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

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 Cmax was 8.39 (6.8) and 13.77 (10.7) ng/mL for oral and nasal, respectively. Rivastigmine AUC0-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 Cmax was 185.83% (134.22, 257.28) and for rivastigmine AUC0-inf was 257.35% (197.26, 335.73). Rivastigmine tmax for nasal (0.7 h) was significantly lower than oral (1.2 h, P < .05), however, NAP226-90 tmax for nasal (1.9 h) and oral (1.8 h) were similar. NAP226-90 Cmax was 3.93 (1.1) and 3.01 (0.8) ng/mL for oral and nasal, respectively. NAP226-90 AUC0-inf was 22.9 (5.3) and 23.2 (5.1) ng h/mL for oral and nasal, respectively. Median NAP226-90 to rivastigmine AUC0-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 Cmax and AUC0-inf, respectively, and 2.5-fold lower NAP226-90 to rivastigmine AUC0-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.