A feasibility study prior to an international multicentre paediatric study to assess pharmacokinetic/pharmacodynamic sampling and sample preparation procedures, logistics and bioanalysis

Abstract

Background: Variability in pre-analytical procedures such as blood sampling, sample preparation and transport can substantially influence bioanalytical results and subsequently impair reliability of data gathered during clinical trials. Especially in vulnerable populations, all efforts should be made to facilitate high-quality data extraction excluding unnecessary or repeated intervention.

Methods: The EU-funded LENA project (Labeling of Enalapril from Neonates up to Adolescents) included a feasibility study in its preparatory procedures prior to first-in-child studies. Derived from a regular study visit, it encompassed all procedures, from sampling of two study-specific drugs and four sensitive humoral parameters to bioanalysis, to evaluate the quality of obtained samples and applicability of logistical and bioanalytical procedures. Drug administration to healthy adults was circumvented by pre-spiking the blood collection tubes with a drug solution. Five clinical sites were evaluated.

Results: Clinical teams' preparedness and applicability of required sampling procedures was investigated in 18 volunteers, on-site. 97% of collected pharmacokinetic (PK) samples and 93% of samples for humoral parameters were obtained eligibly. Results met expectations, though one team had to be re-trained and performed a re-run. Planned procedures for sampling, sample preparation, transport and analysis were found to be suitable for being applied within paediatric trials.

Conclusion: The concept of the presented feasibility study that simultaneously assesses PK/PD sampling, sample preparation, logistics and bioanalysis proved to be a promising tool for trial preparation. It revealed improperly installed processes and bottlenecks that required adjustments prior to start of recruitment. It facilitated high-quality conduct from the first moment of paediatric pivotal studies.

Keywords: ACE, Angiotensin-converting-enzyme; Clinical trial; Cmax, maximum serum concentration; ELISA, Enzyme-linked immunosorbent assay; EMA, European Medicines Agency; EU, European Union; FDA, U.S. Food and Drug Administration; Feasibility; GCP, Good Clinical Practice; LC-MS/MS, Liquid chromatography-tandem mass spectrometry; LENA, Labeling of Enalapril from Neonates up to Adolescents; PD, Pharmacodynamic(s); PK, Pharmacokinetic(s); Pharmacodynamic; Pharmacokinetic; Pilot; RAA system, Renin-angiotensin-aldosterone system; RIA, Radioimmunoassay; Training concept; pp, Percentage points.

Fig. 1

Flow chart of the intended study design of the feasibility study.

Fig. 2

Circumvention of drug administration in the feasibility study. Procedures from spiking of blood collection tubes to the determination of drug concentration are shown by bold/blue arrows. Additional variability in results induced by this approach is indicated by thin/red arrows. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 3

Accuracy of enalapril/enalaprilat samples, obtained with pre-spiked blood collection tubes, in relation to reference values. The dark grey area indicates the acceptable accuracy of the bioanalytical method according to EMA/FDA Guidelines (±15%). The light grey area indicates the extended tolerance range based on additional influencing factors of the artificial setting of the feasibility study (58%–153%). * denotes results from the re-run for the site that did not pass the feasibility study in its first attempt.

Fig. 4

(A–D) Results for humoral parameters aldosterone, renin, plasma renin activity and angiotensin I. Each black circle represents an analytical result for an evaluable sample. Hatched areas indicate applied reference ranges for healthy adults, as far as established or given by the laboratory. * denotes analytical results from the re-run for sites that did not pass the feasibility study in their first attempt.