Pharmacogenomics of blood-brain barrier transporters: impact of ABCB1, ABCG2 and OATP1A2 transporters on the pharmacokinetics of amphotericin B in patients undergoing treatment for neurocryptococcosis

• Grant number: 22/16668-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: May 01, 2023
• End date: February 19, 2025
• Field of knowledge: Biological Sciences - Pharmacology - Clinical Pharmacology
• Principal Investigator: João Paulo Bianchi Ximenez
• Grantee: Valéria Matinatti Valério Martins
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 18/05616-3 - Clinical pharmacokinetics in infectious diseases, AP.TEM
• Associated scholarship(s): 24/09765-4 - Closing the gap in paediatric TB-treatment through integration of in vitro hollow fibre data and modelling and extrapolation studies., BE.EP.IC

Abstract

Neurocryptococcosis is a subacute meningoencephalitis caused by the fungus Cryptococcus spp., occurring more commonly in patients infected with HIV or with other forms of immunosuppression. Amphotericin B (AnfB), the drug of choice for the treatment of neurocryptococcosis, has low permeability in the blood-brain barrier (BBB), with consequent low concentrations in the cerebrospinal fluid (CSF). P-glycoprotein (P-gp) is widely expressed in the BBB and functions as an important pathway for the efflux of AnfB into the systemic circulation; consequently, its continuation increases the permeability of AnfB in the CNS. In addition to P-gp, the BBB also expresses the ATP-binding cassette transporter protein of the G subfamily (ABCG2), which works in conjunction with P-gp as an efflux transporter, and the organic anion transporter polypeptide 1A2 (OAT1A2), which acts as an influx transporter. The coding genes for these transport proteins are extremely polymorphic, which can impact the kinetic disposition of their substrates. The aim of the present study is to investigate the influence of genetic polymorphisms of the ABCB1, ABCG2 and SLCO1A2 genes and other possible covariates on AnfB concentrations in plasma and CSF of patients with neurocryptococcosis. Fifteen patients undergoing treatment at the HCFMRP-USP for neurocryptococcosis with indication for treatment with AnfB will be included. Blood and CSF samples will be collected for AnfB pharmacokinetic analysis and genotyping. Plasma and CSF concentrations of AnfB will be evaluated using liquid chromatography coupled to mass spectrometry (LC-MS/MS). Patients will be genotyped for polymorphisms ABCB1 (c.1236 T>C, c.2677T>G/A, c.3435T>C), ABCG2 (c.2677T>G/A) and SLCO1A2 (c.516A>C) . From the statistical analysis of the results, it will be possible to evaluate the contribution of genetic variability and other variables (gender, age, menopausal status, body mass index) in the kinetic disposition of AnfB.