Tenofovir (Viread) has been the most important entrant to the HIV treatment arena in the past couple of years, but questions remain about some of its interactions. Data were presented yesterday at the Tenth Conference on Retroviruses and Opportunistic Infections, Boston, on three potential interactions, with ddI, d4T and with the combination of ritonavir and atazanavir.
In the case of ddI, Gilead scientists reported that when dosed with tenofovir, the dose of ddI can be reduced from 400mg once daily to 250mg once daily. The findings also suggest that taking ddI and tenofovir together with a light meal has little negative impact on ddI absorption, removing an important obstacle to constructing a true once-daily regimen for people who can tolerate both drugs.
Twenty-eight healthy volunteers received ddI EC 400mg for one day to identify ddI plasma levels, and then tenofovir doses until tenofovir levels reached steady state. From day 8 a 250mg dose of ddI was administered on three consecutive days. On the first day, ddI was administered two hours prior to tenofovir dosing; ddI was taken on an empty stomach and tenofovir with a light meal (373kcal, 20% fat). On the second day, ddI was taken at the same time as tenofovir and a light meal, and on the third day, the two drugs were taken together on an empty stomach.
For each dosing pattern, ddI total exposure (AUC) and peak levels (Cmax) were measured. When ddI was dosed two hours prior to tenofovir, ddI exposure was similar to the levels seen when ddI is dosed alone at 400mg once daily.
Taking the two drugs together with a light meal resulted in a slightly lower ddI AUC (-11%) when compared to ddI 400mg alone, whilst taking the two drugs on an empty stomach resulted in slightly higher AUC (+14%). Peak levels were slightly lower when the two drugs were coadministered.
Bristol Myers Squibb scientists reported on the lack of interaction between tenofovir and the extended release formulation of d4T. Eighteen healthy volunteers received Zerit XR 100mg with a light meal for seven days until steady state levels were reached; on the eighth day tenofovir was added and d4T levels were assessed over a 24 hour period on day 9. No difference in d4T exposure was noted compared with d4T dosing alone, and no serious adverse events were noted.
French researchers reported a potentially problematic interaction between tenofovir, atazanavir and ritonavir that is still not fully understood. The interaction was detected in a sub-study of the French Puzzle study, in which individuals experiencing failure of a PI-containing regimen were randomised to continue their existing regimen or switch to atazanavir 300mg qd, boosted with ritonavir 100mg qd, and unchanged NRTIs. After week 2, all patients were switched to atazanavir, ritonavir, tenofovir and recycled nucleoside analogues.
Therapeutic drug monitoring was carried out in ten patients at weeks 2 and 6. At week 2, atazanavir and ritonavir levels were similar to those seen in healthy volunteers, but by week 6 they had fallen, although the difference was not statistically significant. The researchers say that the potential interaction needs further investigation.
Further information on this website
Kaul S et al. Lack of interaction between stavudine extended-release formulation and tenofovir disoproxil fumarate. Tenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 534, 2003.
Kearney BP et al. Didanosine and tenofovir DF drug-drug interaction: assessment of didanosine dose reduction. Tenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 533, 2003.
Taburet AM et al. Pharmacokinetic parameters of atazanavir/ritonavir when combined to tenofovir in HIV infected patients with multiple treatment failures: a sub-study of Puzzle 2 – ANRS 107 trial. Tenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 537, 2003.