Assessing the risk of combination drug treatment in patients without clinical trials

In 2021, the United States FDA approved Lybalvi®, a combination therapy consisting of the antipsychotic olanzapine and samidorphan, an opioid receptor antagonist. Lybalvi, developed by Alkermes, treats schizophrenia and bipolar I disorder. The Alkermes team needed to determine drug-drug interaction (DDI) risk in patients and understand how hepatic impairment affects pharmacokinetics (PK).

Patients with schizophrenia tend to have comorbidities, requiring additional medicines and exposing them to higher DDI risks. Also, there is a high prevalence of smoking among this population, which alters plasma drug levels and can affect the efficacy or safety of psychiatric medications. Performing clinical studies on this patient group is not always practical or ethical.

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Using physiologically-based pharmacokinetic modeling (PBPK) modeling to evaluate DDI risk in adults

PBPK models have become valuable tools in the drug development process. They are mathematical models that simulate the human body’s response to drugs and help to assess the impact of different variables on drug exposure and response. Certara’s Simcyp™ Simulator was used to develop a PBPK model, which was validated with clinical data to evaluate the DDI impact of CYP1A2 and CYP3A4, the major enzymes involved in the metabolism of OLZ/ SAM. The Simcyp Simulator is a population-based simulator that streamlines drug development through the modeling and simulation of pharmacokinetics and pharmacodynamics (PD) in virtual populations. PBPK modeling was used to determine DDIs between olanzapine and samidorphan when administered separately and in combination. These models helped the Alkermes team understand how the olanzapine/samidorphan combination affects patients.3, 4

CYP3A4 inhibition was predicted to have a weak effect on samidorphan exposure and a negligible effect on olanzapine exposure. The model predicted CYP3A4 induction as reducing both samidorphan and olanzapine exposure and CYP1A2 inhibition or induction as increasing or decreasing, respectively, olanzapine exposure only. The model showed no DDIs between olanzapine and samidorphan when administered in combination.

Modeling can predict the role that hepatic function has on olanzapine/samidorphan

Hepatic metabolism plays a major role in both olanzapine and samidorphan clearance. Impaired hepatic function could affect the PK of both compounds. To assess this risk, the Simcyp PBPK model was refined to predict changes in olanzapine and samidorphan PK after multiple once-daily doses of OLZ/SAM in subjects with mild, moderate, and severe hepatic impairment.5

To evaluate the PK changes in subjects with moderate hepatic impairment, model parameters such as absorption rate constant and fraction unbound to plasma protein were modified. PBPK model outputs were compared with observed data from PK studies in healthy subjects given OLZ/ SAM.

The PBPK modeling indicated that mild hepatic impairment would have minimal impact on steady-state exposures of olanzapine and samidorphan, and moderate to severe hepatic impairment would result in up to 1.6-fold and 2.3-fold increases in total exposure (area under the curve; AUC) of olanzapine and samidorphan, respectively. PBPK modeling allowed for predicting untested clinical scenarios of varying degrees of hepatic impairment in lieu of conducting additional clinical studies.

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The importance of PBPK modeling

PBPK modeling is becoming more widely accepted by regulatory agencies around the world. This cost-effective, powerful tool can provide the evidence needed to determine DDI risks   without relying on clinical trials involving sensitive patient groups.

About Alkermes

Alkermes is a pharmaceutical company focused on developing innovative medicines to address the unmet needs of people living with serious mental illness, addiction, and cancer. Founded in 1987, Alkermes is headquartered in Dublin, Ireland, and has manufacturing and R&D facilities in the United States.


  1. World Health Organization. Schizophrenia.
    Published 2022. Accessed September 10, 2022.
  2. Komossa K, Rummel-Kluge C, Hunger H, Schmid F, Schwarz S, Duggan L, Kissling W, Leucht S. Olanzapine versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev. 2010 Mar 17;(3). Accessed on September 10, 2022.
  3. Certara. Simcyp Discovery Simulator. 2022. Accessed 10 September, 2022.
  4. Lei S, L, von Moltke, L, Rowland Yeo, K, Physiologically-Based Pharmacokinetic Modeling for Predicting Drug Interactions of a Combination of Olanzapine and Samidorphan, CPT Pharmacometrics Syst Pharmacol. 2020 Feb;9(2):106-114. Accessed on September 10, 2022.
  5. Sun L, Barter Z, von Moltke L, Rowland Yeo K. Using physiologically-based pharmacokinetic modeling for predicting the effects of hepatic impairment on the pharmacokinetics of olanzapine and samidorphan given as a combination tablet. CPT Pharmacometrics Syst Pharmacol. 2021 Sep;10(9):1071-1080. Accessed on September 10, 2022.
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