Application of pharmacokinetics to improve antiretroviral treatment

Abstract

The introduction of protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) has allowed for treatment of HIV-infected patients with 'highly active antiretroviral treatment' (HAART). The studies in this thesis aimed to optimize dosage regimens for PIs and NNRTIs by the assessment and interpretation of the pharmacokinetic characteristics of these agents.The thesis first presents a review of the literature on analytical methods for measurement of PIs in plasma, and a review of the practice of Therapeutic Drug Monitoring (TDM) for antiretroviral drugs. Subsequently an international interlaboratory quality control (QC) program was developed for measurement of antiretroviral drugs in plasma. The program revealed large variability in the ability of laboratories to measure PIs and NNRTIs accurately. By participating in the program, laboratories were alerted to previously unknown errors in their methods. A series of pharmacokinetic studies evaluated undesirable pharmacokinetic interactions between antiretroviral drugs, food and other drugs. One study revealed that indinavir/ritonavir (800/100 mg BID) should preferably be administered with food to reduce high, nephrotoxic peak plasma (Cmax) values of indinavir. Based on other studies it was concluded that the addition of efavirenz to indinavir/ritonavir (800/100 mg BID) results in significant decreases in plasma concentrations of indinavir. These decreases are not strong enough to warrant dose modifications of the indinavir/ritonavir combination in treatment-naïve HIV-infected patients. A low-dose of ritonavir (100 mg BID) appeared to exert a modest inhibitory effect on the activity of CYP2D6 in extensive metabolizers for CYP2D6. Finally, pharmacokinetic studies were performed that evaluated the interaction between PIs and low-dose ritonavir as a means to achieve once-daily dosing for PIs. It was assessed that both nelfinavir and indinavir can be combined with low-dose ritonavir to yield adequate trough (Cmin) levels during a once-daily 24-h dosing interval.