Antiretroviral Drug Interaction Studies Show Favorable Effects

Various antiretroviral drug-drug interaction studies presented at the National Conference on Retroviruses and Opportunistic Infections showed favorable effects which may be beneficial in clinical practice. These pharmacokinetic studies combined either single or multiple doses of one of several protease inhibitors or nonnucleoside reverse transcriptase inhibitors and determined whether the blood levels achieved of each drug were inhibitory to HIV.

One study conducted by Kravcik and others from Ottowa General Hospital in Ontario combined the new formulation of saquinavir (soft gel capsule--SGC) with nelfinavir. In the study 14 HIV positive patients received either saquinavir SGC (1200 three times daily) for 4 days and a single dose of nelfinavir (750 mg) or nelfinavir (750 three times daily) for four days and a single dose of saquinavir SGC (1200 mg). Plasma sampling allowed for measurement of the concentrations of either drug over time. No effect on the concentration of nelfinavir was observed when saquinavir was added, yet there was a 4.9 fold increase in the concentration of saquinavir when nelfinavir was added. After 12 weeks of therapy with the double protease combination a 2 log reduction in HIV RNA was observed with 62% of patients remaining under the level of detection (< 500 copies/ml of HIV RNA). An average CD4 cell increase of 217 cells above baseline was also observed. The side effects noted included abdominal pain (1), asthenia 1), diarrhea (2) and flatulence (2), but none were considered to be serious. No laboratory abnormalities were noted.

Another drug interaction study presented by Kerr from Agouron Pharmaceuticals showed that drugs which use the cytochrome p450 isoform for metabolism are likely to have altered drug levels when coadministered with nelfinavir. Nelfinavir should not be co-administered with terfenadine since increased blood levels of the latter can be cardiotoxic; whereas ethinyl estradiol levels are decreased which may cause failures in contraception. Ketoconazole, indinavir and ritonavir all increase nelfinavir blood levels, thus twice daily dosing regimens are being studied with the latter. Rifampin on the other hand lower nelfinavir blood levels by 82% and should not be co-adminsitered with nelfinavir.

Another study combined delavirdine with each of the available protease inhibitors to determine the pharmacokinetic interactions among these drugs. In the delavirdine-saquinavir interaction study which involved 15 healthy volunteers, saquinavir was given for a week before delavirdine was added, or viceversa. The steady state plasma concentrations of saquinavir increased five fold when delavirdine was added, achieving similar levels as seen with 3,600-7,200 mg of saquinavir-hard gel capsule. Saquinavir however did not change the pharmacokinetics of delavirdine. One subject experienced elevated liver function tests (AST and ALT) after three weeks of dual therapy which required drug discontinuation. The authors concluded that the two drugs can be administered safely, yet liver function tests should be monitored after several weeks of combined therapy.

In a similar indinavir-delavirdine interaction study, indinavir plasma levels were also greatly increased by delavirdine (149%), which suggests that lower doses of indinavir may be required to avoid toxicity (400 or 600 mg three times daily instead of 800 mg three times daily). A study of ritonavir and delavirdine did not reveal any significant interactions in the pharmacokinetics of either drug thus no doses adjustments are recommended for this combination.

Finally, results of a pharmacokinetic study of the combination of indinavir and nevirapine was presented by Dr. Robert Murphy of Northwestern University in Chicago. Nevirapine is known to induce the CYP3A hepatic enzyme as well as its own metabolism. Initially indinavir monotherapy (800 mg three times daily) was administered to 24 HIV positive patients with CD4 counts 200-500 for seven days, followed by the addition of nevirapine (200 mg every day for 14 days followed by 200 mg twice daily thereafter). Nineteen patients were evaluable, of which 3 (13%) had adverse events (kidney stones in one and rashes in two). There was a 28% reduction in the area under the curve concentration of indinavir, despite a sustained reduction in HIV viral load over the 16 weeks of the study. Ninety percent of the patients and HIV RNA levels below the level of detection (< 400 copies/ml) and an average CD4 elevation of 150 cells. Murphy concluded that despite the pharmacokinetic interaction the two drugs can be safely administered together, although some may want to increase the dose of indinavir to 1000 mg three times daily. A similar study combining nevirapine and ritonavir showed no significant pharmacokinetic interaction between these agents.