Population Pharmacokinetics of Theophylline in Premature Korean Infants
Sung Eun Kim, SeungHwan Lee, Bo-Hyung Kim, Han-Suk Kim, MD, PhD*, Sang-Goo Shin, MD, PhD, Kyung-Sang Yu, MD, PhD, In-Jin Jang, MD, PhD
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea, *Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea
Objectives: The aim of this study was to investigate the population pharmacokinetics of theophylline in premature Korean infants and to assess the influence of demographic and clinical covariates.
Methods: Forty-eight premature infants (24.4 - 36.6 weeks of gestational age (GA)), who received intravenous aminophylline or oral theophylline approximately every 8 or 12 hours were included in the population analysis. Trough levels (128 observations) and peak levels 1 to 4 hours after dosing (46 observations) were obtained from all infants. Body weight (BW), height, postnatal age (PNA), conceptional age (GA + PNA), presence of oxygen support, sex, delivery mode, serum AST, ALT, BUN, and creatinine (Cr) levels were included in the dataset for covariate analysis. Population pharmacokinetic models were built using NONMEM®, version VI).
Results: Theophylline population pharmacokinetics was described by a one-compartment model with rapid absorption (ka=100) and first-order elimination using the subroutines ADVAN2 and TRANS2. Regarding covariate selection, the effects of BW and serum Cr level were found significant for clearance and the effects of BW were found significant for volume of distribution, with BW most significant. The final estimates of pharmacokinetic parameters were CL (L/h) = 0.03 . (BW/1.3)1.15 . (Cr/0.54) -0.382 and V (L) = 1.7 . (BW/1.3)1.82. Interindividual variabilities (CV%) were 17% and 47% for clearance and volume of distribution, respectively.
Conclusions: The final model represented that BW and serum Cr level had significant effects on the theophylline pharmacokinetics in Korean premature infants. Further studies will be needed in a larger population to validate these results.