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.