DRUG-INTERACTIONS WITH ANTIVIRAL DRUGS

Antiviral drug interactions are a particular problem among immunocompr omised patients because these patients are often receiving multiple di fferent drugs, i.e. antiretroviral drugs and drugs effective against h erpesvirus. The combination of zidovudine and other antiretroviral dru gs with different adverse event profiles, such as didanosine, zalcitab ine and lamivudine, appears to be well tolerated and no relevant pharm acokinetic interactions have been detected. The adverse effects of did anosine and zalcitabine (i.e. peripheral neuropathy and pancreatitis) should be taken into account when administering these drugs with other drugs with the same tolerability profile. Coadministration of zidovud ine and ganciclovir should be avoided because of the high rate of haem atological intolerance. In contrast, zidovudine and foscarnet have syn ergistic effect and no pharmacokinetic interaction has been detected. No major change in zidovudine pharmacokinetics was seen when the drug was combined with aciclovir, famciclovir or interferons. However, conc omitant use of zidovudine and ribavirin is not advised. Although no ph armacokinetic interaction was documented when didanosine was first adm inistered with intravenous ganciclovir, recent studies have shown that concentrations of didanosine are increased by 50% or more when coadmi nistered with intravenous or oral ganciclovir. The mechanism of this i nteraction has not been elucidated. Lack of pharmacokinetic interactio n was demonstrated between foscarnet and didanosine or ganciclovir. Cl inical trials have shown that zidovudine can be administered safely wi th paracetamol (acetaminophen), nonsteroidal anti-inflammatory drugs, oxazepam or codeine. Inhibition of zidovudine glucuronidation has been demonstrated with fluconazole, atovaquone, valproic acid (valproate s odium), methadone, probenecid and inosine pranobex; however, the clini cal consequences of this have not been fully investigated. No interact ion has been demonstrated with didanosine per se but care should be ta ken of interaction with the high pH buffer included in the tablet form ulation. Drugs that need an acidic pH for absorption (ketoconazole, it raconazole but not fluconazole, dapsone, pyrimethamine) or those that can be chelated by the ions of the buffer (quinolones and tetracycline s) should be administered 2 hours before or 6 hours after didanosine. Very few interaction studies have been undertaken with other antiviral drugs. Coadministration of zalcitabine with the antacid 'Maalox' resu lts in a reduction of its absorption. Dapsone does not influence the d isposition of zalcitabine. Cotrimoxazole (trimethoprim-sulfamethoxazol e) causes an increase in lamivudine concentrations by 43%. Saquinavir, delavirdine and atevirdine appeared to be metabolised by cytochrome P 450 and interactions with enzyme inducers or inhibitors could be antic ipated. Some studies showed that interferons can reduce drug metabolis m but only a few studies have evaluated the pathways involved. Further studies are required to better understand the clinical consequences o f drug interactions with antiviral drugs. Drug-drug interactions shoul d be considered in addition to individual drug clinical benefits and s afety profiles.