Population K-PD Model of Sodium Nitroprusside in Neonates and Children During Anesthesia or Sedation
Sarapee Hirankarn (1), Gregory B Hammer (2), Scott R Schulman (3), David R Drover (2), Erin Dombrowsky (1), Anne Zajicek (4), Carol Cohane (2), Nick Holford (5), Brian Anderson (6) and Jeffrey S. Barrett (1)
Laboratory for Applied PK/PD, Division of Clinical Pharmacology and Therapeutics, The Children's Hospital of Philadelphia; Philadelphia, PA (1); Departments of Anesthesia, Stanford University School of Medicine, Stanford, CA (2); Duke University Medical Center, Durham, NC (3); Obstetric and Pediatric Pharmacology Branch, National Institute of Health, Bethesta, MD (4); Department of Pharmacology & Clinical Pharmacology, University of Auckland, New Zealand (5); Department of Anesthesia, University of Auckland, New Zealand (6)
Objectives: Sodium nitroprusside (SNP) is an effective hypotensive agent. Due to a short half-life and chemical instability, measurement of SNP concentration in vivo is not practical. The kinetic-pharmacodynamic (K-PD) model offers an approach that circumvents the absence of pharmacokinetic (PK) data. The objective of this analysis is to use a K-PD model to describe mean arterial pressure (MAP) response to SNP in neonates and children.
Methods: A total of 3038 MAP measurements were collected from 202 patients following IV administration of SNP. A population K-PD model was developed using NONMEM VI (FOCE). A one compartment disposition model with a nominal distribution volume of 1 L/70kg was assumed for SNP. Size and maturation differences in CL and V were described using theory based allometry and a sigmoid hyperbolic function . An inhibitory sigmoidal Emax model was used to describe the effect of SNP. The effect on MAP was assumed to be proportional to the amount in the effect compartment. The infusion rate producing 50% of Emax (ER50) at steady state was calculated from the product of the nominal EC50 and CL. A power function of age was used to describe age related differences in baseline MAP. A mixture model was used to explain the wide variability in MAP response.
Results: The K-PD model with a mixture model on EC50 described the data with adequate precision. Population mean parameters (RSE) for baseline MAP, Emax, low ER50, and high ER50 were estimated to be 77 (1.4%) mm Hg, 19 (7%) mm Hg, 0.9 (14.8%) mg/h/70kg and 4.3 (21.0%) mg/h/70kg, respectively. The percentage of the sub-population with a high EC50 was 45% (13.3%). Baseline MAP increased with age. The estimated time for this population to reach 50% of mature CL is 107 (25%) weeks post-menstrual age. The effect compartment half-life of SNP was 6 (14.2%) minutes.
Conclusions: In the absence of PK data, the K-PD model provided plausible parameter estimates. The finding of two phenotypes with a 5 fold difference in infusion rate to reach the same MAP fall indicates that dose individualization based on MAP response is essential. These phenotypic differences may be due to a polymorphism in either clearance or EC50 or in both parameters.
 Anderson BJ, Holford NHG. Mechanistic basis of using body size and maturation to predict clearance in humans. Drug Metab Pharmacokinet 2009; 24: 25-36.