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Compound files from publication: Physiologically Based Pharmacokinetic Modeling for Predicting the Effect of Intrinsic and Extrinsic Factors on Darunavir or Lopinavir Exposure Coadministered With Ritonavir Wagner, C., Zhao, P., Arya, V., Mullick, C., Struble, K. and Au, S (2017). https://doi.org/10.1002/jcph.936 /PMID#: 28569994 The compound file is the final model used for simulations in combination with ritonavir (submitted to repository referencing the same article). Correction: Ritonavir's pKa 2 should be 2.6, reported in Supp. Table 1 was 2.8 https://accp1.onlinelibrary.wiley.com/doi/full/10.1002/jcph.936
Brand Name: Tivicay
Disease: HIV
Drug Class: HIV integrase inhibitor
Version: 21
Date Updated: March 2023
Absorption Model |
ADAM (precipitation with solution) |
Volume of Distribution Details |
Full PBPK (Method 3) |
Route of Elimination |
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Perpetrator DDI |
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Validation |
Model can recover positive food effect for single and multiple dose. The UGT1A1 fm was verified against UGT1A1 genotype study and with rifampin and atazanavir DDI studies. The fm of CYP3A4 was verified against nevirapine, rifabutin, rifampin, atazanavir, efavirenz, and carbamazepine. One clinical study in which dolutegravir was administered with metformin was used to verify the Ki of OCT2 and MATE. Nine clinical DDI studies where dolutegravir was administered with either nevirapine, rifampicin, rifabutin, ritonavir, atazanavir, efavirenz, and carbamazepine were used to verify the PBPK model. In comparison of predicted vs. observed AUC, 100% of the studies were 2-fold and 67% were within 1.25-fold. |
Limitations |
DDI with efavirenz and carbamazepine are underpredicted, likely because efavirenz and carbamazepine are inducers of UGT1A1 which is not considered in the current efavirenz and carbamazepine compound files. |
Brand Name(s) include: Prezista, Prezcobix, Rezolsta
Disease: HIV
Drug Class: Antiretroviral
Date of Review: 2020
Number of Models Reviewed: 2
Number of Models added to the Repository: 2
Publication – MODEL 1 |
Wagner et al., Physiologically-Based Pharmacokinetic Modeling for Predicting the Effect of Intrinsic and Extrinsic Factors on Darunavir or Lopinavir Exposure Co-administered with Ritonavir. J Clin Pharmacol. 2017 October ; 57(10): 1295–1304. (FDA model) |
Simcyp Version |
V13 |
Published Model Application |
Prediction of exposure in hepatic impairment |
Absorption Model |
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Volume of Distribution Details |
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Route of Elimination |
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Perpetrator DDI |
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Advantages and Limitations |
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Model Compound Files |
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Publication – MODEL 2 |
Colbers, A., Greupink, R., Litjens, C., Burger, D., & Russel, F. G. (2016). Physiologically Based Modelling of Darunavir/Ritonavir Pharmacokinetics During Pregnancy. Clinical pharmacokinetics, 55(3), 381–396. |
Simcyp Version |
V13 |
Published Model Application |
Prediction of exposure in pregnancy |
Absorption Model |
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Volume of Distribution Details |
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Route of Elimination |
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Perpetrator DDI |
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Advantages and Limitations |
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Model Compound Files |
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Brand Name: Edurant, Rekambys
Disease: HIV
Drug Class: non-nucleoside reverse transcriptase inhibitor
Version: 21
Date Updated: March 2024
Absorption Model |
First order |
Volume of Distribution Details |
Full PBPK (Method 3) |
Route of Elimination |
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Perpetrator DDI |
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Validation |
The refined model was able to recover clinically observed concentration-time profiles of rilpivirine following single and multiple dosing. Seven clinical DDI studies where rilpivirine was administered with either efavirenz, ketoconazole, rifampin, or rifabutin were used to verify the PBPK model of rilpivirine as a victim. In comparison of predicted vs. observed AUC, 85.7% of the studies were within 1.5-fold. Three clinical DDI studies where rilpivirine was administered with either sildenafil, ethinylestradiol, or midazolam were used to verify the PBPK model of rilpivirine as a perpetrator. In comparison of predicted vs. observed AUC, 100% of the studies were within 1.25-fold. |
Limitations |
The net in vivo effect of rilpivirine as either an inhibitor or an inducer of CYP3A appears to be negligible based on the available DDI studies |
14 |