Assessment of algorithms for predicting drug-drug interactions via inhibition mechanisms: Comparison of dynamic and static models

School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Oxford Road, Manchester, UK.
British Journal of Clinical Pharmacology (Impact Factor: 3.88). 01/2011; 71(1):72-87. DOI: 10.1111/j.1365-2125.2010.03799.x
Source: PubMed


• The prediction of drug–drug interactions (DDIs) from in vitro data usually utilizes an average dosing interval estimate of inhibitor concentration in an equation-based static model.
• Simcyp®, a population-based ADME simulator, is becoming widely used for the prediction of DDIs and has the ability to incorporate the time-course of inhibitor concentration and hence generate a temporal profile of the inhibition process within a dynamic model.
• Prediction of DDIs for 35 clinical studies incorporating a representative range of drug–drug interactions, with multiple studies across different inhibitors and victim drugs.
• Assessment of whether the inclusion of the time course of inhibition in the dynamic model improves prediction in comparison with the static model.
• Investigation of the impact of different inhibitor and victim drug parameters on DDI prediction accuracy including dosing time and the inclusion of active metabolites. Assessment of ability of the dynamic model to predict inter-individual variability in the DDI magnitude.
AIMS Static and dynamic models (incorporating the time course of the inhibitor) were assessed for their ability to predict drug–drug interactions (DDIs) using a population-based ADME simulator (Simcyp®V8). The impact of active metabolites, dosing time and the ability to predict inter-individual variability in DDI magnitude were investigated using the dynamic model.
METHODS Thirty-five in vivo DDIs involving azole inhibitors and benzodiazepines were predicted using the static and dynamic model; both models were employed within Simcyp for consistency in parameters. Simulations comprised of 10 trials with matching population demographics and dosage regimen to the in vivo studies. Predictive utility of the static and dynamic model was assessed relative to the inhibitor or victim drug investigated.
RESULTS Use of the dynamic and static models resulted in comparable prediction success, with 71 and 77% of DDIs predicted within two-fold, respectively. Over 40% of strong DDIs (>five-fold AUC increase) were under-predicted by both models. Incorporation of the itraconazole metabolite into the dynamic model resulted in increased prediction accuracy of strong DDIs (80% within two-fold). Bias and imprecision in prediction of triazolam DDIs were higher in comparison with midazolam and alprazolam; >50% of triazolam DDIs were under-predicted regardless of the model used. Predicted inter-individual variability in the AUC ratio (coefficient of variation of 45%) was consistent with the observed variability (50%).
CONCLUSIONS High prediction accuracy was observed using both the Simcyp dynamic and static models. The differences observed with the dose staggering and the incorporation of active metabolite highlight the importance of these variables in DDI prediction.

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    • "It is challenging to understand the mechanistic basis for these differences, but it may reflect pharmacodynamic differences in that inactivation and induction result in downstream enzyme changes to achieve an altered steady-state, whereas competitive inhibition is a more direct interaction, requiring inhibitory drug present at the site of interaction. Current PBPK software packages such as Simcyp provide flexibility in terms of applying unbound liver inlet or outlet concentrations, although the latter is standard and considered more predictive of clinical outcome (Jamei et al., 2009a; Guest et al., 2011). "
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    • "Wang (2010) compared the models for 54 interactions perpetrated by mechanism-based inhibitors of CYP3A4. Guest et al. (2011) used 35 DDIs to compare Simcyp V8's time-based model with its implementation of static models. All evaluations showed a comparable performance for the two models. "
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