Impact of ontogeny on linezolid disposition in neonates and infants.
The impact of age on linezolid disposition during the first few months of life has not been previously investigated. We characterized linezolid pharmacokinetics after a single, 10.0-mg/kg intravenous dose in 42 infants stratified as follows: group 1 (n = 9), gestational age <34 weeks and postnatal age <8 days; group 2 (n = 7), gestational age <34 weeks and postnatal age 8 days to 12 weeks; group 3 (n = 11), gestational age >or=34 weeks and postnatal age <8 days; and group 4 (n = 15), gestational age >or=34 weeks and postnatal age 8 days to 12 weeks. Linezolid was quantitated by a validated HPLC-triple-quadrupole mass spectrometer method from repeated blood samples (n = 7, 0.3 mL each) obtained over a 12-hour period. Pharmacokinetic parameters were determined by standard model-dependent techniques. The values (mean +/- SD) for total body clearance (CL) (0.25 +/- 0.12 L x h(-1) x kg(-1)), apparent volume of distribution (VD(ss)) (0.75 +/- 0.19 L/kg), and elimination half-life (t(1/2)) (2.8 +/- 2.1 hours) from the entire study cohort were similar to values reported previously for children and adolescents. Examination of the linezolid pharmacokinetics as a function of age revealed that CL increased rapidly during the first week of life and as a function of postnatal age. Age stratification revealed lower values for CL in those infants aged less than 8 days (group 1, 0.12 +/- 0.06 L x h(-1) x kg(-1); group 3, 0.23 +/- 0.12 L x h(-1) x kg(-1)) as compared with those aged 8 days to 12 weeks (group 2, 0.31 +/- 0.07 L x h(-1) x kg(-1); group 4, 0.31 +/- 0.10 L x h(-1) x kg(-1)). In contrast to the results for CL, gestational age served to be the most useful predictor of VD(ss). Evaluation of the pharmacokinetic data would appear to support the use of linezolid dosing regimens currently approved for infants and young children in neonates with postnatal age greater than 7 days.
Division of Pediatric Pharmacology and Medical Toxicology, Children's Mercy Hospitals and Clinics, Kansas City, MO 64108, USA. gkearns@cmh.edu
Gregory L
GL
Kearns
Gail L
GL
Jungbluth
Susan M
SM
Abdel-Rahman
Nancy K
NK
Hopkins
Ian R
IR
Welshman
Rosie P
RP
Grzebyk
Jon B
JB
Bruss
John N
JN
Van Den Anker
D000081:Acetamides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000375:Aging / Q000378:metabolism*; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D005260:Female; D005865:Gestational Age; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007234:Infant, Premature; D000069349:Linezolid; D008297:Male; D023303:Oxazolidinones / Q000008:administration & dosage / Q000493:pharmacokinetics*
D000081:Acetamides; D000890:Anti-Infective Agents; D023303:Oxazolidinones; D000069349:Linezolid