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Polly Clayden, HIV i-Base\u2028<\/strong><\/p>\n Daily raltegravir was safe and well tolerated at six weeks of life and met pharmacokinetic targets in HIV-exposed infants, according to data from IMPAACT P1110 presented at CROI 2017.<\/strong><\/p>\n Previous studies have shown raltegravir (RAL) elimination to be highly variable in the first weeks of life due to low UGT1A1 activity.<\/p>\n IMPAACT P1110 is a phase I multicentre study in full-term HIV-1 exposed neonates at high risk of HIV with or without maternal RAL exposure. It includes two cohorts: cohort 1 infants received two single RAL doses one week apart; cohort 2 infants received daily RAL dosing for first six weeks of life.<\/p>\n The study sites are in Brazil, South Africa and the US.<\/p>\n PK data from cohort 1 and from older infants and children in IMPAACT P1066 were combined in a population PK model. The model included maturation of absorption rate from 16% of max at birth to 90% at two weeks, and clearance from close to nil to max at approximately six months of age.<\/p>\n The model was used to perform simulations of possible daily dosing regimens for RAL-naive infants in cohort 2 (using oral granules for suspension). See Table 1.<\/p>\n Plasma samples were collected at the following time points. First dose: pre-dose, 1-2, 6-10 and 20-24 hours post dose. Second dose: 3-6 hours post dose. Day 6-9 of life: pre-dose. Day 15-18 of life: pre-dose, 4-6 and 8-12 hours post-dose. Day 28-32 of life: pre-dose. Week 5-6 of life: pre-dose and 3-6 hours post-dose.<\/p>\n Exposure targets are: AUC24 12-40 mg*h\/L; AUC12 6-20 mg*h\/L; C12 or C24 > 33 ng\/mL; and Cmax <8724 ng\/mL.<\/p>\n Cohort 2 enrolled 26 infants: 46% female; 69% black, 12% white and 19% other; median gestation age 38.5 weeks and birth weight 2.93 kg. Evaluable PK and 6-week safety data were available for 25 infants.<\/p>\n The investigators reported no drug related adverse events. All RAL exposure targets were met; PK parameters are shown in Table 2.<\/p>\n (41.9%)<\/p><\/td>\n The investigators noted that after the initial dose some infants had AUC24 slightly above target range – but they considered this to be acceptable given the rapid increase in RAL metabolism over the first week of life.<\/p>\n Infants born to mothers who received RAL and low birth weight infants are to be studied in IMPAACT P1110.<\/p>\n Reference:<\/p>\n\n
\n Days of life<\/th>\n Dose mg\/kg<\/th>\n Frequency<\/th>\n<\/tr>\n \n 1-7<\/td>\n 1.5<\/td>\n Once daily<\/td>\n<\/tr>\n \n 8-28<\/td>\n 3.0<\/td>\n Twice daily<\/td>\n<\/tr>\n \n after 28<\/td>\n 6.0<\/td>\n Twice daily<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n \n
\n <\/td>\n After initial dose: 1.5 mg\/kg once daily (n=25)<\/th>\n Day 15-18: 3.0 mg\/kg twice daily (n=24)<\/th>\n<\/tr>\n \n Geometric mean (CV)<\/td>\n Target<\/td>\n Geometric mean (CV)<\/td>\n Target<\/td>\n<\/tr>\n \n AUC (mg*h\/L)<\/td>\n 38.2 (38.4%)<\/td>\n 11 above 13 met 0 below<\/td>\n 14.3 (43.3%)<\/td>\n 8 above 14 met 1 below<\/td>\n<\/tr>\n \n Trough (ng\/mL)<\/td>\n 948 (64.2%)<\/td>\n 25 above 0 below<\/td>\n 176 (93.8%)<\/td>\n 22 above 1 below<\/td>\n<\/tr>\n \n Cmax (mg\/mL)<\/td>\n 2350 (35.0%)<\/td>\n 0 above 25 below<\/td>\n 2850\n 0 above 24 below<\/td>\n<\/tr>\n \n Tmax (mg\/mL)<\/td>\n 5.4 (57.5%)<\/td>\n <\/td>\n 5.4 (57.5%)<\/td>\n <\/td>\n<\/tr>\n \n T1\/2 (hours)<\/td>\n 15.8 (174.8%)<\/td>\n <\/td>\n 15.8 (174.8%)<\/td>\n <\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n