Clinical Pharmacokinetics of the Depot Antipsychotics

Michael W. Jann, Larry Ereshefsky, Stephen R. Saklad

The clinical pharmacokinetics of the 4 depot antipsychotics for which plasma level studies are available (i.e. fluphenazine enanthate and decanoate, haloperidol decanoate, clopenthixol decanoate and flupenthixol decanoate) are reviewed. The proper study of these agents has been handicapped until recently by the necessity of accurately measuring subnanomolar concentrations in plasma. Their kinetic properties, the relationship of plasma concentrations to clinical effects, and conversion from oral to injectable therapy are discussed. The depot antipsychotics are synthesised by esterification of the active drug to a long chain fatty acid and the resultant compound is then dissolved in a vegetable oil. The absorption rate constant is slower than the elimination rate constant and therefore, the depot antipsychotics exhibit 'flip-flop' kinetics where the time to steady-state is a function of the absorption rate, and the concentration at steady-state is a function of the elimination rate. Fluphenazine is available as both an enanthate and decanoate ester (both dissolved in sesame oil), although the decanoate is more commonly used clinically. The enanthate produces peak plasma concentrations on days 2 to 3 and declines with an apparent elimination half-life (i.e. the half-time of the apparent first-order decline of plasma concentrations) of 3.5 to 4 days after a single injection. The decanoate produces an early high peak which occurs during the first day and then declines with an apparent half-life ranging from 6.8 to 9.6 days following a single injection. After multiple injections of fluphenazine decanoate, however, the mean apparent half-life increases to 14.3 days, and the time to reach steady-state is 4 to 6 weeks. Withdrawal studies with fluphenazine decanoate suggest that relapsing patients have a more rapid plasma concentration decline than non-relapsing patients, and that the plasma concentrations do not decline smoothly but may exhibit 'lumps' due to residual release from previous injection sites or multicompartment redistribution. Cigarette smoking has been found to be associated with a 2.33-fold increase in the clearance of fluphenazine decanoate. In 3 different studies, fluphenazine has been proposed to have a therapeutic range from less than 0.15 to 0.5 ng/ml with an upper therapeutic range of 4.0 ng/ml. Plasma concentrations following the decanoate injection are generally lower than, but clinically equivalent to, those attained with the oral form of the drug. Haloperidol decanoate plasma concentrations peak on the seventh day following injection although, in some patients, this peak may occur on the first day.(ABSTRACT TRUNCATED AT 400 WORDS)