Calculating occupancy when one does not have baseline: a comparison of different options

Area of Science:

• Neuroscience
• Pharmacology
• Psychiatry

Background:

• Dopamine D(2) receptor occupancy is crucial for antipsychotic drug efficacy.
• Estimating baseline D(2) receptor binding potential (BP) in schizophrenia patients is challenging due to ethical and practical limitations.
• Current methods using population means introduce bias and error into occupancy calculations.

Purpose of the Study:

• To develop and validate a novel method (Imax method) for estimating individual baseline D(2) receptor BP.
• To improve the reliability and accuracy of antipsychotic drug occupancy measurements in schizophrenia.
• To overcome limitations of the substitution method in patient populations.

Main Methods:

• Developed an inhibitory Emax (Imax) model to estimate individual baseline D(2) receptor BP based on plasma drug concentration.
• Validated the Imax method by comparing its results against actual occupancy and the traditional substitution method.
• Utilized data from two antipsychotic studies (YKP1358 and aripiprazole) for validation.

Main Results:

• The Imax method demonstrated higher intraclass correlation coefficients (ICCs) indicating better reliability than the substitution method in both studies.
• Variability in occupancy measurements was significantly lower with the Imax method compared to the substitution method.
• The Imax method achieved ICCs above 0.8 in the YKP1358 study, surpassing the substitution method.

Conclusions:

• The Imax method provides a more reliable and accurate estimation of dopamine D(2) receptor occupancy in antipsychotic drug studies.
• This method is particularly valuable for patient populations where baseline measurements are impractical or unethical.
• The Imax method enhances the precision of receptor occupancy studies in schizophrenia treatment.