Non-nucleoside Reverse Transcriptase Inhibitors Delavirdine Research Articles

Electrospray tandem mass spectroscopic characterisation of 18 antiretroviral drugs and simultaneous quantification of 12 antiretrovirals in plasma

The determination of antiretroviral drug concentrations in patients treated with highly active antiretroviral therapy (HAART) is an essential part of optimum patient management because of the multitude of pharmacokinetic drug interactions between these drugs and the risk of treatment failure or viral resistance if therapeutic concentrations are not reached. Currently, 21 different antiretrovirals are used in various combinations rendering therapeutic drug monitoring a laborious task. We therefore aimed to simultaneously determine as many antiretrovirals as possible using triple quadrupole mass spectroscopy with electrospray ionisation. For this purpose, spectra and fragmentation patterns of the protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir, the non-nucleoside reverse transcriptase inhibitors delavirdine, efavirenz, and nevirapine, the nucleoside reverse transcription inhibitors abacavir, didanosine, emtricitabine, lamivudine, stavudine, zalcitabine, and zidovudine, and the nucleotide reverse transcriptase inhibitor tenofovir were evaluated. A bioanalytical method to determine all protease and non-nucleoside reverse transcriptase inhibitors, and zalcitabine and zidovudine concentrations in biological matrices was developed. Samples were prepared by protein precipitation with methanol after addition of three different internal standards. Antiretrovirals were separated by high-performance liquid chromatography on a Nucleosil C18-100 Nautilus column using a gradient of 20 mM ammonium acetate including 0.1% aqueous acetic acid and acetonitrile and detected by electrospray ionisation/tandem mass spectrometry in the negative (efavirenz, stavudine, zidovudine) or positive ionisation mode (all other compounds). The bioanalytical method was successfully validated according to FDA guidelines and applied to plasma and cerebrospinal fluid samples of patients treated for acquired immunodeficiency syndrome (AIDS).

Interactions between antiretroviral drugs and drugs used for the therapy of the metabolic complications encountered during HIV infection.

Treatment of HIV infection with potent combination antiretroviral therapy has resulted in major improvement in overall survival, immune function and the incidence of opportunistic infections. However, HIV infection and treatment has been associated with the development of metabolic complications, including hyperlipidaemia, diabetes mellitus, hypertension, lipodystrophy and osteopenia. Safe pharmacological treatment of these complications requires an understanding of the drug-drug interactions between antiretroviral drugs and the drugs used in the treatment of metabolic complications. Since formal studies of most of these interactions have not been performed, predictions must be based on our understanding of the metabolism of these agents. All HIV protease inhibitors are metabolised by and inhibit cytochrome P450 (CYP) 3A4. Ritonavir is the most potent inhibitor of CYP3A4. Ritonavir and nelfinavir also induce a host of CYP isoforms as well as some conjugating enzymes. The non-nucleoside reverse transcriptase inhibitor delavirdine potently inhibits CYP3A4, whereas nevirapine and efavirenz are inducers of CYP3A4. Drug interaction studies have been performed with HIV protease inhibitors and HMG-CoA reductase inhibitors. Coadministration of ritonavir plus saquinavir to HIV-seronegative volunteers resulted in increased exposure to simvastatin acid by 3059%. Atorvastatin exposure increased by 347%, but exposure to active atorvastatin increased by only 79%. Conversely, pravastatin exposure decreased by 50%. Similar results have been obtained with combinations of simvastatin and atorvastatin with other HIV protease inhibitors. Thus, the lactone prodrugs simvastatin and lovastatin should not be used with HIV protease inhibitors. Atorvastatin may be used with caution. Although there are no formal studies available, calcium channel antagonists and repaglinide may have significant interactions and toxicity when used with HIV protease inhibitors because of their metabolism by CYP3A4. Sulfonylurea drugs utilise mainly CYP2C9 for metabolism, and this isoenzyme may be induced by ritonavir and nelfinavir with a resulting decrease in efficacy of the sulfonylurea. Losartan may have increased effect when coadministered with ritonavir and nelfinavir because of the induction of CYP2C9 and the expected increase in formation of the active metabolite, E-3174. Overall, well-designed drug-drug interaction studies at steady state are needed to determine whether antiretroviral drugs may be safely coadministered with many of the drugs used in the treatment of the metabolic complications of HIV infection.