Ageing-driven gastrointestinal variability in Parkinson's disease: implications for oral levodopa pharmacokinetics and formulation design.

Parkinson's disease is a distinctly age-associated neurodegenerative disorder in which oral levodopa remains the therapeutic foundation, particularly in older adults. Yet with advancing age, the reliability of oral therapy progressively declines not simply due to inadequate dosing, but because ageing reshapes the gastrointestinal environment on which drug absorption depends. This review integrates evidence spanning neuromuscular decline, epithelial barrier fragility, altered luminal chemistry, immune dysregulation, microbiome remodelling, and enteric neurodegeneration to explain how the ageing gut generates exposure instability. Delayed gastric emptying, inconsistent proximal intestinal delivery, microbial drug metabolism, and real-world administration constraints collectively amplify pharmacokinetic variability, producing erratic onset, fluctuating plasma profiles, and reduced therapeutic predictability. Using levodopa as a clinically established model system, we extend these insights to the broader challenge of ensuring reliable performance of oral therapies in ageing populations. We argue that therapeutic success in older adults depends less on maximizing mean bioavailability and more on stabilising exposure under heterogeneous physiological and practical conditions. Accordingly, the review integrates ageing-associated gastrointestinal decline, altered luminal and epithelial determinants of drug absorption, pharmacokinetic instability, and formulation design responses into a unified translational framework for ageing-aware oral therapy. By reframing levodopa failure as a consequence of ageing-driven gut-drug instability, this review proposes an ageing-aware formulation framework and identifies exposure-stability endpoints to guide the development and evaluation of physiologically resilient oral therapies for older adults.