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Concentration-QTc Modeling of Ozanimod's Major Active Metabolites in Adult Healthy Subjects.


ABSTRACT: Ozanimod, approved by regulatory agencies in multiple countries for the treatment of adults with relapsing multiple sclerosis, is a sphingosine 1-phosphate (S1P) receptor modulator, which binds with high affinity selectively to S1P receptor subtypes 1 and 5. The relationships between plasma concentrations of ozanimod and its major active metabolites, CC112273 and CC1084037, and the QTc interval (C-QTc) from a phase I multiple-dose study in healthy subjects were analyzed using nonlinear mixed effects modeling. QTc was modeled linearly as the sum of a sex-related fixed effect, baseline, and concentration-related random effects that incorporated interindividual and residual variability. Common linear, power, and maximum effect (Emax ) functions were assessed for characterizing the relationship of QTc with concentrations. Model goodness-of-fit and performance were evaluated by standard diagnostic tools, including a visual predictive check. The placebo-corrected change from baseline in QTc (??QTc) was estimated based on the developed C-QTc model using a nonparametric bootstrapping approach. QTc was better derived using a study-specific population formula (QTcP). Among the investigated functions, an Emax function most adequately described the relationship of QTcP with concentrations. Separate models for individual analytes characterized the C-QTcP relationship better than combined analytes models. Attributing QT prolongation independently to CC1084037 or CC112273, the upper bound of the 95% confidence interval of the predicted ??QTcP was ~ 4 msec at the plateau of the Emax curves. Therefore, ??QTcP is predicted to remain below 10 msec at the supratherapeutic concentrations of the major active metabolites.

SUBMITTER: Briggs E 

PROVIDER: S-EPMC7894403 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Concentration-QTc Modeling of Ozanimod's Major Active Metabolites in Adult Healthy Subjects.

Briggs Emily E   Chapel Sunny S   Zhang Peijin P   Palmisano Maria M   Tran Jonathan Q JQ  

CPT: pharmacometrics & systems pharmacology 20210105 2


Ozanimod, approved by regulatory agencies in multiple countries for the treatment of adults with relapsing multiple sclerosis, is a sphingosine 1-phosphate (S1P) receptor modulator, which binds with high affinity selectively to S1P receptor subtypes 1 and 5. The relationships between plasma concentrations of ozanimod and its major active metabolites, CC112273 and CC1084037, and the QTc interval (C-QTc) from a phase I multiple-dose study in healthy subjects were analyzed using nonlinear mixed eff  ...[more]

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