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Absence of TMC114 exposure-efficacy and exposure-safety relationships in POWER 3
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Predictors of TMC114 Response: IQ, Fold-Change, Sensitive ARVs
Reported by Jules Levin
XVI IAC Toronto, Aug 2006
Sekar V,1 De Meyer S,2 Vangeneugden T,2 Lefebvre E,1 De Pauw M,2 Van Baelen B,2 De Paepe E,2 Vis P,3 de Bethune MP,2 Miralles D,2 Hoetelmans R2
1Tibotec Inc., Yardley, USA; 2Tibotec BVBA, Mechelen; 3Exprimo NV, Lummen, Belgium
poster TUPE0078
Author Conclusions
- PK/PD relationships in this large POWER 3 analysis at the 600/100 mg bid dose of TMC114/r showed that there was a strong relationship between TMC114 IQ and virologic response; these results support the findings from the similar
PK/PD analysis of TMC114/r in POWER 1 and 2 trials.
- The relationship between IQ and virologic response was driven primarily by BL
TMC114 FC and not by TMC114 PK, as TMC114 PK did not show a significant
association with response.
- In the absence of exposure-efficacy and exposure-safety relationships at the
TMC114/r 600/100mg bid dose recommended for treatment-experienced
patients, there is no added value for routine therapeutic drug monitoring when
treating patients with TMC114/r at this dose.
In POWER 1 and 2, the highest virologic responses were observed in the TMC114/r 600/100mg bid group (recommended dose); 45% of patients receiving this dose achieved HIV-1 RNA <50 copies/mL vs 12% of patients receiving investigatorselected control PI(s).4 TMC114/r was generally well tolerated, with no clear doseresponse relationship for the safety parameters evaluated.
- The TMC114/r 600/100mg bid dose was selected for treatment-experienced patients. To further define the safety and efficacy of this dose, 327 additional patients were enrolled in the non-randomized, open-label studies TMC114-C215 and TMC114-C208 (POWER 3).
- Here we report the analysis of patients in POWER 3 after 24 weeks of treatment with the 600/100mg bid TMC114/r dose, to evaluate the relationship between TMC114:
- PK parameters and efficacy
- IQ and efficacy
- PK and safety.
ABSTRACT
Background: TMC114 (darunavir) is an HIV protease inhibitor (PI) that is
potent against wild-type and PI-resistant HIV strains. The POWER 3 (TMC114-C215/C208) analysis examined the efficacy, safety and pharmacokinetic/pharmacodynamic (PK/PD) relationships of TMC114
co-administered with low-dose ritonavir (TMC114/r) at the recommended dose of 600/100mg bid, in treatment-experienced HIV patients receiving an optimized background regimen (OBR; composed of NRTIs ± enfuvirtide [ENF]).
Methods: The TMC114 PK parameters, area under the curve (AUC) and trough concentration (C0h) were determined by sparse blood sampling of 292 patients
from POWER 3 at Week 24. TMC114 PK/PD relationships were assessed using
analysis of covariance models. PD efficacy measures included viral load (VL) change from baseline (BL) and proportion of patients with 31.0 log10 VL reduction. The inhibitory quotient (IQ), which is the ratio between the steady-state TMC114 C0h and BL TMC114 fold-change (FC) in EC50, was also related to the PD efficacy measures. The relationship between TMC114 PK and the occurrence of adverse events of interest as well as TMC114 PK and maximum changes in laboratory parameters were investigated using descriptive methods.
Results:
At the recommended TMC114/r dose of 600/100mg bid, TMC114 PK parameters were not significantly associated with virologic response at Week 24.
The IQ was the strongest predictor of virologic response (p<0.001), with the relationship driven by BL TMC114 FC in EC50; other predictors were BL VL and the number of sensitive antiretrovirals (ARVs) in the OBR. No clinically relevant exposure-safety relationships were observed.
Conclusions: In the absence of exposure-efficacy and exposure-toxicity
relationships at the recommended TMC114/r dose, therapeutic drug monitoring of TMC114 is unlikely to play a role in the management of HIV infection.
RESULTS
Patient characteristics
- The majority of patients in POWER 3 were Caucasian (75%) and male (87%).
The mean BL VL was 4.62±0.76 log10 copies/mL, and median CD4 cell count was 115 cells/mm3, respectively.
Pharmacokinetics
- TMC114 PK parameters were available for 292 patients and are summarized in Table 1.
- The predefined target C0h for TMC114 of 550ng/mL (based on the EC50 value for PI-resistant HIV-1 strains when corrected for protein binding [EC50 for wild-type virus = 55]) was exceeded in all patients in this analysis.
- The derived estimates for drug exposure in this analysis were comparable to those in POWER 1 and POWER 2 at the same dose of 600/100mg bid.6
Relationship between PK and efficacy
- There was no relationship between TMC114 PK and efficacy (change in log10 VL from BL at Week 24) at the recommended dose:
- neither TMC114 AUC24h nor C0h were statistically significantly associated with changes in VL from BL and virologic response at Week 24 (Figures 1a and 1b).
- TMC114 FC at BL, BL VL, and use of sensitive ARVs in the OBR were stronger predictors of response than TMC114 PK (Table 2).
Relationships between IQ and efficacy
- The TMC114 IQ was a strong predictor of virologic response, with the relationship being primarily driven by BL TMC114 FC and not by TMC114 exposure
- ANCOVA models showed that IQ was significantly and positively associated with change in log10 VL and virologic response at Week 24 (Table 3).
- Higher values for IQ were significantly and positively associated with a higher probability of response, with the relationship being driven by BL TMC114 FC (Figures 2a and 2b).
- BL VL and use of sensitive ARVs in the OBR were also significantly associated with the probability of response (Table 3).
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