Pharmacokinetic-pharmacodynamic modeling of S(+)-ketamine in healthy volunteers

The NMDA-receptor antagonist ketamine, at relatively low-dose, is a potent
analgesic. It is used in the perioperative setting as well as in chronic pain,
for example in the treatment of neuropathic pain and pain from malignancies. We
are currently assessing ketamine*s analgesic efficacy in CRPS type 1 patients
in an experimental study (protocol P05.100).

Despite its wide use, relatively little is knows about ketamine*s
pharmacokinetics -PK- and pharmacodynamics -PD- or the link between the two.
For example, there is no knowledge on the link parameter ke0, which is an
estimate of the drugs onset and offset-times. Knowledge of ketamine*s PK and PD
is needed to be able to fully understand clinical ketamine data in patients,
such as CRPS type 1 patients. Furthermore, it will enable the optimization of
infusion schemes and hence the treatment of patients on ketamine.

Ketamine is a racemic mixture. Recently the S(+) form became available
(Ketanest). In contrast to the racemic mixture, S(+)-ketamine shows less
psychomimetic side effects. This is the reason that the S(+) form is now widely
used with the racemic mixture rapidly loosing market.

In this study we will assess the pharmocokinetics and pharmacodynamics of
intravenous S(+)-ketamine in healthy volunteers. This will result in a
pharmacokinetic/pharmaco-dynamic (PK/PD) model which may be used to predict
S(+)-ketamine concentration and pain relief after intravenous infusion.

Aims of the study:

1) To obtain pharmacokinetic parameters of S(+)-ketamine;

2) To study the pharmacodynamic effects of intravenous S(+)-ketamine on
experimental pain;

The design of the study is placebo-controlled, single-blind, randomized
cross-over

Nausea

There is a chance that the subjects become nauseated. In that case they will
receive 4 mg iv ondansentron (Zofran), a potent antiemetic. This will not end
the study.

Psychomimetic side effects

S(+)-ketamine may cause psychedelic side effects such as hallucinations, vivid
dreams, feeling of inebriation, confusion, drowsiness, and dizziness. All of
these side effects are temporarily and will disappear spontaneously or after
discontinuation of the S(+)-ketamine infusion. These side effects will be
monitored by using the Bowdle scales.

We are currently performing a S(+)-ketamine study (P05.107) and have now some
additional knowledge on the psychomimetic effects of the S(+)-variant of
ketamine. The psychomimetic effects of S(+)-ketamine are minimal with some
dizziness as most pronounced side effect. If side effects occur they do so only
after prolonged infusion. Hence we do not expect serious problems from
S(+)-ketamine with respect to psychomimetic side effects in our current study.
We cannot exclude, however, that some hallucinations or vivid dreams during the
ketamine infusion occur. They will dissappear upon the termination of the
infusion. In case such side effect do occur in our study, the infusion of
ketamine will immediately be terminated and the study will continue without
further drug infusion.

Arterial line

Due to the venous and arterial lines some bruising may occur. In rare cases,
especially after prolonged placement (>> 36 hours) thrombosis or infection have
been described. In this study, duration of arterial line placement is not more
than 8 hours.