Background

Several models describing the pharmacokinetics of ketamine are published with differences in model structure and complexity. A systematic review of the literature was performed, as well as a meta-analysis of pharmacokinetic data and construction of a pharmacokinetic model from raw data sets to qualitatively and quantitatively evaluate existing ketamine pharmacokinetic models and construct a general ketamine pharmacokinetic model.

Methods

Extracted pharmacokinetic parameters from the literature (volume of distribution and clearance) were standardized to allow comparison among studies. A meta-analysis was performed on studies that performed a mixed-effect analysis to calculate weighted mean parameter values and a meta-regression analysis to determine the influence of covariates on parameter values. A pharmacokinetic population model derived from a subset of raw data sets was constructed and compared with the meta-analytical analysis.

Results

The meta-analysis was performed on 18 studies (11 conducted in healthy adults, 3 in adult patients, and 5 in pediatric patients). Weighted mean volume of distribution was 252 l/70 kg (95% CI, 200 to 304 l/70 kg). Weighted mean clearance was 79 l/h (at 70 kg; 95% CI, 69 to 90 l/h at 70 kg). No effect of covariates was observed; simulations showed that models based on venous sampling showed substantially higher context-sensitive half-times than those based on arterial sampling. The pharmacokinetic model created from 14 raw data sets consisted of one central arterial compartment with two peripheral compartments linked to two venous delay compartments. Simulations showed that the output of the raw data pharmacokinetic analysis and the meta-analysis were comparable.

Conclusions

A meta-analytical analysis of ketamine pharmacokinetics was successfully completed despite large heterogeneity in study characteristics. Differences in output of the meta-analytical approach and a combined analysis of 14 raw data sets were small, indicative that the meta-analytical approach gives a clinically applicable approximation of ketamine population parameter estimates and may be used when no raw data sets are available.

Editor’s Perspective
What We Already Know about This Topic
  • There has been a renewed interest in ketamine because of potentially new indications

  • A broad range of models have been published to describe ketamine pharmacokinetics in different populations and after different methods of administration and blood sampling

  • A general pharmacokinetic model could greatly aid in the development of dosing schemes that maximize therapeutic effects while minimizing side effects

What This Article Tells Us That Is New
  • A meta-analysis was successfully performed on 18 studies that had conducted mixed-effect pharmacokinetic analyses despite large heterogeneity in study characteristics

  • A populations pharmacokinetic analysis was performed on raw data sets obtained from 14 unique sources

  • Parameter estimates in the population pharmacokinetic analysis were comparable with those obtained in the meta-analysis of three-compartment pharmacokinetic models

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