IMPAACT P1090 is a Phase I/II study of etravirine (ETR) pharmacokinetics (PK), dose- finding, and safety in antiretroviral (ARV) treatment-experienced HIV-infected children 1 to <6 yrs from the U.S., South Africa (SA) and Brazil.
Treatment-experienced children on a failing ARV regimen for ≥8 wk or on a treatment interruption for ≥4 wk with a history of virologic failure (VF) were enrolled into one of two age cohorts (2-<6 yr; 1-<2 yr). ETR was combined with at least two active ARVs, one of which was a ritonavir-boosted protease inhibitor (PI/r). ETR was dosed by weight-band. Participants 8-<10 kg received 75mg twice daily [bid]; 10-<20 kg, 100mg bid; and 20-<25 kg, 125mg bid. Tablets were swallowed whole or dispersed in liquid. All participants underwent 12-hr PK sampling on day 14 (±4 days). Participants with ETR AUC12h <10th percentile of adults (<2350 ng*hr/mL) had an individual ETR dose increase and repeat PK. For each cohort, PK and safety were confirmed in the first six participants before further enrolling at the same dose. The target geometric mean ETR AUC12h was 2713 to 6783 ng*hr/mL (60-150% of adult AUC12h). Criteria for acceptable safety included no suspected adverse drug reaction resulting in death, life-threatening toxicity, any grade 4 event, or ≥3 participants discontinuing due to grade ≥3 toxicity.
Twenty-one participants (nine each from SA and Brazil, three from U.S.) received ETR weight-band based doses. Demographics, ETR dosing and PK are shown for each cohort in the table. Both cohorts passed pre-determined PK and safety criteria, but seven (33%) children, all taking ETR dispersed, had an AUC12h of <2350 ng*hr/mL and underwent an ETR dose increase. Geometric mean ETR AUC12hr was significantly higher in participants that swallowed the tablet whole vs. dispersed, 7943 ng*hr/mL (n=6) vs. 2697 ng*hr/mL (n=15), respectively (p=0.0002). After a median (range) follow-up of 62 (9-234) weeks, three (14%) participants (2/3 with day 14 AUC12h <2350 ng*hr/mL) have discontinued due to VF. One participant discontinued due to a treatment-related toxicity (grade 4 lipase).
Weight-band based ETR dosing achieved predefined AUC12h targets in HIV-infected children receiving an ARV regimen including a PI/r, but 33%, all taking dispersed tablets, had AUC12h <10th percentile of the adult AUC12h. To date, ETR is well-tolerated and the rate of VF in these 21 treatment-experienced children is low.