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The models provided have been collated from published examples which authors have shared in our Published Model Collection or developed as part of various global health projects in our Global Health Collection. This search facility searches both model collections simultaneously.

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Found 9 Matches

Brand Name(s) include: Jasoprim, Malirid, Neo-Quipenyl, Pimaquin, Pmq, Primachina, Primacin, Primaquina, Primaquine, Primaquine diphosphate, Primaquine Phosphate, and Remaquin

Disease: Malaria, Plasmodium vivax, Plasmodium ovale

Drug Class: Antimalarial

Related Files: Carboxyprimaquine (metabolite)

Date Updated: March 2022

 The model at-a-glance

Absorption Model

  • First-Order

Volume of Distribution 

  • Full PBPK (Method 2)

Routes of Elimination

  • 89% MAO (entered using ‘user-UGT’ as a surrogate in the Simulator), 11% CYP2D6

Perpetrator DDI

  • CYP1A2 Inhibitor (in vitro)

Validation

  •  6 studies with single (15 to 45 mg) and multiple (15 mg QD) dosing. 100% of Cmax and AUC values within 1.5-fold.
  • No clinical DDI studies to verify contribution of metabolic routes

Limitations

  •  The active metabolites of primaquine have not characterized due to their instability. Therefore, a PBPK model for active metabolites cannot be developed in their own right.
  • Qualitative data suggests a role of P-gp, however, Jmax and Km values have not been measured.
  • There is evidence of enantiomer specific metabolism for primaquine which has not been considered in the current model.

Updates in Version 19

  • Updated in vitro protein and blood binding data and subsequent back calculation of CLint (retrograde approach)
    •  fu: 0.19 -> 0.26
    • B:P: 1 -> 0.82
  • Converted from minimal PBPK model to full PBPK model

 

Chlorpromazine

Brand Name(s) include: Thorazine, Largactil, Ormazine

Indication: Schizophrenia, manic-depression

Drug Class: Conventional anitpsychotic

Date Updated: March 2024

The model at-a-glance

  Absorption Model

  • First-Order, fa and ka predicted by Caco-2 data

  Volume of Distribution

  • Minimal (optimized to IV data)

  Route of Elimination

  • fmCYP3A4 = 80, fmCYP2D6 = 20

  Perpetrator DDI

  • Inhibition of CYP2D6

  Validation

  • Model performance was verified in healthy volunteers and psychiatric patients. Two clinical studies with IV administration (7 to 10 mg) and ten clinical studies with oral administration (25 to 200 mg) were used for model verification. Simulations for eight of eleven clinical studies with a reported AUC were within 2-fold of the observed value.
  • The fmCYP1A2 was verified through simulations of chlorpromazine in smokers and non-smokers. The fmCYP2D6­ was verified through simulations of chlorpromazine coadministered with and without quinidine.

  Limitations

  • Model was developed using 10 mg IV and 100 mg PO. Use of 7-10 mg IV dosing and oral doses of 100-200 mg were verified, but predictions of oral doses <100 mg PO are overestimated.
  • Model does not include P-gp efflux.
  • Model is not verified for use in perpetrator DDI simulations with CYP2D6 substrates.

 

Brand Name: Invirase (hard gel); Fortovase (soft gel)

Disease: HIV

Drug Class: protease inhibitor

Version: 21

Date Updated: March 2024

The model at-a-glance

 Absorption Model

First order (different absorption parameters for each formulation)

 Volume of Distribution Details

Minimal PBPK with Vsac and Q (Method 2)

 Route of Elimination

  • CYP3A4 = 95%; Additional HLM = 5%

 Perpetrator DDI

  • CYP3A4 Mechanism Based Inhibition

 Validation

The exposure of 1000mg BID saquinavir with 100 mg BID ritonavir regimen for hard gel were reasonably well recovered (3/3 within 2-fold). With the exception of the 1000 mg BID saquinavir with 100 mg BID ritonavir regimen for soft gel, the exposures of ritonavir-boosted regimens were well recovered (4/5 within 1.5-fold).

Ten clinical DDI studies where saquinavir (soft gel) was administered with either ritonavir, cimetidine, ketoconazole, rifampin, erythromycin, or rifabutin were used to verify the PBPK model of saquinavir as a victim. In comparison of predicted vs. observed AUC, 80% of the studies were within 2-fold.

Two clinical DDI studies where saquinavir (hard gel) was administered with either ritonavir or nelfinavir were used to verify the PBPK model of saquinavir (hard gel) as a victim. In comparison of predicted vs. observed AUC, 50% of the studies were within 2-fold.

Three clinical DDI studies where saquinavir was administered with either midazolam or rifabutin were used to verify the PBPK model of rifabutin (soft gel) as a perpetrator. In comparison of predicted vs. observed AUC, 100% of the studies were within 2-fold.

 Limitations

  • The variability within studies has presented a significant challenge to developing a single model to recover all data.
Eltrombopag_RES_V21R1_Simcyp_20230615

Prepared: June 2023 The RES-Eltrombopag_V21 model has been developed primarily as an inhibitor of hepatic OATP1B1 and OATP1B3, and intestinal BCRP using the New GI physiology in Simcyp V21 with altered GI tract population inputs that became default in V22. The file is verified as tablet in the fasted state as that formulation was used in the Rosuvastatin DDI (Allred et al., 2011). The PK for Eltrombopag was evaluated at 25mg, 50mg and 75mg SD; 50mg QD, 100mg QD, 150mg QD, and 200mg QD.  Note, the Rosuvastatin DDI with 75mg QD was used to fit the BCRP component in Rosuvastatin V21 file using the New GI physiology. The BCRP component of Rosuvastatin was then verified with other BCRP-Inhibitors available on the members area (as specified in the attached document) or within the Simcyp Simulator. Allred, A. J., C. J. Bowen, J. W. Park, B. Peng, D. D. Williams, M. B. Wire, and E. Lee. 2011. “Eltrombopag Increases Plasma Rosuvastatin Exposure in Healthy Volunteers.” Journal Article. Br J Clin Pharmacol 72 (2): 321–29.

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