E Capparelli, J Connor, J Lane, Ja Englund, P Palumbo, C Baker and PAGTG 152 Team.
Univ. Calif. San Diego, School of Medicine, La Jolla CA, Baylor College of Medicine, Houston TX, Harvard School of Public Health, Cambridge MA, NIAID/NIH Bethesda MD.
Clinical studies suggest infants experience increased toxicity from Zidovudine (ZDV) compared to older children. To assess whether this difference could be due to PK or PD differences, we performed a pediatric population PK/PD analysis of ZDV. This analysis included 2437 serum ZDV levels from 394 subjects in Pediatric ACTG Study #152 obtained during the first 18 months of therapy at doses of 120/m2 (with ddI) or 180mg/m2 (without ddI) every 6 hours. The median age of children was 2.4 years (range 0.2 -17.9). Serum ZDV concentrations were fit to a one compartment PK model using NONMEM (FOCE). Allometric scaling of parameters described the data as well or better than modeling size dependant PK parameters by WT and/or BSA and was included before evaluating other potential covariates. Estimated PK parameters are:
Cl/F = 4.08 + (1.7-LOGAST)*0.11 – ddI*0.35 + 1stDose*0.53+ CHILD*0.80 (l/hr/kg^0.75)
Vd/F = 3.79 + ddI*0.28 (l/kg)
Where LOGAST = Log AST, Child = 1 if age > 2years, ddI=1 if ZDV+ddI, 1stDose=1 if drawn after the first dose.
Inter-subject variabilities for Vd/F and Cl/F were 28% and 31%. IOV (F) was 35% and residual error was 49.7% + 12 ng/ml. There was no apparent relationship between estimated ZDV exposure and change in HIV plasma RNA. Anemia (average Hgb <10 gm/dl) occurred in 8.2% of subjects with average ZDV conc =<290 ng/ml versus 24.0% of subjects with average ZDV conc > 290 ng/ml (p<0.001). A linear function adequately described the relationship between ZDV levels and Hgb. This relationship was similar between infants and older children. In conclusion, ZDV elimination is reduced in infants compared to older children. This lower clearance leads to higher ZDV levels in infants and is in part responsible for the increased hematologic toxicity.
Reference: PAGE 9 (2000) Abstr 115 [www.page-meeting.org/?abstract=115]
Poster: poster