Influence of rheumatoid arthritis on pharmacokinetics and pharmacokinetics-pharmacodynamics (PK-PD) of the enantiomers of fluvastatin

• Grant number: 14/02802-0
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: October 01, 2014
• End date: April 30, 2018
• Field of knowledge: Biological Sciences - Pharmacology - Clinical Pharmacology
• Agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal Investigator: Vera Lúcia Lanchote
• Grantee: Juciene Aparecida Caris
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disease with autoimmune characteristic. Its prevalence in Brazil is from 0.2 to 1%, with high morbidity and mortality rates from cardiovascular disease compared to normal population. Dyslipidemia is one of the coadjuvant traditional risk factors for atherosclerosis acceleration, increasing cardiovascular disease likelihood in patients with RA. Clinical studies have demonstrated the statins effectiveness in reducing cardiovascular morbidity and mortality. In addition to work through of the lipidic modulation, recent studies have demonstrated widest properties to statins, especially in the inflammatory pathways modification by inhibiting the production of cytokines. Fluvastatin, in particular, has its uptake via the transporter OATP1B1, being metabolized by CYP2C9 isoenzyme and efflux via BCRP transporter. In this context, PK-PD modeling is used to describe and quantify the dose-concentration-effect relation under the influence of an inflammatory disease, the rheumatoid arthritis. This study covers the investigation of healthy volunteers (n=15) and RA patients (n=15) and will be developed in two phases: in phase 1, the healthy volunteers and patients with RA will be evaluated for baseline concentrations of non-esterified fatty acids (NEFA) and mevalonic acid; in phase 2, the healthy volunteers and patients will be treated, for 1 week, with racemic fluvastatin (Lescol, 20 or 40 mg capsules). After administration of the last fluvastatin dose, the serial blood samples will be carried out up to 24 h for determination of plasma concentrations of the enantiomers of fluvastatin, NEFA and mevalonic acid. The PK-PD modeling will be developed using the plasma concentrations of fluvastatina as pharmacokinetic parameters and the biomarkers mevalonic acid and NEFA as pharmacodynamic parameters. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

CARIS, JUCIENE APARECIDA; DE LIMA BENZI, JHOHANN RICHARD; LIMA DE SOUZA, FLAVIO FALCAO; RIBEIRO DE OLIVEIRA, RENE DONIZETI; DONADI, EDUARDO ANTONIO; LANCHOTE, VERA LUCIA. Rheumatoid arthritis downregulates the drug transporter OATP1B1: Fluvastatin as a probe. European Journal of Pharmaceutical Sciences, v. 146, APR 15 2020. (14/02802-0)