Dried Blood Spots and Sparse Sampling: A perfect combination for minimally invasive PK/PD studies in children
Parul Patel (1), Hitesh Pandya (2), Neil Spooner (3), Oscar Della Pasqua (3), Sonya Gade (3), Venkatesh Kairamkonda (4), Graham Lawson (1), Sangeeta Tanna (1) and Hussain Mulla (5)
(1) Leicester School of Pharmacy, De Montfort University, UK; (2) University of Leicester, UK; (3) GlaxoSmithKline, R&D, UK; (4) Neonatal Intensive Care Unit, University Hospitals of Leicester NHS Trust, UK; (5) Centre for Therapeutic Evaluation of Drugs, Glenfield Hospital, UK
Background: Dried blood spots (DBS) have recently received considerable interest for application to PK studies. The technique requires a micro (~50µl) blood-volume sample, and is therefore particularly advantageous to studies involving children and neonates. In-vitro validation of DBS based quantification techniques indicate a comparable performance to methods based on large blood-volumes. However, validation in the clinic is necessary to ascertain the robustness of the DBS sampling methodology as a means of generating population PK data in children.
Objective: To perform a clinical validation of the DBS technique in preterm neonates receiving caffeine therapy for apnoea of prematurity.
Method: In a prospective study, between 1-10 (15µl) DBS samples (total 338) were collected opportunistically from 67 preterm neonates at random times intervals post caffeine dose. Neonates received oral and iv caffeine doses according to the local protocol. Caffeine exhibits low plasma protein binding, does not bind to red blood cells (RBC) and has a blood-to-plasma ratio of 1. Therefore conversion of blood values for comparison was not necessary. The DBS caffeine concentration data was used to develop a Pop-PK model, and compared with a previously reported model based on conventional plasma caffeine concentrations.
Results: A 1 compartmental model with zero and first order absorption described the DBS data well. Parameters derived from DBS data were estimated with precision (RSE <10%) and were comparable to CL and V estimates from plasma (6.83 vs. 6.96ml/h/kg and 614 vs. 851ml/kg, respectively). Weight and postnatal age were the most influential covariates in the CL model which is in accordance to previous findings (Charles, 2008). Similar to Charles et al. the BOV in CL (31.2%) was higher than the BSV in CL (24.7%) which has important implications for caffeine TDM. Model evaluation using bootstrap and PC-VCP confirmed the robustness of the model.
Conclusion: The DBS based population model enabled precise estimation of caffeine PK parameters in preterm neonates. Furthermore, estimates were comparable to plasma literature values derived from a demographically similar neonatal population. DBS is potentially a more practical and ethical sampling technique in PK /PD studies involving young children provided there is sufficient understanding of the behaviour of the drug with respect to RBC association and protein binding.
Charles, B. G., Townsend, S. R., Steer, P. A., Flenady, V. J., Gray, P. H. & Shearman, A. 2008. Caffeine Citrate Treatment for Extremely Premature Infants With Apnea: Population Pharmacokinetics, Absolute Bioavailability, and Implications for Therapeutic Drug Monitoring. Therapeutic Drug Monitoring, 30, 709-716.