NNRTI interactions Protease inhibitors

TABLE 51.4 Interactions Between NNRTIs and Protease Inhibitors... 

Table 21.3 Summary of the pharmacokinetic interactions of NNRTIs and protease inhibitors...

The NNRTIs efavirenz and nevirapine interact with a number of drugs metabolized in the liver. The doses of protease inhibitors may need to be increased when they are given with efavirenz or nevirapine. Nevirapine is associated with a high incidence of... 

At the present time, there are at least 14 compounds that have been formally approved for the treatment of human immunodeficiency virus (HIV) infections. There are six nucleoside reverse transcriptase inhibitors (NRTIs) that, after their intracellular conversion to the 5 -triphosphate form, are able to interfere as competitive inhibitors of the normal substrates (dNTPs). These are zidovudine (AZT), didanosine (ddl), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), and abacavir (ABC). There are three nonnucleoside reverse transcriptase inhibitors (NNRTIs) — nevirapine, delavirdine, and efavirenz — that, as such, directly interact with the reverse transcriptase at a nonsubstrate binding, allosteric site. There are five HIV protease inhibitors (Pis saquinavir, ritonavir, indinavir, nelfinavir, and amprenavir) that block the cleavage of precursor to mature HIV proteins, thus impairing the infectivity of the virus particles produced in the presence of these inhibitors. 

By inhibiting their metabolism, ritonavir potentiates the actions of other protease inhibitors. The addition of delavirdine instead of another NNRTI in three patients taking protease inhibitors plus ritonavir further increased the exposure to the protease inhibitors (6). Combining delavirdine with indinavir removes the food restrictions during indinavir administration (4). The superior virological response observed in antiretroviral regimens containing delavirdine and protease inhibitors has been attributed in part to the pharmacokinetic interaction. 

The NNRTis are extensively metabolised by the cytochrome P450 isoenzyme system, particularly by CYP3A4. They are also inducers (nevirapine, efavirenz) or inhibitors (delavirdine) of CYP3A4. NNRTis would therefore be expected to interact with each other, and with protease inhibitors, but not with NRTIs (see below). They also have the potential to interact with other drugs metabolised by CYP3A4, and are affected by CYP3A4 inhibitors and inducers. Delavirdine and efavirenz may also inhibit some other P450 isoenzymes. For a summary, see Table 21.2 , (p.773). 

Lamivudine is cleared predominantly from the body by the kidneys using the organic cationic transport system. Didanosine is not cleared by this mechanism and so is unlikely to interact with lamivudine by this mechanism. Didanosine does not affect the intracellular activation of lamivudine in vitro. In UK and US guidelines, the combination of didanosine with lamivudine is currently a recommended alternative dual NRTI option for use with an NNRTI or a protease inhibitor, for the treatment of HIV-infection in treatment naive patients. 

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