Update from Study A4001031: maraviroc pharmacokinetics in CCR5-tropic HIV-1-infected children aged 2 to < 18 years
Background: Maraviroc is a CCR5 antagonist, approved to treat adults infected with CCR5-tropic HIV-1 but not yet approved for pediatric use.
Methods: Study A4001031 is an ongoing open-label, two-stage (stage 1: dose finding, stage 2: safety/efficacy), non-comparative, multicenter study of maraviroc plus optimized background therapy (OBT) in treatment-experienced children aged 2-< 18 years. Serial maraviroc pharmacokinetics (PK) were determined at Weeks 2 and 48. 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 maraviroc (adult-recommended doses with/without CYP3A 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 33 subjects taking maraviroc with a potent CYP3A inhibitor (all protease inhibitors), three failed to meet the PK target (Cavg ≥100 ng/mL) with the initial dose (2/3 subjects failed to achieve target PK due to poor compliance). Conversely, six subjects not receiving a potent CYP3A inhibitor (two nevirapine-based regimens; three raltegravir-based regimens; one NRTI-regimen) required at least doubling of the initial maraviroc dose. Since amending the protocol to double initial doses for this group, one subject achieved the PK target with their initial dose. At enrollment into Stage 2, one subject (non-inhibitor regimen) did not achieve the target after two dose adjustments but demonstrated good clinical response and was therefore included in the PK analysis (table).
| Includes data up to Aug 2012; updated data will be presented | Cohort 1 ³2-<6 years Liquid Maraviroc (n=8) | Cohort 2 ³6-<12 years Tablet Maraviroc (n=10) | Cohort 3 ³6-<12 years Liquid Maraviroc (n=9) | Cohort 4 ³12-<18 years Tablet Maraviroc (n=17) |
| Sex (males/females) | 6/2 | 4/6 | 5/4 | 7/10 |
| Race (White/Black/Asian/Other) | 1/5/2/0 | 2/8/0/0 | 1/8/0/0 | 5/8/3/1 |
| Week 2 - Cavg geometric mean (ng/mL) | 261 (n=6) | 248 (n=10) | 263 (n=7) | 246 (n=15) |
| Week 48 - Cavg geometric mean (ng/mL) | 131 (n=3) | 278 (n=7) | 191 (n=5) | 199 (n=8) |
Conclusions: BSA-scaled maraviroc doses when co-administered with potent CYP3A inhibitors provide exposures (Cavg>100 ng/mL) associated with near-maximal efficacy in all cohorts. Doses for non-inhibitor regimens are still being evaluated; however, PK data suggest that doses are likely to be higher than the initial 300 mg adult BSA-scaled dose.
M. Vourvahis1, L. McFadyen2, T. Checchio3, C. Giaquinto4, L. Keet5, S.R. Valluri6, A. Fang6, G. Mukwaya6, J. Heera7
1Pfizer Inc, Specialty Care, New York, United States, 2Pfizer Inc, Primary Care, Sandwich, United Kingdom, 3Pfizer Inc, Primary Care, Groton, United States, 4Department of Pediatrics, University of Padova, Padova, Italy, 5Department Pediatrics, University of the Free State, Bloemfontein, South Africa, 6Pfizer Inc, New York, United States, 7Pfizer Inc, Specialty Care, Groton, United States