Dried blood spots and sparse sampling: a practical approach to estimating pharmacokinetic parameters of caffeine in preterm infants

Abstract

AIMSDried blood spots (DBS) alongside micro-analytical techniques are a potential solution to the challenges of performing pharmacokinetic (PK) studies in children. However, DBS methods have received little formal evaluation in clinical settings relevant to children. The aim of the present study was to determine a PK model for caffeine using a 'DBS/microvolume platform' in preterm infants. METHODSDBS samples were collected prospectively from premature babies receiving caffeine for treatment of apnoea of prematurity. A non-linear mixed effects approach was used to develop a population PK model from measured DBS caffeine concentrations. Caffeine PK parameter estimates based on DBS data were then compared with plasma estimates for agreement. RESULTSThree hundred and thirty-eight DBS cards for caffeine measurement were collected from 67 preterm infants (birth weight 0.6-2.11 kg). 88% of cards obtained were of acceptable quality and no child had more than 10 DBS samples or more than 0.5 ml of blood taken over the study period. There was good agreement between PK parameters estimated using caffeine concentrations from DBS samples (CL = 7.3 ml h -1 kg -1; V = 593 ml kg; t1/2 = 57 h) and historical caffeine PK parameter estimates based on plasma samples (CL = 4.9-7.9 ml h -1 kg -1; V = 640-970 ml kg -1

Predictive Performance of a Gentamicin Population Pharmacokinetic Model in Neonates Receiving Full-Body Hypothermia

“…5–7 Due to these limitations, population PK (popPK) models for neonates are often developed from a single medical center using a small sample with sparse PK sampling and are evaluated using the same information used to develop the model. 8–10 …”

Neonatal medicines research: challenges and opportunities

“…Consequently, PK studies in neonates should be designed and performed within these blood sampling limitations that cover both PK and safety labs, Methods to limit blood sampling volume and frequency are encouraged to be used and developed as well as alternative methods to using blood [38]. DSB samples, combined with population PK modeling techniques is one potential method for facilitate PK studies in neonates [39,40]. Interestingly, the same rationale can be built for preclinical PK studies in small animals.…”

“…The development of such methods to measure a range of environmental toxicants, excipients or drugs in DBS has been a more recent goal. The approach has been proved to be effective in the field of neonatal pharmacology, based on compoundspecific reports, for example, caffeine, diphantoine or fenytoine, topiramate, canrenoate, propranolol, linezolid, metronidazole or dexamethasone [39][40][41][42][43][44]49,51].…”

Dosing in neonates: special considerations in physiology and trial design

“…DBS sampling techniques offer other benefits, as they require less training of research personnel, no additional sample processing, storage at room temperature, and simple bioanalytical analysis methods (3, 53). This technique has been successfully used in pharmacokinetic studies of metronidazole and caffeine in premature neonates (53–55). …”