Important note: Information in this article was accurate in November 2006. The state of the art may have changed since the publication date.
HIV Treatment Bulletin - Vol. 7, No. 11/12, November/December 2006
Simon Collins, HIV i-Base
An overview of drug interactions with the investigational NNRTI etravirine (TMC-125) was presented by Thomas Kakuda. Etravirine is a substrate and inducer of CYP3A4 and a substrate and inhibitor of CYP2C, and has a different interaction profile compared to nevirapine and efavirenz.
Two-way PK interaction studies at steady-state were conducted with TMC-125 and didanosine (ddI), tenofovir (TDF), the ritonavir (rtv)-boosted PIs darunavir (DRV), fosamprenavir (FPV) and tipranavir (TPV). The 1-way effect of omeprazole (OME) and ranitidine (RAN) on TMC-125, and the 1-way effect of TMC-125 on lopinavir (LPV) with saquinavir (SQV), methadone (MET) and sildenafil (SIL) were also studied.
| Table 2: Summary of drug interaction studies with etravirine (TMC-125) | ||
| TMC-125 | Recommendation | |
| Fosamprenavir | FPV inc by 69% TMC-125 no change | Consider dose reduction of FOS using TDM |
| Atazanavir | TMC Cmin, Cmax, AUC all inc by 50% (30% with ATZ/r) ATZ Cmin red. by 47%, AUC by 17% (ATZ/r by 38% & 14% | Do not use unboosted ATZ. Use 300mg ATZ/100mg RTV. |
| Sildenafil N-desmethyl-SIL |
SIL reduced by 57% N-sSIL reduced by 41% No significant effect on TMC-125 |
Consider increasing dose of SIL |
| Tipranavir/r | TMC-125 reduced by 75% No significant effect on TPV/r | Do not administer together |
| Darunavir/r | TMC-125 reduced by 37% No significant effect on DRV | Not clinically relevant |
| Omeprazole | TMC-125 increased by 41% | Not clinically relevant |
Results are summarised in Table 1. TMC-125 should not be coadministered with nevirapine, efavirenz, tipranavir/r, full dose ritonavir or unboosted PIs. Fosamprenavir and sildenafil may require dose adjustment. Coadministration with clarithromycin is not recommended for treatment of MAI. No significant effect on levels of either drug were seen with ddI, tenofovir, lopinavir/r, saquinavir/r, methadone, and oral contraceptives ethnylestradiol (exposure slightly increased) and norethindrone (similar PK with slighlly lower Cmin by 22%).
Ref: Kakuda T, Schöller-Gyüre M, Woodfall B et al. TMC125 in combination with other medications: summary of drug-drug interaction studies. Int Cong Drug Therapy HIV 2006 Nov 12-16;8 (abstract PL5.2).
Comment
Both these overviews highlight the complexity of drug interactions and the important of expert interpretation.
Effects on individual drugs need to be interpreted in the context of the pharmacokinetics of that compound – a 25% reduction for example may have clinical implications for one drug and not another.
Although both TMC-114 and TMC-125 are relatively free of clinically important interactions, it is essential to be aware of the few contraindications with these new agents, and of the potential interactions that may require monitoring or dose modification.
2006-11-10
IB060711-14
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