Hospital Universitario de la Princesa, Spain
Title: The Contribution of Polymorphisms in CYP2B6 in Pharmacokinetics, Pharmacodynamics and Safety of Efavirenz.
Pablo Zubiaur is a first year Predoctoral Researcher in Hospital Universitario de la Princesa (HUP), Madrid, Spain. He is Pharmacist (MPharm) and Biotechnologist (BSc), for what he is keen on Research, always tightly linked to the clinical praxis. He is specialized in Pharmacogenomics. His PhD thesis tries to assess the consequences of several polymorphisms in ABCB1 (P-glycoprotein) on the transporter’s function in a cell culture-based approach. Additionally, he participates in several retrospective pharmacogenetic studies based on Phase I Bioequivalence Clinical trials, like the one presented in this abstract.
Background: Efavirenz (EFV) is a Human Immunodeficiency Virus non-nucleotidic reverse transcriptase inhibitor(1). CYP2B6 has been described as its main metabolizing enzyme whereas CYP3A or CYP2A6 have been identified as secondary enzymes (2). In this study, we evaluated the influence of polymorphisms in these enzymes and P-glycoprotein (3)(ABCB1) on the pharmacokinetics, pharmacodynamics sand safety of EFV.
Methods: Forty-seven healthy volunteers that received a 600 mg single oral dose of EFV were genotyped (with TaqMan™ probes in a StepOne RealTime PCR System®) for eleven polymorphisms in the following genes: CYP2B6, CYP2A6, CYP3A4, CYP3A5, and ABCB1.
Results: we have detected significant associations between CYP2B6 G516T G/T and T/T genotypes and higher Area Under the Curve (AUC) as well as lower clearance (Cl) as compared to the wildtype T/T genotype. Although this SNP accounts for the majority of EFV pharmacokinetic variability, CYP2B6 rs4803419 and rs3211371 could explain some of the variability detected in AUC and Cl (Table 1). Individuals with the CYP2B6 G516T G/T and rs4803419 heterozygote genotype exhibited noteworthy high AUC, as well as extremely low Cl. This result was similar in CYP2B6 G516T T/T carriers. Additionally, carriers of the combined CYP2B6 G516T G/G + CYP2B6 rs3211371 heterozygote genotyped showed an impaired AUC and an enhanced Cl.
Conclusion: CYP2B6 is recognized to mainly alter EFV disposal. PGx guidelines consider CYP2B6 G516T for EFV dosage adjustment with high levels of evidence (4,5). However, we have demonstrated that other SNPs in CYP2B6 can explain a non-insignificant percentage of variability in EFV exposure. For this reason, CYP2B6 G516T, rs4803419 and rs3211371 should be considered together to propose EFV metabolizing phenotypes in base to which perform dosage adjustment.he function of CYP2B6 should not be assessed with a unique SNP since other can condition EFV disposal. Here, not only have we confirmed the importance of G516T, also of rs4803419 and rs3211371, which are two variants that had been reported previously. This study enhances the evidence of the latter as EFV pharmacokinetic predictos.