Journal of Antimicrobial Chemotherapy (2001) 47, 51-59
© 2001 The British Society for Antimicrobial Chemotherapy
Population pharmacokinetics of panipenem in neonates and retrospective evaluation of dosage
a Department of Pharmacy, b Division of Neonatology and c Division of Infectious Disease, Kitasato University Hospital 1-15-1 Kitasato, Sagamihara-shi, Kanagawa 228-8555, Japan; d Laboratory of Analytical Chemistry, School of Pharmaceutical Sciences, Kitasato University, 108-8641 Shirogane, Minatoku, Tokyo, Japan
The population pharmacokinetics of panipenem was studied in 23 neonates. Their postconceptional age (PCA) was 24.7–42.6 weeks and their body weight was 530–4455 g at initiation of therapy. Panipenem was infused over a period of 60 min in a dose of 10.2–34.7 mg/kg bd in 21 patients, tid in one patient and four times daily in one patient for a mean of 10.7 days. Blood samples were obtained just before the infusion and 1–2 h after and again 6 h after the infusion. All the data for the 108 serum panipenem concentrations were evaluated with a non-linear mixed-effect model (NONMEM with first-order method), a computer program designed for population pharmacokinetic analysis. One- and two-compartment population pharmacokinetic parameters were measured. The two-compartment parameters were as follows: panipenem clearance CL = 0.150 L/h, central volume of distribution = 0.54 L, intercompartmental clearance = 0.014 L/h and peripheral volume of distribution = 0.28 L. The one-compartment parameters were CL = 0.175 L/h and volume of distribution = 0.55 L. In the fitting process using the one-compartment model, significantly fixed effects related to CL were PCA, postnatal age (PNA), gestational age (GA), body weight (BW) and serum creatinine, and that for the distribution volume (V) was BW. CL showed a logarithmic rise with PCA (CL = 0.00176 x exp0.14 x PCA). The CL levels in the patients with PCA < 33 weeks (0.098 L/h) were significantly lower (P < 0.001) than those with PCA 33 weeks (0.25 L/h). The final formulae for the population pharmacokinetic parameters are as follows: CL = 0.0832 (PCA < 33 weeks), CL = 0.179 x BW (PCA 33 weeks), V = 0.53 x BW (coefficient of variation; 23.9% for CL, 28.5% for V). Based on these data, a simulated time–concentration curve was compared with that for adult data in a clinical Phase I study. Our findings suggest that the panipenem dosage regimen of 10–20 mg/kg every 12 h should yield concentrations within the accepted therapeutic range.
* Corresponding author. Tel: +81-427-78-7580; Fax: +81-427-78-9430; E-mail: gr4t-kmr{at}asahi-net.or.jp
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