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Mario Sampson, PharmD Duke Clinical Research Institute

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. Background.

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Mario Sampson, PharmD Duke Clinical Research Institute

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

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

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

  5. Subject Demographics

  6. Population Pharmacokinetics • 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 r2=0.95, slope=0.80 [95% CI, 0.74, 0.85], p<0.001 r2=0.85, p<0.001 N=46 paired samples

  9. Adverse Events

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

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