Arun Dhandayudham and Devon De Silva

Dr Arun Dhandayudham is WDP’s Medical Director, leading on medical practice across the organisation. Dr Dhandayudham is a Consultant in Addictions Psychiatry and trained in Oxford and Cambridge. Dr Dhandayudham has extensive experience setting up community drug and alcohol services, prison services and dual diagnosis services. He has an interest in online shopping addiction, PTSD and chronic arousal states such as pain and anxiety.

Devon De Silva manages WDP’s Innovation and Research Unit (IRU) which aims to bridge the gap between academia and service delivery. The IRU achieves this by designing and contributing to research within the addictions sector, whilst also developing and evaluating innovations that enhance service delivery. Devon’s primary research focus is the evaluation of pilot programmes launched within WDP e.g. WDP’s Buvidal pilot, GLOVES Programme, Capital Card, and Open Dialogue.

Dr Della Santhakumar and Dr Vivienne Gosnell are highly experienced Clinical Leads involved in the successful delivery of Buvidal within WDP. They have also been integral in the collection of quantitative and qualitative data during the Pilot.

An approach to optimise methadone treatment throughout the peri-natal period using pharmacokinetics guided virtual-clinical trials

Aims: Methadone dose titration during pregnancy requires consideration of pharmacokinetics to optimise clinical outcomes. Physiologically based pharmacokinetic (PBPK) virtual clinical trials analysis was applied to pragmatically assess the extent of gestational related changes in maternal / fetal concentrations to identity an optimal dosing schedule throughout gestation.

Design: We developed a maternal / fetal virtual clinical trial model using the research tool Simcyp to assess R-/S-methadone concentrations. Models were robustly validated using retrospective pharmacokinetic concentration profiles and applied to predict maternal / fetal methadone pharmacokinetics across doses of 30-180 mg once daily (10×10 trial design).

Findings / Conclusions Significant decreases in maternal R-/S-methadone plasma concentrations were noted during gestation, with concomitant increases in fetal concentrations. For R-methadone a pre-natal target of 90 mg daily was followed by escalation to 110 mg by week 5 and increased by 10 mg every 5 weeks to a maximum dose of 180 mg daily near term. Dose ranges 140-180 mg in trimester 3 resulted in < 30 % of subjects For S-methadone, QT [c] prolongation is an important safety concern and a similar dosing strategy resulted in 11 % of subjects with peak levels above target threshold at a final dose of 180 mg. The final optimised dosing regimen yielded < 20 % of subjects with peak and trough concentration outside of the therapeutic window with dose ranges of 90-120 mg, 120-140mg and 140-180 mg during trimester 1,2 and 3 respectively. Specific and gestation-dependent dose titrations are required during pregnancy to reduce the risks associated with illicit drug use and to maintain fetal safety.