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GRACE PK Study: Median (range) AUC12h and C0h were similar between women and men, and across
black, Hispanic and white patients; Pharmacokinetic results from GRACE demonstrated no clinically relevant differences in exposure to DRV across a range of covariates, including sex, race/ethnicity, use of ETR, use of TDF, age, body weight and hepatitis B co-infection status
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"Intrinsic/Extrinsic Covariates and Darunavir
Pharmacokinetics in Treatment-Experienced Patients
in GRACE (Gender, Race And Clinical Experience)"
Reported by Jules Levin
11th International Workshop on Clinical Pharmacology of HIV Therapy (IWCPHIV), Sorrento, Italy, April 7-9, 2010
Thomas N. Kakuda, PharmD1, Vanitha J. Sekar, PhD1, Peter Vis, MSc2, Bruce Coate, BS, MPH1, Robert Ryan, MS1, Guy De La Rosa, MD3, Joseph Mrus, MD, MSc3
1Tibotec Inc, Titusville, NJ, USA; 2Tibotec BVBA, Mechelen, Belgium; 3Tibotec Therapeutics, Titusville, NJ, USA
AUTHOR CONCLUSIONS
Pharmacokinetic results from GRACE demonstrated no clinically relevant differences in exposure to DRV across a range of covariates, including sex, race/ethnicity, use of ETR, use of TDF, age, body weight and hepatitis B co-infection status
The results from this study are in agreement with previous findings in
DRV/rtv-treated, treatment-experienced HIV-infected patients4,9
AUTHOR DISCUSSION
The GRACE trial demonstrated that DRV/rtv-based therapy is effective, generally safe
and well tolerated across sexes and racial/ethnic groups1,2
- Furthermore, no clinically relevant relationships between DRV PK parameters and the
efficacy or safety outcomes of DRV/rtv-based therapy were noted3
DRV C0h was above the protein binding corrected EC50 value for resistant virus (550ng/
mL) for all patients, regardless of individual covariates
Exposure to DRV was not influenced by sex, race/ethnicity, age, body weight, hepatitis B
co-infection status, or use of ETR or TDF
- Differences in AUC12h and C0h between subgroups and across the overall population
were small and not considered clinically relevant
INTRODUCTION
GRACE was a Phase IIIb study specifically designed to enroll a high proportion of treatment-experienced women and people of color to assess sex- and race-based outcomes of a darunavir/ritonavir (DRV/rtv)-based regimen
- Patients received DRV/rtv 600/100mg twice daily plus an optimized background regimen, which could include etravirine (ETR; 200mg twice daily)
Of the 429 patients enrolled, virologic response rates (HIV-1 RNA <50 copies/mL) at Week 48 were 53.4% in the intent-to-treat (ITT) population (all patients who took at least one dose of study medication) and 73.2% in the non-virologic failure (non-VF) censored population (censored patients that discontinued for reasons other than VF)1
- In the ITT population at Week 48, the virologic response rate was 50.9% in women and 58.5% in men1; the virologic response rates by race were 48.5%, 61.5% and 60.0% in black, Hispanic and white patients, respectively2
- In the non-VF censored population at Week 48, the virologic response rate was
73.0% in women, 73.5% in men, 68.8% in black patients, 79.7% in Hispanic
patients and 78.0% in white patients1,2
Previously presented results from GRACE showed that there was no relevant relationship between DRV pharmacokinetic (PK) parameters and the efficacy or safety outcomes of DRV/rtv-based therapy,3 consistent with findings from previous studies4,5,6
Here we evaluated the effect of extrinsic and intrinsic covariates on DRV PK parameters over 48 weeks of therapy in GRACE
aFour patients self-identified as Asian or Other and were not included in the analysis by race; bvirco TYPE HIV-1 resistance analysis; cTwo patients, one Hispanic and one white (both women), did not have resistance testing at baseline; SE, standard error; CDC, US Centers for Disease Control and Prevention; DRV, darunavir; PI, protease inhibitor
Intensive PK sampling from 32 patients showed no time-dependent relationship for DRV exposure over 48 weeks and demonstrated results similar to the population PK results (Figure 3)
Use of ETR or TDF, hepatitis B co-infection status, age or body weight did not affect DRV AUC12h or C0h (Table 2)
REFERENCES
1. Squires K, et al. Poster presented at the 5th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town, South Africa, July 19-22, 2009. Poster MOPEB042.
2. Smith K, et al. Poster presented at the 49th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, USA, September 12-15, 2009. Poster H-918.
3. Sekar V, et al. Presented at the 12th European AIDS Conference (EACS), Cologne, Germany, November 11-14, 2009. Poster PE4.1/8.
4. Sekar V, et al. Oral presentation at the 11th European AIDS Conference, Madrid, Spain, October 24-27, 2007. Abstract PS4/5.
5. Sekar V, et al. Poster presented at the 15th Conference on Retroviruses and Opportunistic Infections, Boston, MA, USA, February 3-6 2008. Poster 769.
6. Sekar V, et al. Poster presented at the 16th International Aids Conference (AIDS 2006); Toronto, Canada, August 13-18, 2006. Poster TUPE0078.
7. Vis P, et al. Poster presented at the 15th Population Approach Group in Europe, Bruges, Belgium, June 14-16, 2006. Poster 964.
8. Scholler-Gyure et al. Pharmacokinetics of darunavir/ritonavir and TMC125 alone and coadministered in HIV-negative volunteers. Antivir Ther 2007; 12:789-726
9. Sekar V. Poster presented at the 9th International Workshop on Clinical Pharmacology of HIV Therapy,
New Orleans, LA, USA, April 7-9, 2008. Poster P41.
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