Haloperidol Pharmacokinetics after Oral and Intravenous administration in Elderly

Delirium is a common but very serious complication in post-operative elderly
with long term consequences such as increased mortality, cognitive decline and
institutionalisation. Prevention of delirium would be advantageous for both
patients and their caregivers. Prophylactic haloperidol administration has been
studied in a couple of studies obtaining mixed results. In these studies
different routes of administration and haloperidol doses were used. Based on
these differences in haloperidol dosing the obtained mixed results could be
explained by haloperidol pharmacokinetics; the haloperidol concentration might
just have been too low during the operation to obtain a protective effect.
Pharmacokinetics of drugs change during aging due to changes in liver- and
kidney function, fatdistribution and permeability of the blood-brain barrier.
As a result pharmacokintetics of healthy volunteers cannot be extrapolated to
elderly. To date, however the pharmacokinetics of haloperidol in elderly are
unknown. In this study the pharmacokinetics of haloperidol, administered orally
and intravenously are studied to gain insight in the pharmacokinetics of
haloperidol both in blood and the cerebrospinal fluid (CSF) and to establish a
pharmacokinetic population model for haloperidol after intravenous and oral
administration.

To obtain a nonlinear mixed effects model (NONMEM) describing the population
pharmacokinetics of haloperidol in the central (CSF) and peripheral compartment
after oral and intravenous injection.

Open randomized controlled trial

All patients will receive a single dose of 3 mg haloperidol, 10 patients will
receive this by way of oral administration and 10 patients by way of
intravenous injection.

So far, haloperidol pharmacokinetic studies in elderly have never been done.
Because the pharmacokinetics of drugs change with age due to changes in fat
distribution, liver/kidney function and changes in de blood brain barrier, this
study can only be performed with elderly. Also, elderly patients undergoing
acute surgery e.g. hip fracture have the highest risk for developing a
delirium. In other studies low dose haloperidol has been well tolerated. A
total of 10 blood and 10 CSF samples will be collected within a period of 3
days. Before surgery patients will be given a spinal catheter by the
anesthesiologist for spinal anesthesia and postoperative pain treatment.
Patients will also be given an intravenous catheter for administration of
preoperative medication. Both catheters will be removed after three days.
Blood- and CSF samples will be collected through these catheters, minimizing
the burden of sample collection. As infection, bleeding and neurologic injury
are rare but possible serious complications, patients will be closely monitored
during the study period. Following standard procedure, patients will be
screened preoperatively and admitted to the hospital for the surgery and the
first days following surgery. No extra site visits are necessary.
Questionnaires and diaries are not part of this study.