Enantioselective pharmacokinetics of (R)- and (S)-ketamine after a 5-day infusion in patients with complex regional pain syndrome

Abstract

Introduction: This study determined the pharmacokinetics and pharmacodynamics of (R)- and (S)-ketamine and (R)- and (S)-norketamine following a 5-day moderate dose, as a continuous (R,S)-ketamine infusion in complex regional pain syndrome (CRPS) patients.

Materials and methods: Ketamine was titrated to 10-40 mg/h and maintained for 5 days. (R)- and (S)-Ketamine and (R)- and (S)-norketamine pharmacokinetic and pharmacodynamic studies were performed. Blood samples were obtained on Day 1 preinfusion, and at 60-90, 120-150, 180-210, and 240-300 min after the start of the infusion, on Days 2, 3, 4, 5, and on Day 5 at 60 min after the end of infusion. The plasma concentrations of (R)- and (S)-ketamine and (R)- and (S)-norketamine were determined using enantioselective liquid chromatography-mass spectrometry.

Results: Ketamine and norketamine levels stabilized 5 h after the start of the infusion. (R)-Ketamine clearance was significantly lower resulting in higher steady-state plasma concentrations than (S)-ketamine. The first-order elimination for (S)-norketamine was significantly greater than that of (R)-enantiomer. When comparing the pharmacokinetic parameters of the patients who responded to ketamine treatment with those who did not, no differences were observed in ketamine clearance and the first-order elimination of norketamine.

Conclusion: The results indicate that (R)- and (S)-ketamine and (R)- and (S)-norketamine plasma concentrations do not explain the antinociceptive activity of the drug in patients suffering from CRPS.

Fig. 1

The mean ± SEM ketamine levels for the R (closed circles) and S enantiomers (open circles). Norketamine levels are similarly illustrated with closed and open triangles. The X axis shows the baseline and infusion period with the corresponding ketamine and norketamine blood levels during the 4–5 h incremental dosing period. The subjects’ pain scores are illustrated along the X axis to provide a reference to the achieved level of analgesia Blood levels for both ketamine and norketamine were significantly (P < 0.05) increased from baseline at all time points with a corresponding decrease in pain scores.

Fig. 2

Time course of (R,S)-ketamine and (R,S)-norketamine plasma concentrations in two representative subjects. Symbols show measured concentrations. Lines are model-predicted profiles using individual pharmacokinetic parameters, where solid and dashed lines represent the R- and S-enantiomers, respectively.

Fig. 3

Diagnostic plots for me final population pharmacokinetic model showing the agreement between observed and individual predicted concentrations.

Fig. 4

Temporal progression of the probability of achieving a pain score less than or equal to three over the duration of me study. Symbols represent calculated probability, and the line represents the model-fitted profile according to eq. 6.