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Investigation of molecular mechanisms regulating drug-drug interactions in antiretroviral therapy

Antiretroviral therapy is challenging due to the drug-drug interactions (DDIs) arising from the co-medications administered to treat co-morbidities and opportunistic infections. Drugs causing induction/inhibition of enzymes and transporters, or displacement from plasma proteins can alter drug pharmacokinetics (PK) and result in treatment failure due to elevated toxicities or suboptimal efficacy. Furthermore, inter-individual differences conferred by genetic variability responsible for modulating antiretroviral PK complicates treatment. Favourable PK is of paramount importance for successful treatment of any disease. Excipients are frequently used in drug formulations. These excipients not only transform the PK of drugs, but also exert biological effects in the body. These properties may be exploitable to modify PK for optimal outcomes. Evidently, investigations into the pharmacological properties of drugs and excipients are imperative for designing rational formulations and therapies to treat HIV. Knowledge about the effect of genetic polymorphisms on drugs will aid in vigilance of disparate outcomes and help personalising treatment. The NEAT 001 / ANRS 143 was conducted to analyse the efficacy of a novel NRTI- sparing dual combination of darunavir/ritonavir and raltegravir against a standard-of- care triple therapy of darunavir/ritonavir and tenofovir/emtricitabine in HIV-infected antiretroviral naive subjects. The single nucleotide polymorphisms (SNPs) that have known to have a clinical effect in previous literature were chosen and analysed for their influence on the drugs administered in this study, described in Chapter 2 and 3. In Chapter 4, the plasma protein binding and displacement of protease inhibitors – darunavir, atazanavir, lopinavir and ritonavir – were studied using Rapid Equilibrium Dialysis for their putative implications for DDIs. In Chapter 5, the effects of 25 commonly used excipients were analysed for their effects on P-glycoprotein (P-gp) by assessing the change in the cellular accumulation of a P-gp substrate digoxin in cells over-expressing P-gp. There is little data on the transport of the anti-tuberculosis agent linezolid which is frequently co-administered with antiretroviral drugs. Linezolid was assessed for transport by P-gp, MRP and the BCRP in Chapter 6. Darunavir and ritonavir plasma levels were significantly lower in patients receiving raltegravir compared to those receiving tenofovir/emtricitabine, suggesting DDIs. SLCO1B1 521T>C (rs4149056) and SLCO3A1 G>A (rs4294800) were associated with higher darunavir and ritonavir plasma concentrations, respectively. It was seen that the protease inhibitors bind to both AAG and albumin, suggesting a compensatory mechanism between the plasma proteins. P-gp inhibition by excipients was demonstrated by the following order of effects: Cremophor EL > Vit-E-PEG > Brij 58 > Tween 80 > NaCMC > Tween 20 > CTAB > Solutol HS 15 > AOT. Linezolid was found to be a substrate for P-gp, MRP and the BCRP and the results suggested involvement of additional transporters in linezolid disposition. These findings not only corroborate previously published findings, but also presents novel findings that throw light on the mechanism of genetic variability, plasma protein displacement and induction/inhibition of transporters giving rise to DDIs.