Pharmacokinetics and Bioavailability of a Novel Rivastigmine Nasal Spray Compared to Rivastigmine Oral Capsule in Healthy Men

Abstract To compare the pharmacokinetics, bioavailability, tolerability, and safety of a novel 4 mg rivastigmine nasal spray to 3 mg rivastigmine oral capsule, a single‐dose, open‐label, randomized, crossover study was conducted in 16 fasted healthy young men (18 to 55 years). Mean (SD) rivastigmine C max was 8.39 (6.8) and 13.77 (10.7) ng/mL for oral and nasal, respectively. Rivastigmine AUC 0‐inf was 19.6 (14.9) and 40.6 (24.4) ng h/mL for oral and nasal, respectively. The ratio of LS means (nasal test / oral reference; 90% C.I.) for rivastigmine C max was 185.83% (134.22, 257.28) and for rivastigmine AUC 0‐inf was 257.35% (197.26, 335.73). Rivastigmine t max for nasal (0.7 h) was significantly lower than oral (1.2 h, P < .05), however, NAP226‐90 t max for nasal (1.9 h) and oral (1.8 h) were similar. NAP226‐90 C max was 3.93 (1.1) and 3.01 (0.8) ng/mL for oral and nasal, respectively. NAP226‐90 AUC 0‐inf was 22.9 (5.3) and 23.2 (5.1) ng h/mL for oral and nasal, respectively. Median NAP226‐90 to rivastigmine AUC 0‐inf ratio for nasal (0.55) was significantly lower than oral (1.38, P < .05) because nasal bypassed first‐pass metabolism. Both single‐dose treatments were safe and well tolerated. Nasal and throat irritation were mostly perceived as mild and transient following nasal administration. The 4 mg rivastigmine nasal spray had 1.5‐ and 2.0‐fold higher dose normalized rivastigmine C max and AUC 0‐inf , respectively, and 2.5‐fold lower NAP226‐90 to rivastigmine AUC 0‐inf ratio compared to 3 mg oral capsule. This nasal spray has good potential to improve the local and gastrointestinal tolerability of rivastigmine treatment in Alzheimer's and Parkinson's disease dementia patients.