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 clinical studies of drug interactions with the protease inhibitor darunavir (TMC-114), already approved in the US, was given in an oral presentation by David Back.
TMC114/r was studied with atazanavir (ATV), indinavir (IDV), lopinavir/r (LPV/r), saquinavir/r (SQV/r), efavirenz (EFV), nevirapine (NVP), tenofovir disoproxil fumarate (TDF), atorvastatin (AVS), omeprazole (OME), ranitidine (RAN), sildenafil (SIL), clarithromycin (CLA), sertraline (SER), paroxetine (PAR), oral contraceptives (OC) and ketoconazole (KTZ).
Results are summarised in Table 1 below. TMC114/r increased exposure to EFV (21%), NVP (27%), TDF (22%), IDV (23%), LPV (37%), KTZ (212%), CLA (57%), AVS and SIL (4-fold), and decreased exposure to SER (49%), PAR (39%) and ethinyl estradiol (44%). There was no change in ATV or SQV. TMC114 exposure increased by 21%, 24% and 42%, respectively, when combined with TDF, IDV and KTZ, decreased by 13%, 13%, 26% and 53%, respectively, when combined with EFV, CLA, SQV/r and LPV/r, and was unchanged when combined with ATV, NVP, AVS, OME, RAN, SER and PAR.
The study concluded that combining TMC114/r with LPV/r or SQV/r is not recommended and that some co-administered drugs may require dose adjustments (SIL, AVS, KTZ and IDV). Additional contraception should be used when OC are combined with TMC114/r.
| Table 1: Summary of drug interaction studies with darunavir (TMC-114) | |||
| Interaction effect with TMC-114 | Recommendation | ||
| ARVs | |||
| Efavrenz | EFV increased by 21% | TMC-114 decreased by 13% | Not clinically relevant |
| Nevirapine | NVP increased by 27% | TMC-114 no change | Not clinically relevant |
| Tenofovir | TDF increased by 22% | TMC-114 increased by 21% | Not clinically relevant |
| Indinavir | IDV increased by 23% | TMC-114 increased by 24% | Consider TDM for IDV |
| Lopinavir.r | LPV increased by 37% | TMC-114 decreased by 53% | Do not coadminister |
| Saquinavir | SQV no change | TMC-114 decreased by 26% | Do not coadminister |
| Atazanavir | ATV no change | TMC-114 no change | No interaction |
| Antibiotics | |||
| Ketaconazole | KTZ increased by 212% | TMC-114 increased by 41% | Consider reducing KTZ |
| Clarithromycin | CLA increased by 57% | TMC-114 decreased by 13% | Only relevant with renal impair |
| SSRI’s | |||
| SER | SER AUC decreased by 49% | TMC-114 no change | Monitor clinically, titrate SSRI |
| PAR | PAR AUC decreased by 39% | TMC-114 no change | Monitor clinically, titrate SSRI |
| Other | |||
| Atorvastatin | AVS increased by 400% | TMC-114 no change | Start with lowest AVS dose |
| Pravastatin | PVS increased by 81% (23-166%) | Start with lowest PVS dose | |
| Sildenafil | SIL increased by 400% | Reduce SIL dose | |
| ethinyl estradiol | EE exposure decreased by 44% | Use other contraception | |
| Ranitedine | TMC-114 no change | No dosing change | |
| Omeprazole | TMC-114 no change | No dosing change | |
Ref: D Back, V Sekar, E Lefebvre et al. Use of TMC114 in combination with other drugs: guidance from pharmacokinetic studies. Int Cong Drug Therapy HIV 2006 Nov 12-16;8: (abstract PL5.1).
2006-11-10
IB060711-12
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