Influence of formulation and route of administration on ketamine's safety and tolerability: systematic review

Purpose Ketamine has rapid-onset antidepressant effects in patients with treatment-resistant depression. Common side effects include dissociation (a sense of detachment from reality) and increases in systolic and diastolic blood pressure. The objective of this structured review was to examine the effect of ketamine formulation and route of administration on its pharmacokinetics, safety and tolerability, to identify formulation characteristics and routes of administration that might minimise side effects. Methods This was a structured review of published ketamine pharmacokinetics, safety and tolerability data for any ketamine formulation. The ratio of ketamine:norketamine was calculated from reported C-max values, as a measure of first pass metabolism. The effect of formulation and route of administration on safety was evaluated by measuring mean changes in systolic blood pressure and tolerability by changes in dissociation ratings. Data were correlated using Spearman's method. Results A total of 41 treatment arms were identified from 21 publications, and included formulation development studies in healthy volunteers, and studies in clinical populations (patients undergoing anaesthesia, or being treated for pain or depression). Ketamine:norketamine ratios were strongly positively correlated with change in dissociation ratings (r = 0.89) and change in blood pressure (r = 0.96), and strongly negatively correlated with ketamine T-max (r = - 0.87; p < 0.00001 for all). Ketamine T-max strongly positively correlated with a change in dissociation ratings (r = - 0.96) and change in blood pressure (r = - 0.99; p < 0.00001 for all). Conclusion Ketamine formulations that maximize first pass metabolism and delay T-max will be better tolerated and safer than formulations which lack those characteristics.