MOPE232 - Poster Exhibition
Maraviroc (MVC) pharmacokinetics (PK) in CCR5-tropic HIV-1-infected children aged 2-< 18 years: preliminary results from study A4001031
M. Vourvahis1, L. McFadyen2, B. Duncan3, T. Checcio3, C. Giaquinto4, S.R. Lavoie5, S.R. Valluri6, A. Fang6, G. Mukwaya6, J. Heera1, H. Valdez6
1Pfizer, Inc., Specialty Care, New London, United States, 2Pfizer, Primary Care, Sandwich, United Kingdom, 3Pfizer, Inc., Primary Care, New London, United States, 4Department of Pediatrics, University of Padova, Padova, Italy, 5Division of Pediatric Infectious Diseases, Virginia Commonwealth University, Richmond, United States, 6Pfizer, Inc., Specialty Care, New York, United States
Background: MVC is a potent CCR5 antagonist approved for treatment of CCR5-tropic HIV-1 in adults.
Methods: Study A4001031 is an ongoing open-label, two-stage (stage 1:dose finding; stage 2:safety/efficacy), non-comparative, multi-center study in treatment-experienced HIV-infected children receiving MVC 40-450 mg BID with optimized background therapy (OBT). MVC PK were determined at Week 2. Subjects infected with CCR5-tropic HIV-1 were enrolled and stratified into four age cohorts (table). Participants were dosed twice-daily, initially according to body surface area (BSA) and OBT based on interactions with MVC (adult-recommended doses with/without CYP3A4 inhibitors/inducers). Dose adjustment and PK re-evaluation occurred if average concentrations (Cavg) at Week 2 were < 100 ng/mL. Cavg was estimated from AUC (AUC/12) calculated from seven samples taken over 12 hours.
Results: Of the 22 subjects taking MVC with a potent CYP3A4 inhibitor (all protease inhibitors), only one failed to meet the PK target with the initial dose (due to poor compliance). Conversely, all five subjects not receiving a potent CYP3A4 inhibitor (two nevirapine-based regimens; two raltegravir-based regimens; one NRTI-regimen) required at least doubling of the initial MVC dose. At the time of enrolment into Stage 2 one subject did not achieve the target after two dose adjustments but demonstrated good clinical response and was therefore included in the PK analysis (table).
| ||Cohort 1||Cohort 2||Cohort 3||Cohort 4|
| ||³2 - <6 years Liquid MVC
(N=2)||³6 - <12 years
(N=10)||³6 - <12 years
(N=5)||³12 - <18 years
|Sex (males/females)||2 / 0||4 / 6||3 / 2||4 / 8|
|Race (White/Black/Asian)||0 / 0 / 2||0 / 8 / 2||1 / 4 / 0||4 / 6 / 2|
|Cavg, geometric mean (ng/mL)||178 (n=2)||247 (n=10)||221 (n=5)||242 (n=9)|
Conclusion: Preliminary data show that BSA-based MVC doses when co-administered with CYP3A inhibitors provide exposures (Cavg>100 ng/mL) associated with near-maximal efficacy in all cohorts. However, additional PK analyses are necessary to further evaluate the appropriate dose when MVC is administered without inhibitors.
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