Pharmacokinetics and Potential Interactions Amongst Antiretroviral Agents Used To Treat Patients with HIV Infection

Abstract

There are 3 groups of drugs available for the treatment of patients with HIV disease. These are the nucleoside reverse transcriptase inhibitors ('nucleoside analogues') [zidovudine, didanosine, zalcitabine, lamivudine and abacavir]; the non-nucleoside reverse transcriptase inhibitors (nevirapine, delavirdine and efavirenz); and the protease inhibitors (saquinavir, ritonavir, indinavir, nelfinavir and amprenavir). The preferred initial regimen should reduce and maintain plasma HIV RNA below the level of detection. Presently, the regimen of choice consists of 2 nucleoside analogues plus a protease inhibitor with high in vivo efficacy. An alternative combination consists of 2 nucleoside analogues plus a non-nucleoside reverse transcriptase inhibitor. Drug interactions are one of the major problems associated with these multidrug regimens. Changes in plasma concentrations of the nucleoside analogues are unlikely to be of clinical relevance as drug effect is mainly dependent on the rate and extent of intracellular phosphorylation. Combinations of zidovudine plus stavudine, and probably zalcitabine plus lamivudine, should be avoided as competition for phosphorylating enzymes may occur. The antiviral efficacy of some nucleoside analogues, e.g. stavudine, may be compromised by prior treatment with other nucleosides (e.g. zidovudine). However, these data need to be clarified in further studies. It is unlikely that administration of other antiretrovirals will influence the activity of nucleoside analogues. Protease inhibitors are metabolised by hepatic cytochrome P450 (CYP) 3A4. Combination protease inhibitor therapy can result in drug interactions mediated by enzyme inhibition. Ritonavir is the most potent inhibitor, saquinavir the least. The protease inhibitors also interact with the non-nucleoside reverse transcriptase inhibitors. Nevirapine and efavirenz induce drug metabolising enzymes and may reduce plasma concentrations of protease inhibitors. A study in healthy volunteers showed that nelfinavir concentrations are increased by combination with efavirenz. Delavirdine inhibits drug metabolising enzymes and increases the plasma concentration of coadministered protease inhibitors. The nucleoside analogues would not be expected to interact with the protease inhibitors. Apart from the ability of didanosine to reduce the area under the concentration-time curve of delavirdine, there are no reports of clinically significant interactions of other antiretrovirals with the non-nucleoside reverse transcriptase inhibitors. Triple therapy is the current standard of care for patients with HIV disease. However, studies of quadruple therapy are already under way. Drug interactions are likely to remain one of the major considerations when selecting a therapeutic regimen for patients with HIV.

HIV Protease Inhibitors Stimulate Hepatic Triglyceride Synthesis

“…Consistent with these in vivo studies, ABT-378, NFV, RTV, and SQV, but not APV or IDV, increased TG synthesis and RTV increased CH synthesis in HepG2 cells. These and other observations 1,7,[12][13][14]20,21 indicate that select PIs affect multiple, distinct metabolic pathways, perhaps accounting for the different side effects observed for each PI in the clinic. This may be due to differences in affinity for cellular proteins (eg, proteases), cell permeability, tissue distribution, or metabolism of PI.…”

“…N ucleoside reverse transcriptase inhibitors (NRTIs), 1 nonnucleoside reverse transcriptase inhibitors (NNRTIs), and HIV protease inhibitors (PIs) are 3 classes of antiretroviral drugs that are used in the treatment of patients with AIDS. NRTIs and NNRTIs inhibit HIV reverse transcriptase and suppress replication of the virus.…”

“…Highly active antiretroviral therapy (HAART) includes combinations of a PI, an NRTI, and an NNRTI. 1 HAART has been associated with numerous affects on lipid metabolism, including subcutaneous fat wasting, abdominal obesity, insulin resistance, and hyperlipidemia. 2,3 Metabolic complications arising from HAART may be due to drug-drug interactions, exacerbation of preexisting conditions, reconstitution of immune system function, or a combination.…”

Pharmacokinetic interaction between efavirenz and dual protease inhibitors in healthy volunteers

“…The use of compartmental pharmacokinetic analysis for examining efavirenz disposition in ACTG 5043 yielded estimates and comparisons of pharmacokinetic microconstants that would not have been identified with standard non-compartmental analysis. The rationale for our modeling approach relates to known characteristics of efavirenz that include, ~50% bioavailability [12,13] and oxidative metabolism via CYP3A and CYP2B6 to inactive hydroxylated metabolites including 8-and 7-hydroxyefavirenz, with subsequent urinary and biliary excretion after glucuronidation in the liver [3,14,15]. In a previous investigation, nevirapine, an inducer of CYP2B6 and CYP3A4, significantly decreased the plasma concentrations of efavirenz, indicating that either CYP2B6 or CYP3A4 or both contribute to the biotransformation of efavirenz [16].…”

Role of Clinical Pharmacist to Reduce Risk in Patients Involving Antiretroviral Drugs at Abidjan Cohort

“…Computerized systems can support electronic prescribing; however, a systematic review of such systems showed that 55-91.2% of drug interaction alerts are ignored by physicians [26,27].…”