APPLYING ANTIPSYCHOTIC PHARMACOKINETICS TO BEST …

[Pages:1]APPLYING ANTIPSYCHOTIC PHARMACOKINETICS TO BEST DOSING PRACTICES: DEPOT MEDICATIONS

Objectives

? Review the kinetic parameters of depot antipsychotics ? Review loading strategies for those depot medications which can be loaded ? Describe how knowledge of plasma antipsychotic data can inform appropriate use of depot medications

The Value of Antipsychotic Plasma Levels

Concepts

a. Plasma levels and not dose are the best predictors of antipsychotic response

? P450 genetics of patients are usually unknown ? Some patients are nonadherent ? Many patients receive concurrent medications that are P450 or PGP

inhibitors or inducers

b. Clinical studies provide one source of plasma level/response relationships c. For newer antipsychotics, PET scans provide data on plasma level thresholds to achieve 80% D2 blockade

D2 Antagonist: Receptor Occupancy Sweet Spot: 60%-80%

Kapur S and Seeman P. Does fast dissociation from the dopamine D2 receptor explain the action of atypical antipsychotics? - A New Hypothesis. Am J Psych 2001;158(3):360-369.

D2 Partial Antagonist: Receptor Occupancy Sweet Spot: 85%-100%

Mamo D, et al. Differential Effects of Aripiprazole on D2, 5-HT2, and 5-HT1A Receptor Occupancy in Patients With Schizophrenia: A Triple Tracer PET Study. Am J Psych 2007;164(9): 1411-1417.

Response and Tolerability Threshold Levels

Data From Clinical Studies

Data From Imaging Studies

Response

Tolerability

Level associated with Level associated with

Threshold (ng/ml) threshold (ng/ml) 60% D2 occupancy

80% D2 occupancy

Haloperidol Fluphenazine Risperidone + 9-OH Risperidone Olanzapine Clozapine

3-5 0.8 ? 1.0

?? 23.2 350

18 ? 20 2.7 ? 2.8

?? 176 ? 800-1000

1.2 ?? ~ 17 ng/ml ~ 20 ng/ml ??

2.0 ?? 45-47 70-78 ??

Meyer JM. A rational approach to employing high plasma levels of antipsychotics for violence associated with schizophrenia: case vignettes. CNS Spectrums 2014;19(5):432-38.

Levels and Adherence

? Clinicians grossly underestimate medication nonadherence. Using 70% as the threshold for medication adherence, 57% of chronic schizophrenia patients are nonadherent using MEMS cap technology, patient self-report is 5%, and physician estimate 7%.1

? Many patients characterized as treatment resistant have subtherapeutic plasma levels.2

"The purpose of the present study was to determine the extent of subtherapeutic antipsychotic plasma levels in a group of patients clinically identified as treatment-resistant. Antipsychotic plasma levels were measured in 36 patients identified as having treatmentresistant schizophrenia by their treating clinicians. Sixteen (44%) patients showed either undetectable (19%) or subtherapeutic levels (25%), and 20 (56%) patients had levels in the therapeutic range."

1. Byerly M, et al. Psychiatric Services 2007;58:844-847. 2. McCutcheon R., et al. Journal of Psychopharmacology 2015;29(8) 892-897.

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