Using Modeling & Simulation Expertise on Quizartinib & Pimavanserin Exposure

Division: Cognigen

Two recent reports showcase modeling and simulation analyses performed by Cognigen; first in the Journal of Clinical Pharmacology (Kang et al., 2020, 60(12):1629-41); and the second, a poster presented at the American College of Neuropsychopharmacology (ACNP) 59th Annual Meeting (virtually) in December.

The first publication describes the evaluation of population pharmacokinetics of quizartinib and its active metabolite (AC866) using data from healthy subjects and patients with acute myeloid leukemia (AML). Quizartinib is an oral, once-daily, highly potent, and selective type II FLT3 inhibitor that has shown high clinical activity levels in patients with FLT3-ITD-positive relapsed/refractory AML. Assessment of concomitant use of drugs known to strongly inhibit cytochrome P450 (CYP) 3A on quizartinib exposures was of interest since quizartinib and AC866 are metabolized via the CYP3A pathway, and quizartinib concentration is highly correlated with QTc prolongation. Evaluation of patient-level covariates and subsequent simulations based on the population pharmacokinetic model demonstrated a significant increase in quizartinib exposure with concomitant use of strong CYP3A inhibitors. These results supported the recommendation of a quizartinib dose reduction when patients are given potent CYP3A inhibitors concomitantly in the clinical setting.

In our second contribution, the poster evaluated the relationship between pimavanserin exposure and psychosis relapse in patients with dementia-related psychosis in an exposure-response analysis described at CTAD. Pimavanserin, an atypical antipsychotic, is being investigated to treat hallucinations and delusions associated with dementia-related psychosis. Exposure-response analysis of pimavanserin efficacy was performed using patient data from the Phase 3 HARMONY study’s double-blind period. Pimavanserin was predicted to reduce the risk of relapse by 62% at the median area under the curve (AUC) for a 34 mg dose compared to placebo. In addition, Cox proportional hazards models showed a significant relationship between higher pimavanserin exposure and a greater probability of remaining relapse-free.

These publications highlight Cognigen’s pharmacometrics and clinical pharmacology expertise and our contributions to our clients’ drug development programs. For more information on how we can help move your program forward, contact our scientists at or give us a call at       (716) 633-3463.


[Correction: Beth Ludwig’s LinkedIn profile was incorrectly linked, please contact her on LinkedIn here.]