Human Pharmacogenomic Variations and Their Implications for Antifungal Efficacy

Abstract

SUMMARY Pharmacogenomics is defined as the study of the impacts of heritable traits on pharmacology and toxicology. Candidate genes with potential pharmacogenomic importance include drug transporters involved in absorption and excretion, phase I enzymes (e.g., cytochrome P450-dependent mixed-function oxidases) and phase II enzymes (e.g., glucuronosyltransferases) contributing to metabolism, and those molecules (e.g., albumin, A1-acid glycoprotein, and lipoproteins) involved in the distribution of antifungal compounds. By using the tools of population genetics to define interindividual differences in drug absorption, distribution, metabolism, and excretion, pharmacogenomic models for genetic variations in antifungal pharmacokinetics can be derived. Pharmacogenomic factors may become especially important in the treatment of immunocompromised patients or those with persistent or refractory mycoses that cannot be explained by elevated MICs and where rational dosage optimization of the antifungal agent may be particularly critical. Pharmacogenomics has the potential to shift the paradigm of therapy and to improve the selection of antifungal compounds and adjustment of dosage based upon individual variations in drug absorption, metabolism, and excretion.

Posaconazole: A Broad-Spectrum Triazole Antifungal Agent

“…Posaconazole is both a substrate and inhibitor of Pglycoprotein, but despite genetic polymorphisms resulting in significant variability in P-glycoprotein expression among racial groups, neither race nor ethnicity significantly affect the pharmacokinetics of posaconazole [23]. Single-nucleotide polymorphisms in UGT that encode uridine diphosphate-glucuronotransferase may play a role [24], but this has not been confirmed. Thus, the reasons for the intersubject bioavailability of posaconazole-a problem also observed with both itraconazole and voriconazole-remain poorly defined.…”

Translational and Reverse Translational Research Supporting Precision Medicine: Acanthamoeba Keratitis as a Model of Linkage between Clinical and Basic Research Focused on Personalized Ophthalmology

“…For this reason, serum levels of hepatic enzymes are currently used as standard biomarkers for therapeutic monitoring, mainly of fungal infections. Pharmaco genomic models based on genetic polymorphisms of drug-metabolizing enzymes and drug transporters have the potential to improve medical decisions based on individual genomic profiles [54]. (Figure 2) presents an outlook of possible benefits of the cyclic interaction of TR, RTR and PM in the context of AK.…”

“…Ocular toxicity of current anti-Acanthamoeba drugs [4,47,48,49] Proof of efficacy of off-label drugs [50,51] or novel anti-Acanthamoeba compounds previously approved in pre-clinical trials. Identification of the patient's drug metabolizing profile through pharmacogenomics tests [54] to implement personalized therapy Inflammatory response is mediated by TLR4 receptor [30] TLR4 as a therapeutic target. Identification of TLR4 polymorphisms [31] associated with differential prognosis and establishment of personalized therapy Available omics technologies, complex analysis tools and personal genome [39][40][41][42] Development of new biomarkers and genetic tests for prognosis, therapy selection and follow-up [43] …”

Pharmacokinetic Behaviors of Orally Administered Drugs

“…Therefore, it can be observed that genetic polymorphism plays an important role in the ADME parameters of drugs, and that the field of pharmacogenetics is blooming due to the necessity to better predict PK disposition of drugs in order to design individualized drug regimens that can better predict therapeutic effects and compliance. There are extensive reviews on this topic dealing with genetic polymorphisms of different molecules and their effect on PK and PD (Bolt et al, 2003;Kirchheiner et al, 2005;Sakaeda, 2005;Chen, 2006;Meletiadis et al, 2006).…”