This proposal is an integrated career development plan that includes training in clinical and antiretroviral (ARV) pharmacokinetic (PK) research methods. The goal is to enable the candidate to establish an independent research career focused on ARV clinical pharmacology. The didactic training component will expand on the MSc in Clinical Research program and the AIDS Clinical Trials Group training fellowship which the candidate recently completed. The candidate's mentors have been involved in mentoring the candidate over the past two years and are committed to fostering his career development. The chief clinical conundrum of ARV therapy is that toxicity is often due to higher circulating drug concentrations, while viral resistance and treatment failure are related to inadequate ARV exposure. The plasma free fraction of ARV is inversely related to protein binding. Protease inhibitors (PI) are bound primarily to cc-1-acid glycoprotein (AAG), an acute phase protein whose plasma levels vary with HIV disease severity and in the setting of inflammation. As a result of this variability, and because of the high binding affinity and low saturation capacity of AAG, this protein has been shown to modulate the disposition and the therapeutic outcomes of chemotherapeutics agents used in oncology. It is therefore conceivable that changes in AAG levels could have similar effects on the PK and pharmacodynamic (PD) of the PIs. We hypothesize that plasma AAG levels in ARV-treated HIV-infected subjects decrease over time due to virologic suppression and immune reconstitution;and that changes in plasma AAG levels are inversely correlated with free concentrations of lopinavir (LPV). Changes in plasma AAG levels over time following institution of LPV/r based therapy will be measured, and correlated with changes in free LPV PK profile from baseline to week-16. Plasma AAG and LPV free levels will be measured by a fixed-time nephelometric method and HPLC-MS/MS respectively. The mean changes in AAG level from baseline to week-16 will be estimated and compared overtime using repeated-measures analyses. The correlation between week-16 changes in AAG levels and week-16 changes in free LPV PK profile following ARV therapy will be evaluated using a Pearson product moment correlation coefficient and the Spearman rank correlation coefficient. Since the free fraction of drug in plasma more accurately reflects the drug available to the target cell, and as a result its PD activities, the finding of an inverse relationship between plasma AAG levels and free LPV concentrations could have important implication in HIV pharmacotherapy.
|Wang, Kun; D'Argenio, David Z; Acosta, Edward P et al. (2014) Integrated population pharmacokinetic/viral dynamic modelling of lopinavir/ritonavir in HIV-1 treatment-naïve patients. Clin Pharmacokinet 53:361-71|
|Ofotokun, Ighovwerha; McIntosh, Emily; Weitzmann, M Neale (2012) HIV: inflammation and bone. Curr HIV/AIDS Rep 9:16-25|
|Ofotokun, Ighovwerha; Lennox, Jeffrey L; Eaton, Molly E et al. (2011) Immune activation mediated change in alpha-1-acid glycoprotein: impact on total and free lopinavir plasma exposure. J Clin Pharmacol 51:1539-48|
|Vikulina, Tatyana; Fan, Xian; Yamaguchi, Masayoshi et al. (2010) Alterations in the immuno-skeletal interface drive bone destruction in HIV-1 transgenic rats. Proc Natl Acad Sci U S A 107:13848-53|