Darunavir and lopinavir
A pharmacokinetic study in HIV-positive patients found that darunavir levels were reduced by around 40%, even after the darunavir dose was doubled, when the drug was taken alongside Kaletra, leading to a recommendation by Tibotec researchers that Kaletra and Prezista should not be combined together in the same regimen.
The study had a complex design, comparing four groups of patients, each of which received three different regimens during the course of the study. The treatments consisted of:
- A: prescribed HIV therapy, including LPV/r 400/100mg bid plus optimised background regimen (OBR)
- B: prescribed HIV therapy, including LPV/r 400/100mg bid plus OBR, plus TMC114/r 1,200/100mg bid on Days 1–14
- C: prescribed HIV therapy, including LPV/r 400/100mg bid plus OBR, plus LPV/r 133.3/33.3mg bid (total LPV/r dose of 533.3/133.3mg bid) and TMC114 1,200mg bid on Days 1–14
- D: prescribed HIV therapy without LPV/r 400/100mg bid but including OBR, plus TMC114/r 600/100mg bid on Days 1–14.
In three consecutive sessions, Panel 1 received Treatments A, B and D (A-B-D or A-D-B) and Panel 2 received Treatments A, C and D (A-C-D or A-D-C). All treatments were administered under fed conditions with no washout period between subsequent sessions.
The study recruited 33 patients, of whom 29 completed dosing to day 14, at which time plasma sampling took place to establish the pharmacokinetic profiles of darunavir and lopinavir over 12 hours.
The study found:
- Based on the LS means ratio, the C0h, Cmin, Cmax and AUC12h of TMC114 were decreased by 34%, 51%, 21% and 38%, respectively, when TMC114 1,200/100mg bid was coadministered with LPV/r 400/100mg bid (Treatment B), relative to
administration of TMC114/r 600/100mg bid alone.
- The C0h, Cmin, Cmax and AUC12h of TMC114 were decreased by 52%, 55%, 21% and 41%, respectively, when TMC114 1,200/100mg bid was coadministered with LPV/r 533.3/133.3mg bid (Treatment C), relative to administration of TMC114/r 600/100mg bid alone (Treatment D).
Problematic drug interactions between the new protease inhibitor darunavir (Prezista) and lopinavir/ritonavir (Kaletra), Viagra (and other PDE-5 inhibitors), and oestrogen- based contraceptive pills such as Ortho-Novum were reported by manufacturer Tibotec at the Forty-Sixth Interscience Conference on Antimicrobial Agents and Chemotherapy in San Francisco last week.
Darunavir and sildenafil (Viagra)
Metabolism of the erectile dysfunction drug sildenafil has been found to slow when administered alongside protease inhibitors, leading to a recommendation that its dose be reduced from 100mg to 25mg.
A pharmacokinetic study in 16 male HIV-negative volunteers found that coadministration of 25mg of sildenafil with 400/100mg darunavir/ritonavir resulted in a similar sildenafil exposure to that seen if 100mg of sildenafil was given without darunavir/ritonavir, confirming that dose reduction will be necessary with darunavir too.
Participants received a single 100mg dose of sildenafil at day 1, and sildenafil concentrations were tracked over the following 24 hours. Participants then received darunavir/ritonavir (400/100mg) twice daily for seven days, and on day 7 received a single dose of 25mg of sildenafil, after which sildenafil concentrations were tracked over 24 hours. Concentrations of darunavir and ritonavir were also monitored.
Tibotec researchers recommend that if sildenafil is taken with darunavir/ritonavir, dosing should be at 25mg over a 48 hour period. Based on these findings, they propose that the vardenafil Levitradose should not exceed 2.5mg in a 72 period, and that the tadalafil (Cialis) dose should not exceed 10mg in 72 hours.
Darunavir/ritonavir and Ortho-Novum (ethinyl estradiol and norethindrone contraceptive pill)
Tibotec recruited 19 HIV-negative women using Ortho-Novum as their oral contraceptive to a two-month study in which levels of the hormones ethinyl estradiol and norethindrone were monitored through two complete menstrual cycles. In the first 28 day period women took Ortho-Novum only for 21 days, and in the second 28 day cycle they took Ortho-Novum for 21 days plus darunavir/ritonavir (600/100mg) for the first 14 days. All participants also used two barrier methods of contraception during the study.
Pharmacokinetic profiles of ethinyl estradiol and norethindrone were obtained at day 14 of both cycles, and showed that levels of both hormones were significantly reduced when administered alongside darunavir/ritonavir (ethinyl estradiol AUC by 44% and norethindrone AUC by 14%.
Investigators recommend that alternative or additional contraceptive measures should be used when oestrogen-based contraceptives similar to Ortho-Novum are used alongside darunavir/ritonavir.
Sekar V et al. Pharmacokinetic interaction between the protease inhibitors TMC114 and lopinavir/ritonavir. Forty-Sixth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, abstract A-0367, 2006.
Sekar V et al. Pharmacokinetic interaction between TMC114, a new protease inhibitor, and sildenafil. Forty-Sixth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, abstract A-0369, 2006.
Sekar V et al. Pharmacokinetic interaction between ethinyl estradiol,norethindrone and TMC114, a new protease inhibitor. Forty-Sixth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, abstract A-0368, 2006.