ICAAC: No drug interactions found between TMC125 and ritonavir-boosted elvitegravir

The newly developed antiretrovirals elvitegravir and TMC125 have no clinically relevant drug/drug interactions and can be used together without dose adjustment, according to a poster presented at the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy by researchers from the drugs' developers.

The findings are of particular importance because an analysis presented this week at ICAAC showed that elvitegravir performs better when used with at least one other active drug.

Combinations of newly developed antiretroviral agents must often be avoided due to lack of data on drug interactions. In this case, investigators from Gilead Sciences and Tibotec investigated the pharmacokinetic interactions between their respective new drugs, the integrase inhibitor elvitegravir and next-generation NNRTI TMC125.

Elvitegravir is metabolized by the liver enzyme pathway CYP3A4. Since TMC125 is an inducer of CYP3A (as well as an inhibitor of two other liver pathways CYP2C9 and CYP2C19), there was a suspected potential for interactions between the two drugs. Elvitegravir is typically dosed with low-dose ritonavir, which also has a very wide range of interactions with other medications.

Therefore, this study evaluated the potential for clinically relevant pharmacokinetic (PK) drug interactions between ritonavir (RTV)-boosted elvitegravir (EVG/r) and TMC125.

Thirty-four healthy, HIV-negative subjects were enrolled (17 male, 17 female, mean age 33 years, mean weight 72.5 kg, 32 white, 2 black). The participants were randomised into two groups, with two subgroups in each. Group 1 (N=20) received 10 days each of EVG/r alone (150/100mg, once daily) and EVG/r (at the same dose) plus TMC125 (200mg, twice daily). The subgroups (10 in each) took the 10-day courses in different sequences – EVG/r alone then in combination, or vice versa.

Group 2 (N=14) received TMC125 alone followed by TMC125 + EVG/r, at the same doses as Group 1. As with Group 1, Group 2 was split in half, with each subgroup taking the courses in opposite order.

All medication doses were given with food (approx. 400 kilocalories, 13 g of fat).

Thirty-one of the 34 enrolled subjects completed the study (3 withdrew consent). The most common treatment-emergent adverse event (AE) was headache, with some nausea and diarrhea reported. There were no serious AEs or discontinuations due to AEs; all AEs resolved after stopping treatment.

Pharmacokinetic (PK) parameters for elvitegravir, ritonavir, and TMC125 were measured on days 10 and 20.

Parameters measured were C_max (maximum serum concentration), C_tau (concentration at the end of the dosing interval, just prior to the next dose), and AUC_tau ("area under the curve", a measure of the total bodily drug exposure during a single interval between doses).

The pharmacokinetics of the drugs were found to be minimally affected when they were co-administered. The following table shows the specific findings in terms of percentage geometric mean ratios (GMRs) of PK values.

(For each separate parameter - C_max, C_tau and AUC_tau - %GMR is the percentage ratio between the parameter when the drug was taken alone, and when it was taken in combination. E.g., a GMR of 100% for C_max would indicate that there was no difference between the C_max for the drug taken separately and its C_max when taken in combination. A GMR of 150% would indicate a 50% increase. %GMRs of close to 100% therefore indicate minimal changes in PK values when the drugs are co-administered.)

The research team concluded that "there is no clinically relevant drug interaction between EVG/r and TMC125," that "co-administration of EVG/r and TMC125 was safe and well tolerated," and that "no dose adjustment is needed when [these two antiretrovirals] are co-administered."