Microneedle biosensors for real-time, minimally invasive drug monitoring of phenoxymethylpenicillin: a first-in-human evaluation in healthy volunteers

BACKGROUND: Enhanced methods of drug monitoring are required to support the individualisation of antibiotic dosing. We report the first-in-human evaluation of real-time phenoxymethylpenicillin monitoring using a minimally invasive microneedle-based β-lactam biosensor in healthy volunteers. METHODS: This first-in-human, proof-of-concept study was done at the National Institute of Health Research/Wellcome Trust Imperial Clinical Research Facility (Imperial College London, London, UK). The study was approved by London-Harrow Regional Ethics Committee. Volunteers were identified through emails sent to a healthy volunteer database from the Imperial College Clinical Research Facility. Volunteers, who had to be older than 18 years, were excluded if they had evidence of active infection, allergies to penicillin, were at high risk of skin infection, or presented with anaemia during screening. Participants wore a solid microneedle β-lactam biosensor for up to 6 h while being dosed at steady state with oral phenoxymethylpenicillin (five 500 mg doses every 6 h). On arrival at the study centre, two microneedle sensors were applied to the participant's forearm. Blood samples (via cannula, at -30, 0, 10, 20, 30, 45, 60, 90, 120, 150, 180, 210, 240 min) and extracellular fluid (ECF; via microdialysis, every 15 min) pharmacokinetic (PK) samples were taken during one dosing interval. Phenoxymethylpenicillin concentration data obtained from the microneedles were calibrated using locally estimated scatter plot smoothing and compared with free-blood and microdialysis (gold standard) data. Phenoxymethylpenicillin PK for each method was evaluated using non-compartmental analysis. Area under the concentration-time curve (AUC), maximum concentration, and time to maximum concentration were compared. Bias and limits of agreement were investigated with Bland-Altman plots. Microneedle biosensor limits of detection were estimated. The study was registered with ClinicalTrials.gov, number NCT03847610. FINDINGS: Ten healthy volunteers participated in the study. Mean age was 42 years (SD 14). Seven (70%) were men. Microdialysis and microneedle results were similar for phenoxymethylpenicillin ECF maximum concentration (0·74 mg/L vs 0·64 mg/L; 95% CI -0·24 to 0·44; p=0·53), time to maximum concentration (1·18 h vs 1·10 h; -0·52 to 0·67; p=0·79), and AUC (1·54 mg × h/L vs 1·67 mg × h/L; -1·10 to 0·85; p=0·79). In total, 440 time points were compared with mean difference between measurements -0·16 mg/L (95% CI -1·30 to 0·82). Mean phenoxymethylpenicillin AUCs for free serum and microneedle PK were similar (1·77 mg × h/L SD 0·59 vs 1·67 mg × h/L 1·00; -0·77 to 0·97; p=0·81). Median coefficient of variation between sensors within individuals was 7% (IQR 4-17). Limit of detection for the microneedles was estimated at 0·17 mg/L. INTERPRETATION: This study is proof-of-concept of real-time, microneedle sensing of penicillin in vivo. Future work will explore microneedle use in patient populations, their role in data generation to inform dosing recommendations, and their incorporation into closed-loop control systems for automated drug delivery. FUNDING: National Institute for Health Research Imperial Biomedical Research Centre, Mérieux Foundation.