Pharmacogenetic determinants of antiretroviral therapy : the case of lopinavir
(2010)
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- Authors
- Supervisors
- Haufroid, Vincent
- Abstract
- (en) Highly active antiretroviral therapy (HAART) was introduced in 1996 and has allowed to rapidly reduce the mortality and morbidity related to AIDS. HAART consists of an association of anti-HIV drugs, typically three to four, which are combined in order to avoid the development of viral resistance. This association has been implemented to achieve a durable virological and immunological response to treatment. However, it is clear that such an association of drugs complicates the treatment in terms of drug interactions, metabolism induction and/or inhibition etc… Moreover, managing the occurrence of adverse events, the compliance of the patient and the apparition of viral mutants remains difficult as the factors involved in those mechanisms remain, at least partially, unidentified. On the other hand, several of the anti-HIV drugs, particularly protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), are characterized by a narrow therapeutic window and high inter- and intra-individual variability in pharmacodynamics and pharmacokinetics, which increase considerably the risk of inadequate drug levels and/or treatment response in each patient. Therapeutic drug monitoring (TDM) is a branch of clinical chemistry defined as the analysis of in vivo drug concentrations followed, if necessary, by an adjustment of the dosage regimen on the basis of these concentrations. Regarding the difficulty of achieving an adequate clinical response with ARV drugs, TDM is thus increasingly recommended for the management of anti-HIV treatment. The first aim of the present work was, therefore, to develop and validate an analytical tool to monitor ARV drug levels in plasma, which have been previously related to the clinical response. Furthermore, since the therapeutic target of antiretroviral drugs is within the infected cell, it appeared, at least intuitively, that intralymphocyte drug concentration would constitute a better biomarker of treatment success or failure than plasma drug levels. Therefore, we focused our second objective on developing a method allowing the measurement of ARV in peripheral blood mononuclear cells (PBMCs), a blood compartment enriched in lymphocytes. Despite its proven effectiveness in the management of patients, TDM has some limitations, as it requires the patient to be already on medication, the plasma concentrations being determined a posteriori. Consequently, the initial regimen and its dosage are not strictly adapted for each patient as they represent a standard treatment defined from a mean pharmacological response in the general population. The time spent to achieve the optimal dosage and to define the right regimen might be reduced if determinants of pharmacokinetic variability could be identified. Greater knowledge in human pharmacogenetics and by extension pharmacogenomics could thus probably lead to a better understanding of interactions between humans and drugs. The promise of pharmacogenetics is precisely that both the choice of a drug and its dose could be determined by the individual genetic makeup, leading to personalized, more efficient and less harmful therapy. More specifically, research in pharmacogenetics is being pursued in HIV therapeutics because of the high prevalence of toxicity, the long-term nature of the treatment, and the complexity inherent to multidrug therapy, that could therefore greatly benefit from predictive tools to identify the drug combination most likely to be tolerated and effective. The present work essentially focused on the genetic determinants of lopinavir (LPV) pharmacokinetic variability. LPV is a potent PI widely used in first-line therapy, which is used in combination with low doses of ritonavir (RTV), the latter literally boosting LPV levels. The first step in any pharmacogenetic investigation is the identification of genetic variations related to differences in drug response. Our first study involved a cohort of 53 patients treated with LPV/r (400/100 mg twice daily) and led to the confirmation that CYP3A5 as well as ABCB1 polymorphisms have no significant influence on the steady-state LPV plasma and intracellular concentrations when administered in combination with RTV. By contrast, this study highlighted the importance of a particular genetic polymorphism, the ABCC2 4544G>A, and its impact on the LPV intracellular distribution. More specifically, it was observed that LPV-treated patients, carriers of the mutated allele 4544A are characterized by higher intralymphocyte accumulation than wild-type homozygous carriers. It was thus hypothesized that the mutation negatively affects the activity of ABCC2 towards LPV. In the last step of the present thesis, we tried to explain those observed in vivo pharmacokinetic differences. In the in vitro study, we demonstrated that the mutation is associated with a substantial decrease of the ABCC2-mediated ATPase activity and logically, that it affects similarly the transport of substrates. In conclusion, we have developed two different tools for the monitoring of anti-HIV treatment, both providing important pharmacokinetic informations for clinicians about the patient's response to therapy. The present work emphasizes the influence of a genetic variant on the pharmacokinetics of LPV and provides possible mechanistic explanations for the observed differences through in vitro investigations. All these discoveries could potentially have direct clinical applications. Indeed, they can lead the pharmacologist to determine a lower plasma target level for carriers of at least one mutated allele to reach similar intracellular levels than wild-type homozygous patients. One could therefore expect that maintaining lower plasma concentrations will have a positive impact on long-term side-effects related to LPV-mediated dyslipidemia in these patients. However, it is clear that dosage recommendations cannot be established based on an isolated study and that these observations must be further confirmed, characterized and explained.
- Affiliations
Citations
Elens, L. (2010). Pharmacogenetic determinants of antiretroviral therapy : the case of lopinavir. https://hdl.handle.net/2078.5/148182