, positron tomography, etc.) are used for non-invasive assessment of atherosclerosis; most of them can identify plaque volume and composition beyond lumen stenosis. An "aggressive" lipid-lowering strategy is able to reduce the plaque burden and the incidence of cardiovascular events; this may be attributable, at least in part, to plaque-stabilizing effects

Frequency of common variants in genes involved in lipid-lowering response to statins in Chilean subjects with hypercholesterolemia / Frecuencia de polimorfismos en genes relacionados a la respuesta terapéutica a estatinas en individuos chilenos con hipercolesterolemia

Interindividual differences in activity and expression of the metabolizing enzymes cytochrome P450 (CYP) 3A4 and 3A5 and the multidrug efflux pump P-glycoprotein (P-gp, encoded by ABCB1 gene) contribute considerably to lipid-lowering efficacy of statin treatment in subjects with hypercholesterolemia. Variability in the activity of CYP3A4, CYP3A5 and P-gp could be considered to result from genetic polymorphisms encoding their genes. However, the available data indicate that the frequencies of ABCB1, CYP3A4 and CYP3A5 gene polymorphisms differ significantly across populations. Thus, the aim of the present study was to determine the allelic frequency of three common variants of these genes in Chilean individuals with primary hypercholesterolemia (HC) and controls. A total of 135 unrelated patients (44 +/- 7 years old) with diagnosis of hypercholesterolemia (Total cholesterol 240 mg/dL) and 120 normolipidemic healthy controls (40 +/- 10 years old; total cholesterol 200 mg/dL) were included in this study. The 3435C>T (MDR1), -290A>G (CYP3A4) and 6986A>G (CYP3A5) gene polymorphisms were analyzed by PCR-RFLP. The genotype distribution for 3435C>T variant of ABCB1 in HC patients (CC: 49 percent, CT: 37 percent, TT: 14 percent) and controls (CC: 41 percent, CT: 48 percent, TT: 11 percent) was comparable (P=0.186). Similarly, the genotype distribution for -290A>G polymorphism of CYP3A4 in HC subjects (AA: 73 percent, AG: 27 percent, GG: 0 percent) and controls (AA: 71 percent, AG: 29 percent, GG: 0 percent) was equivalent (P = 0.863). Finally, the genotype distribution for 6986A>G variant of CYP3A5 in HC individuals (AA: 4 percent, AG: 41 percent, GG: 55 percent) and controls (AA: 4 percent, AG: 47 percent, GG: 49 percent) was similar (P=0.594). The allelic frequencies of 3435C>T (ABCB1), -290A>G (CYP3A4) and 6986A>G (CYP3A5) polymorphisms are similar between Chilean HC patients and controls, and comparable to frequencies found in Asian populations.

Polimorfismos de los genes CYP3A4, CYP3A5 y ABCB1 se han asociado a variaciones en la respuesta a fármacos hipolipemiantes, como las estatinas; principales medicamentos utilizados para disminuir los niveles plasmáticos de colesterol (CT). Sin embargo, la frecuencia de estas variantes genéticas puede variar entre las poblaciones. Así, el objetivo de este trabajo fue evaluar la frecuencia de tres polimorfismos de los genes CYP3A4, CYP3A5 y ABCB1, relacionados previamente a la respuesta a estatinas, en individuos chilenos hipercolesterolémicos (HC) y controles. Se analizaron 135 sujetos con diagnóstico de hipercolesterolemia primaria (CT 240 mg/dL) y 120 controles (CT 200 mg/dL) pertenecientes a la Región de La Araucanía (Chile). La genotipificación de las variantes genéticas se efectuó mediante la técnica de reacción en cadena de la polimerasa seguido de restricción enzimática (PCR-RFLP). La distribución de genotipos para la variante 3435C>T del gen ABCB1 en los individuos HC (CC: 49 por ciento, CT: 37 por ciento, TT: 14 por ciento) y controles (CC: 41 por ciento, CT: 48 por ciento, TT: 11 por ciento) fue semejante (P = 0,186). De forma similar, la distribución de genotipos para el polimorfismo -290A>G del gen CYP3A4 en los pacientes HC (AA: 73 por ciento, AG: 27 por ciento, GG: 0 por ciento) y controles (AA: 71 por ciento, AG: 29 por ciento, GG: 0 por ciento) fue equivalente (P = 0,863). Del mismo modo, la distribución de genotipos para la variante 6986A>G del gen CYP3A5 en el grupo HC (AA: 4 por ciento, AG: 41 por ciento, GG: 55 por ciento) y grupo control (AA: 4 por ciento, AG: 47 por ciento, GG: 49 por ciento) fue similar (P = 0,594). En resumen, nuestro estudio demuestra que las frecuencias de los polimorfismos 3435C>T (ABCB1), -290A>G (CYP3A4) y 6986A>G (CYP3A5) no difieren entre individuos HC y controles, y son comparables a las frecuencias encontradas en poblaciones asiáticas. Su efecto sobre el tratamiento con estatinas en la población chilena debe ser...