Optimising Therapeutic Outcomes in CNS Disorders: Pharmaceutical and Pharmacokinetic Approaches

Abstract

Central nervous system (CNS) disorders have been highlighted by the World Health Organisation (WHO) as one of the biggest threats to public health. This study aimed to improve the clinical outcomes in CNS disorders, with focus on major depression, through pharmaceutical and pharmacokinetic approaches by the use of transdermal base creams and patches for the delivery of a phytochemical and the use of in-silico modelling to optimise antidepressant dosing in challenging populations such as pregnant women. The flavonoid hesperetin, as a potential candidate for CNS disorders, was incorporated into commercial base creams (Vanish-Pen™, Doublebase™ gel, Versatile™, and Pentravan®). In-vitro drug release studies were conducted at week 0 showing that Pentravan® formulation released the highest percentage of hesperetin (12.69 % (0.68 %)), while Versatile™ released the lowest (4.53 % (0.65 %)). Storage studies on Vanish-pen™ and Doublebase™ were consistent for 10 weeks when stored at 4°C and 25°C, respectively, while Versatile™ showed consistent profiles when stored at both 4°C and 25°C. Significant changes were detected in the release profiles of Pentravan® during storage at both temperatures. Transdermal hesperetin patch systems were developed using either Dow Corning® BIO-PSA 7-4501 silicone adhesive or Eudragit® E100 acrylic adhesive. The silicone-based patch that contains 5.5 % glycerol provided the highest release, 39.9 % (0.37 %), but during storage for 3 weeks at 4°C and 25°C, the release significantly decreased. The Eudragit®-based patch that produced the highest release (8 % (0.06 %)) was composed of 5% glycerol and 45% of triacetin. However, during storage the acrylic-based patches degraded. Silicone-based transdermal patches showed higher drug release than creams which could potentially be useful for systemic hesperetin delivery for the treatment of CNS disorders, while hesperetin creams could be more suitable for the localised delivery to the skin for the treatment of skin cancers. In order to highlight non-pharmaceutical approaches to optimise CNS therapeutic outcomes, we applied pharmacokinetic modelling to examine potential dose adjustments that would be required in challenging population groups, namely pregnancy, for two antidepressants, paroxetine and sertraline. Paroxetine has been demonstrated to undergo gestation related reductions in plasma concentrations, to an extent which is dictated by the polymorphic state of CYP 2D6. However, knowledge of appropriate dose titrations is lacking. A pharmacokinetic modelling approach was applied to examine gestational changes in trough plasma concentrations for CYP 2D6 phenotypes, followed by necessary dose adjustment strategies to maintain paroxetine levels within a therapeutic range of 20-60 ng/mL. A decrease in trough plasma concentrations was simulated throughout gestation for all phenotypes. A significant number of ultra-rapid (UM) phenotype subjects possessed trough levels below 20 ng/mL (73-76 %) compared to extensive metabolisers (EM) (51-53 %). For all phenotypes studied there was a requirement for daily doses in-excess of the standard 20 mg dose throughout gestation. The following doses are suggested to be optimal: for EM, 30 mg daily in trimester 1 followed by 40 mg daily in trimesters 2 and 3, for poor-metabolisers (PM), 20 mg daily dose in trimester 1 followed by 30 mg daily in trimesters 2 and 3, and for UM, a 40 mg daily dose throughout gestation. Sertraline is also known to undergo changes in pharmacokinetics during pregnancy. CYP 2C19 has been implicated in the inter-individual variation in clinical effect associated with sertraline activity. However, knowledge of suitable dose titrations during pregnancy and within CYP 2C19 phenotypes is lacking. A pharmacokinetic modelling virtual clinical trials approach was implemented to assess gestational changes in trough plasma concentrations for CYP 2C19 phenotypes and to identify appropriate dose titration strategies to stabilise sertraline levels within a defined therapeutic range throughout gestation. Sertraline trough plasma concentrations decreased throughout gestation, with maternal volume expansion and reduction in plasma albumin being identified as possible causative reasons. All CYP 2C19 phenotypes required dose increase throughout gestation. For EM and UM phenotypes, doses of 100-150 mg daily are required throughout gestation. For PM, 50 mg daily during trimester 1 followed by a dose of 100 mg daily in trimesters 2 and 3 are required. Transdermal system is a promising approach to obtain the CNS benefits of phytochemicals and to overcome the limitations associated with their oral delivery, while more studies are needed to be used clinically. Using PBPK modelling for adjusting the doses of CNS medications in challenging populations could improve quality of life and prevent empirical interventions.