1. Pharmacokinetics and Safety of Metronidazole in Preterm Infants: Validation of Dried Blood Spot Sampling Mario Sampson, PharmD Duke Clinical Research Institute University of North Carolina Eshelman School of Pharmacy

2. Background n In preterm infants, intra-abdominal infections are deadly n These infections are polymicrobial, including anaerobes n Metronidazole has excellent anti-anaerobic activity n Pharmacokinetic data of metronidazole in preterm infants are limited n Blood volume is a limiting factor for studies in neonates l Dried blood spots require 10 times less blood per sample vs. plasma

3. Methods n Multicenter (N=3), open-label, PK study n N=24 n Population l Gestational age at birth <32 weeks l Postnatal age (PNA) <91 days l Suspected serious infection n Dosing (intravenous) l Loading dose 15 mg/kg l Maintenance dose 7.5 mg/kg every 12-24 hours for 5 days

4. Methods Last dose, PNA < 14 days 12-13 24-25 36-37 hours 24-25 48-49 72-73 hours Last dose, PNA ≥ 14 days Dose 1, & 3-5 -0.5 0.2 3-4 4-6 hours n Sampling l Paired plasma and dried blood spots collected if possible n Population PK l Nonlinear mixed effects modeling using NONMEM software and bootstrapping to evaluate precision of parameters l Plasma and dried blood spot samples analyzed separately n Plasma and dried blood spot paired concentrations analyzed by linear regression

5. Subject Demographics

6. Population Pharmacokinetics n Final model: Clearance (L/h) = 0.0421 * Weight * (Postnatal Age/27) 0.451 and Volume (L) = 0.948 * Weight

7. Population Pharmacokinetic Parameters

8. Dried Blood Spots r 2 =0.85, p<0.001 N=46 paired samples r 2 =0.95, slope=0.80 [95% CI, 0.74, 0.85], p<0.001

9. Adverse Events

10. Conclusions n Metronidazole clearance increased with postnatal age l Clearance finding expected with development n The bias in population clearance and volume parameter estimates was <10% using dried blood spots n DBS sampling can be used to evaluate metronidazole pharmacokinetics n Pediatric Trials Network l Daniel Benjamin Jr. l Edmund Capparelli l Gregory Kearns l Philip Brian Smith l Michael Cohen-Wolkowiez l Katherine Berezny l Barrie Harper n Enrolling Sites l Children’s Hospital of Orange County - Antonio Arrieta l Duke University Medical Center - James Wynn l Wesley Medical Center - Barry Bloom - Paula Delmore n Data Coordinating Center l EMMES Corporation n NIGMS/NICHD UNC-Duke Collaborative T32 Clinical Pharmacology Postdoctoral Training Grant, National Institutes of Health (1 T32 GM 86330) l Kim Brouwer l Daniel Benjamin Jr. l Paul Watkins n Eunice Kennedy Shriver National Institute of Child Health and Human Development (NIH) l Contract #: HHSN2752010000031 and HHSN201000003I l Task Order #: HHSN27500003 n Best Pharmaceuticals for Children Act n University of North Carolina Eshelman School of Pharmacy Acknowledgments