Drug interactions with darunavir (TMC-114)

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
Efavirenz EFV increased by 21%. TMC-144 decreased by 13% Not clinically relevant
Nevirapine NVP increased by 27%. TMC-144 no change Not clinically relevant
Tenofovir TDF increased by 22%. TMC-144 increased by 21% Not clinically relevant
Indinavir IDV increased by 23%. TMC-144 increased by 24% Consider TDM for IDV
Lopinavir/r LPV increased by371%. TMC-144 decreased by 53% Do no coadminister
Saquinavir SQV no change. TMC-144 decreased by 26% Do no coadminister
Atazanavir ATV no change. TMC-144 no change. No interaction
Ketaconazole KTZ increased by 212%. TMC-144 increased by 41%. Consider reducing KTZ
Clarithromycin CLA increased by 57%. TMC-144 decreased by 13%. Only relevant with renal impairment
SER SER AUC decreased by 49%. TMC-144 no change. Monitor clinically, titrate SSRI
PAR PAR AUC decreased by 39%. TMC-144 no change. Monitor clinically, titrate SSRI
Atorvastatin AVS increased by 400%. TMC-144 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


D Back, V Sekar, E Lefebvre et al. Use of TMC114 in combination with other drugs: guidance from pharmacokinetic studies. 8th International Congress on Drug Therapy in HIV Infection, 12-16 November 2006, Glasgow. Oral abstract PL5.1.

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