gms | German Medical Science

Background: Ketamine is a widely used anesthetic drug with strong analgesic properties. There is evidence from clinical studies using experimental pain models, from off-label use and pilot efficacy studies in patients with chronic pain that ketamine might be an alternative to other drugs (e.g. opioids, anticonvulsants) particularly in the treatment of neuropathic complaints. However, as ketamine is rapidly eliminated (T½ ~ 6 h) and as only the solutions for intravenous injection and immediate release lozenges are available so far, there is a need for the development of oral dosage forms with prolonged liberation. Therefore, we evaluated rate and extent of absorption and formation of the major active metabolite norketamine (~20-30 % power of ketamine) of prolonged release ketamine (PR) tablets newly developed for the treatment of chronic pain syndromes.

Methods: The pharmacokinetic study was conducted in 15 healthy Caucasian subjects (10 males, 5 females, age 20-35 years, BMI 19.4-27.6 kg/m²). Concentration-time curves of ketamine and norketamine were measured after intravenous infusion of (5 mg ketamine HCl within 30 min) and after single oral administration of PR tablets in escalating doses (10 mg, 20 mg, 40 mg, 80 mg ketamine HCl) with at least 7 days wash-out between the study periods. Ketamine and norketamine were quantified in serum, urine and feces using a validated LC-MS/MS method with adequate quality characteristics.

Results: Ketamine PR was slowly and incompletely absorbed. The PR tablets reached maximum serum concentration (C_max) of ketamine after 4-6 h. Absorption was dose dependent with bioavailability of 11.5±8.09 %, 11.0±8.57 %, 15.9±9.53 % and 17.9±12.3 % after 10 mg, 20 mg, 40 mg and 80 mg, respectively. At the highest dose, C_max was 16.7±13.4 ng/ml. Ketamine after intravenous administration was widely distributed (V_ss = 6.31±3.09 l/kg). The elimination half-lives of 40 mg and 80 mg PR were significantly increased compared to intravenous ketamine and 20 mg and 40 mg PR. Renal clearance of all PR tablets was significantly higher than of intravenous ketamine and significantly lower after 40 mg and 80 mg compared to 20 mg and 40 mg PR tablets. Formation of norketamine was not influenced by the dose of ketamine.

Ketamine PR was safe and well tolerated. Eight reported AEs were judged to be probably related to intravenous ketamine with dizziness being the most frequent (6 subjects), whereas four and three AEs were judged to be possibly and probably, respectively, related to the study medication. Except two cases (palpitations and dizziness), all AEs after PR were of mild severity and not dose dependent.

Conclusions: The newly developed prolonged release tablets of ketamine were shown to be suitable for chronic applications. Their oral absorption and renal elimination are influenced by dose, probably by a saturable mechanism.