Objective: To estimate caffeine PK in premature infants during a clinical evaluation of sterile caffeine citrate (CC) for prevention of AOP.

Methods: A NONMEM analyses was applied to caffeine plasma measurements obtained during an oral/iv regimen of CC; 10 mg/kg caffeine base load followed by a daily maintenance dose of 2.5 mg/kg [double-blind (DB) caffeine phase] or 10 mg/kg load followed by daily maintenance dose of 3 mg/kg[open-label (OL) caffeine phase].

Results: A total of 58 (36 male/22 female) subjects with AOP were examined (DB, n=43 and OL, n=15); mean ± SD gestational age, postconceptual age at study onset, and weight were 30 ± 2 weeks, 31± 1 weeks, and 1,228 ± 240 grams. Subjects race were caucasian(n=21), black american (n=10), oriental (n=2), hispanic (n=22), and other(n=3). Baseline apnea episodes/day prior to CC therapy were grouped: < 8(n=22); 8 - 13 (n=25); ≥ 14 (n=11). The best fit model assumed clearance(Cl) and volume of distribution (Vd) to be proportional to weight: Cl = 4.39 ml/kg·hr (CV = 37%); Vd = 0.834 L/kg (CV = 22%).

Conclusions: PK data support weight-adjusted loading and maintenance dosing. Cl may be higher in infants with increased apnea episodes and hispanics may have a larger Vd.