Exploring low clozapine C/D ratios, inverted clozapine-norclozapine ratios and undetectable concentrations as measures of non-adherence in clozapine patients: A literature review and a case series of 17 patients from 3 studies.

Abstract

Background: Up to 1/3 to 1/2 of outpatients prescribed clozapine may be partially or fully non-adherent, based on therapeutic drug monitoring (TDM). Three indices for measuring partial or full non-adherence are proposed: 1) a clozapine concentration/dose (C/D) ratio which drops to half or more of what is expected in the patient; 2) a clozapine/norclozapine ratio that becomes inverted; and 3) a clozapine concentration that becomes non-detectable. Methods: These 3 proposed indices are based on reviews of the literature and 3 samples which provided 15 cases of possible non-adherence. The three samples include: 1) an inpatient study in a Chinese hospital, 2) an inpatient randomized clinical trial in a United States hospital, and 3) and an outpatient study in Uruguay. Results: Partial non-adherence in average patients can be suspected when the clozapine C/D ratio is less than half the ratio corresponding to the patient’s specific ancestry group and sex-smoking subgroup. Knowing the minimum therapeutic dose of the patient based on repeated TDM makes it much easier to establish non-adherence. Inverted clozapine/norclozapine ratios in the absence of alternative explanations may be a sign of non-adherence. By using half-lives, the chronology of the 3 indices of non-adherence was modeled in two patients: 1) the clozapine C/D ratio dropped to half or more of what is expected from the patient (around day 2); 2) the clozapine/norclozapine ratio becomes inverted (around day 3); and 3) the clozapine concentration became undetectable by the laboratory (around days 9-11). Conclusion: Future prospective studies should explore these proposed indices. Keywords: clozapine/blood; clozapine/metabolism; clozapine/therapeutic use; drug interaction; medication adherence; schizophrenia