Parkinson’s disease

Disease definition & pathophysiology

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor symptoms such as bradykinesia, resting tremor, rigidity, and postural instability. It results primarily from loss of dopamine-producing neurons in the substantia nigra, leading to dopamine deficiency in the basal ganglia. Lewy bodies (aggregates of α-synuclein) are pathologic hallmarks contributing to neuronal dysfunction and death.

Commonly used Pharmacodynamic (PD) Models

• Indirect response or turnover models describing dopamine depletion and symptomatic relief by dopaminergic agents.
• Disease progression models, such as the Unified Parkinson’s Disease Rating Scale (UPDRS) progression models.
• Exposure-response models linking levodopa or dopamine agonist concentrations to motor-symptom improvement or dyskinesia development.

Typical patient population

Typically affects individuals older than 60 years, though early-onset PD (<50 years) accounts for approximately 5–10% of cases. Slightly higher prevalence observed in males compared to females, with global prevalence around 1–2% among elderly populations.

Risk factors & disease progression indicators

Risk factors include older age, family history, exposure to neurotoxins, and possibly head trauma. Disease progression indicators include worsening motor symptoms, onset of motor fluctuations (wearing-off phenomena), dyskinesias, and non-motor symptoms such as cognitive decline, depression, and autonomic dysfunction.

Key Clinical Biomarkers

Diagnosis relies heavily on clinical assessment (presence of cardinal motor symptoms and response to dopaminergic therapy). Imaging biomarkers (e.g., DaTSCAN/SPECT) can confirm dopamine transporter deficiency. MRI may exclude other causes but does not confirm PD.

Disease Severity Classification

Severity often assessed using clinical rating scales, notably the Unified Parkinson’s Disease Rating Scale (UPDRS):

• Mild (early disease): UPDRS motor score ≤ 20
• Moderate: UPDRS motor score ~21–40
• Severe (advanced): UPDRS motor score >40

Hoehn and Yahr staging is also commonly used, ranging from stage 1 (mild, unilateral involvement) to stage 5 (severe, wheelchair-bound or bedridden).

Treatment aim (PD-targets)

Treatment aims at restoring dopamine signaling, improving motor function, and reducing symptoms. PD-targets primarily include dopamine synthesis, metabolism, and receptor activation.

Common Drug Classes & Regimens

Commonly used PK-models

• Population PK models describing levodopa pharmacokinetics, accounting for covariates such as age, body weight, renal function, and concomitant medications.
• Compartmental models (one- or two-compartment) used for dopamine agonists and levodopa.
• PK-PD models linking drug exposure to improvement in UPDRS scores or motor complications (e.g., dyskinesias, motor fluctuations).