title: Pharmacogenetic analysis of SNPs in genes involved in the pharmacokinetics and response to lopinavir/ritonavir therapy.
abstract: Despite the known benefits and the experienced use of lopinavir/ritonavir (LPV/r) in the management of HIV infection, important interindividual variability in the pharmacokinetics (PKs) and the response to treatment with standard doses of this drug has been observed. Host genetic factors have been recently suggested as being responsible for part of this variability as they may affect the expression and functional activity of many proteins involved in the kinetic behavior, the immune recovery or the adverse effects related to LPV/r. Here, we present a genetic association study in 106 HIV-infected individuals collected over a period of 5 years with the aim of identifying and confirming single nucleotide polymorphisms (SNPs) with a significant influence on the PK parameters of LPV/r, the immunovirological response or toxicity derived from treatment with the studied drug. Genotyping was performed by MALDI-TOF and KASPar; LPV/r plasma concentrations were quantified using high-performance liquid chromatography with an ultraviolet detection system and the PK parameters were estimated using Bayesian algorithms. Genetic association analysis was performed with SPSS. The most significant associations were found between SNPs in the dopamine receptor D3 gene and the PK of LPV/r. Additionally, other suggestive relationships were established between genetic factors and the response during treatment with this drug. Thereby, identifying HIV-infected individuals who are at increased risk of achieve non-optimal LPV/r plasma concentrations with the emergence of toxicity, drug resistance or absence of clinical response could be helpful as a tool to optimize the LPV/r-based antiretroviral therapy.
authors.affiliation: Pharmacy Service, University Hospital of Salamanca, Salamanca, Spain.
authors.forename: E
authors.initials: E
authors.lastname: López Aspiroz
authors.forename: S E
authors.initials: SE
authors.lastname: Cabrera Figueroa
authors.forename: G L
authors.initials: GL
authors.lastname: Porras Hurtado
authors.forename: R
authors.initials: R
authors.lastname: Cruz Guerrero
authors.forename: A
authors.initials: A
authors.lastname: Domínguez-Gil Hurlé
authors.forename: A
authors.initials: A
authors.lastname: Carracedo
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018791:CD4 Lymphocyte Count; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000097:blood* / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008055:Lipids / Q000097:blood; D061466:Lopinavir / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D050637:Receptors, Dopamine D3 / Q000235:genetics*; D019438:Ritonavir / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C493593:DRD3 protein, human; D017320:HIV Protease Inhibitors; D008055:Lipids; D050637:Receptors, Dopamine D3; D061466:Lopinavir; D019438:Ritonavir