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Pharmacokinetic interaction study with TMC125 and TMC114/r in HIV-negative volunteers
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Reported by Jules Levin
XVI Intl AIDS Conference, Toronto, Aug 2006
TN Kakuda,1 M Scholler-Gyure,2 M Peeters,2 B Woodfall,2 S Bollen,2 K Vandermeulen,2 C Debroye,2 G De Smedt,2 V Sekar,1 E Lefebvre,1
R Hoetelmans2
1Tibotec, Inc, Yardley, PA, USA; 2Tibotec BVBA, Mechelen, Belgium
Background
TMC125 is an NNRTI and TMC114 (darunavir) a protease inhibitor (PI); agents
with potent activity against HIV. This study evaluated the pharmacokinetic (PK)
interaction between TMC125 and TMC114/r.
Methods
This was an open-label, two-way crossover trial in 32 HIV-negative volunteers,
randomized to two groups. All volunteers received 100mg TMC125 bid (Phase III
formulation) for 8 days. After a washout period of 14 days, volunteers received
TMC114/r 600/100mg bid for 16 days. From Day 9 to 16, group A received
100mg TMC125 bid; group B received 200mg bid.
Results
When 100mg TMC125 bid was combined with TMC114/r, TMC125 AUC12h was
63% (90% confidence interval [CI]: 54-73%) compared to 100mg TMC125 bid
alone; TMC125 Cmax and Cmin were 68% (57-82%) and 51% (44-61%),
respectively. TMC114 PK did not show significant changes when combined with
100mg TMC125 bid. When 200mg TMC125 bid was co-administered with
TMC114/r, AUC12h, Cmax and Cmin of TMC125 were 180% (156-208%), 181%
(156-211%) and 167% (138-203%), respectively, compared with 100mg
TMC125 bid alone. TMC114 AUC12h was increased by 15% (105-126%). The
concomitant administration of TMC125 and TMC114/r was generally safe in HIVnegative volunteers; most common reason for discontinuation was rash (5/32).
Conclusions
No clinically relevant changes in TMC114 were observed with either TMC125
dose. For 100mg TMC125 bid, exposure decreased by 37% when
co-administered compared to 100mg TMC125 bid alone; the magnitude is
comparable with interactions observed with boosted PIs in Phase II trials. For
200mg TMC125 bid in combination with TMC114/r, exposure was 80% greater
than 100mg TMC125 bid alone, and in the range observed for the selected
TMC125 dose from Phase II trials. In Phase III trials, TMC125 will be used at
200mg bid combined with TMC114/r 600/100mg bid.
Author Conclusions
- Concomitant administration of TMC125 and TMC114/r had no clinically significant effect on TMC114 or ritonavir PK.
- TMC125 100mg bid exposure was decreased by 37% with similar decreases in Cmax and Cmin (32% and 49%, respectively). These decreases are comparable to those observed in Phase IIb trials, when TMC125 was co-administered with other boosted PIs and is clinically not relevant.2
- PK parameters for TMC125 observed after co-administration of TMC125 200mg bid with TMC114/r was slightly lower than historical control for healthy volunteers given the same dose and formulation (AUC12h 7,638±2254; Cmax 876±233).6
- Overall, the safety profile for TMC125, TMC114/r, and their co-administration was similar. Apart from rash, which was seen more frequently during co-administration, short-term co-administration of TMC125 with TMC114/r in healthy volunteers was generally safe and well tolerated.
- The higher incidence of skin events in the TMC125 100mg versus 200mg arm and the interaction with TMC114/r suggests no relationship with TMC125 dose or exposure.
- TMC125 200mg bid (formulation F060) is the dose and formulation selected for further clinical development, including the on-going Phase III trials DUET-1 and DUET-2.
- Preliminary efficacy, safety, and tolerability of TMC125 with TMC114/r in HIV
treatment-experienced patients is reported elsewhere.7
- TMC125 can be co-administered with TMC114/r without dose adjustments.
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