title: Pharmacokinetics of intravenous rifampicin (rifampin) in neonates.
abstract: Few reports have addressed neonatal rifampicin plasma concentrations and data on neonatal rifampicin pharmacokinetics are completely lacking. Therefore, plasma concentrations of rifampicin and its main metabolite 25-O-desacetylrifampicin (DES) were measured in 123 surplus plasma samples from routine vancomycin monitoring in 21 neonates using reversed-phase HPLC. Rifampicin peak and trough plasma concentrations were 4.66 +/- 1.47 mg/L and 0.21 +/- 0.20 mg/L, respectively, after a dose of 8.5 +/- 2.1 (mean +/- SD) mg/kg per day. A significant linear relationship between rifampicin dose and peak plasma concentrations was found, but inter-patient variability was high. Pharmacokinetic parameters of rifampicin were calculated according to a one-compartment open model with iterative two-stage Bayesian fitting (MW\PHARM 3.60, Mediware, The Netherlands). First-order elimination constant, volume of distribution corrected for weight, total body clearance corrected for weight (CL/W), and elimination half-life were 0.16 +/- 0.06 h(-1), 1.84 +/- 0.59 L/kg, 0.28 +/- 0.11 Lkg(-1) h(-1), and 4.9 +/- 1.7 h, respectively. A high Pearson correlation was found between CL/W rifampicin and the covariates plasma creatinine and CL/W gentamicin of a preceding gentamicin treatment course, r = 0.728 (n = 17) and r = 0.837 (n = 12), respectively. DES was detected in each plasma sample. Therefore, rifampicin seems to be eliminated by both renal and metabolic pathways in neonates. In 8 study patients, plasma concentrations of rifampicin and DES were measured again after two weeks of therapy. CL/W rifampicin was significantly higher (67 +/- 50%). The authors suggest maintaining the current dose regimen of 10 mg/kg once a day. Because of the large inter-patient variability in rifampicin plasma concentrations and CL/W increase during therapy, the authors suggest monitoring rifampicin peak and trough plasma concentrations to avoid low plasma concentrations. More research is needed to determine well-founded dosing guidelines.
authors.affiliation: Department of Clinical Pharmacy, University Hospital of Maastricht, The Netherlands. jpul@kfls.azm.nl
authors.forename: Joyce
authors.initials: J
authors.lastname: Pullen
authors.forename: Leo M L
authors.initials: LM
authors.lastname: Stolk
authors.forename: Pieter L J
authors.initials: PL
authors.lastname: Degraeuwe
authors.forename: Frank H
authors.initials: FH
authors.lastname: van Tiel
authors.forename: Cees
authors.initials: C
authors.lastname: Neef
authors.forename: Luc J I
authors.initials: LJ
authors.lastname: Zimmermann
mesh_terms: D019540:Area Under Curve; D001499:Bayes Theorem; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007260:Infusion Pumps; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D012293:Rifampin / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014640:Vancomycin / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D014640:Vancomycin; C032393:25-deacetylrifampicin; D012293:Rifampin