Clinical Pharmacokinetics of Intranasal Scopolamine for Space Motion Sickness
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Purpose and Specific Aims: Space Motion Sickness (SMS) is a neurovestibular disturbance experienced by astronauts in microgravity environment, which causes acute symptoms and discomfort requiring treatment with medications during the early, mission critical time of space flight. Scopolamine (SCOP) is a historically known belladonna alkaloid used as an anticholinergic/antiemetic agent for a long time. It is a very common prescription medication for the prevention of nausea and vomiting associated with motion sickness. Earlier reports indicate that scopolamine is the most effective drug for suppressing nausea and vomiting caused by motion sickness. Bioavailability after oral administration of scopolamine is low and variable, and absorption from transdermal patch is slow and prolonged. Since the limitations of oral and other formulations of scopolamine, Pharmacotherapeutics Laboratory of Johnson Space Center developed a gel intranasal dosage form of scopolamine (INSCOP) and the bioavailability were evaluated under the Food and Drug Administration guidelines for phase I clinical trials with an Investigation New Drug (IND) application. Results showed that intranasal administration scopolamine achieves significantly higher and more reliable absolute bioavailability (83% vs 3.7%, p < 0.05). The proposed research focuses on the clinical pharmacokinetics of intranasal Scopolamine used for the treatment of space motion sickness. The data used in this study have been collected in two Phase II IND clinical trials in healthy human subjects with an overall goal of developing a new formulation of scopolamine which is a rapidly acting, efficacious and safe, , countermeasure for the treatment and prevention of space motion sickness in astronauts. The proposed specific aims are to; (1) establish PK of INSCOP with three escalating dose levels of 0.1, 0.2 and 0.4 mg; (2) estimate bioavailability of 0.2 and 0.4 mg doses of INSCOP during ambulation and simulated microgravity, Antiorthostatic Bed Rest, respectively; and (3) characterize the relationship between scopolamine concentrations in plasma, saliva and urine using co-modeling techniques. Methods: Aim 1: PK parameters were calculated by Winnonlin using data collected in a dose escalation pharmacokinetics (PK) study with twelve (6 male and 6 female) healthy subjects after administration of three escalating doses 0.1, 0.2, and 0.4 mgof the Investigational New Drug (IND) formulation of INSCOP administered in a completely randomized, double-blind cross-over study design. Aim 2: A Phase II, “Randomized, Double-Blind, and Bioavailability Study of Intranasal Scopolamine in a Simulated Microgravity Environment” were established with two dose level (0.2 and 0.4 mg) in 12 normal healthy subjects (6 male/ 6 female). Aim 3: Data from 24 subjects from the above two studies were used for PK modeling using Phoenix NLME Software. Concentrations of scopolamine in plasma, saliva and urine collected were determined using a modified LC-MS/MS method. PK parameters were derived by Phoenix WinNonlin. SAS program was used to perform statistical analysis. Results: Aim 1: Dose-linear pharmacokinetics of scopolamine with linear increases in Cmax and AUC within the dose range (0.1mg-0.4mg). Plasma drug concentrations were significantly higher in females than in males after administration of 0.4 mg dose. Aim 2: The absorption and bioavailability of INSCOP were not changed during the microgravity environment which means that the microgravity condition does not change the pharmacokinetics of INSCOP in human. Aim 3: The relationship among scopolamine concentrations in plasma, saliva and urine was satisfactorily described by a validated compartmental PK model and for the first time it satisfactorily predicted PK of INSCOP in plasma, saliva and urine. Conclusion and Significance: Results of this study have a significant clinical implication in understanding the PK of intranasal scopolamine in astronauts as well as terrestrial populations receiving INSCOP for the treatment of motion sickness. Results presented here demonstrate that (1) absorption and bioavailability appear to be linear with respect to administered dose range (0.1-0.4 mg); (2) the impact of sex difference on pharmacokinetics of INSCOP was observed at high dose level of 0.4mg, indicating sex had significant influences on the clearance and volume distribution of scopolamine after IN administration; (3) Absorption and bioavailability are not significantly affected in the simulated microgravity condition; (4) PK model for scopolamine was developed which satisfactorily predicted the PK of INSCOP in plasma, saliva and urine. . Therefore, our findings support the clinical utility of INSCOP for the treatment of space motion sickness for astronauts.