The AAPS Journal

, Volume 17, Issue 2, pp 389–399 | Cite as

Quantitative Prediction of Human Pharmacokinetics for mAbs Exhibiting Target-Mediated Disposition

  • Aman P. Singh
  • Wojciech Krzyzanski
  • Steven W. Martin
  • Gregory Weber
  • Alison Betts
  • Alaa Ahmad
  • Anson Abraham
  • Anup Zutshi
  • John Lin
  • Pratap Singh
Research Article


Prediction of human pharmacokinetics (PK) can be challenging for monoclonal antibodies (mAbs) exhibiting target-mediated drug disposition (TMDD). In this study, we performed a quantitative analysis of a diverse set of six mAbs exhibiting TMDD to explore translational rules that can be utilized to predict human PK. A TMDD model with rapid-binding approximation was utilized to fit PK and PD (i.e., free and/or total target levels) data, and average absolute fold error (AAFE) was calculated for each model parameter. Based on the comparative analysis, translational rules were developed and applied to a test antibody not included in the original analysis. AAFE of less than two-fold was observed between monkey and human for baseline target levels (R 0), body-weight (BW) normalized central elimination rate (K el/BW−0.25) and central volume (V c/BW1.0). AAFE of less than three-fold was estimated for the binding affinity constant (K D). The other four parameters, i.e., complex turnover rate (K int), target turnover rate (K deg), central to peripheral distribution rate constant (K pt) and peripheral to central rate constant (K tp) were poorly correlated between monkey and human. The projected human PK of test antibody based on the translation rules was in good agreement with the observed nonlinear PK. In conclusion, we recommend a TMDD model-based prediction approach that integrates in vitro human biomeasures and in vivo preclinical data using translation rules developed in this study.


ADME of biologics human translation monoclonal antibodies PK/PD modeling TMDD 



We thank Dr. Donald E. Mager, University at Buffalo, for helping in the development and review of this manuscript. This work was partially supported by the stipend Aman P. Singh received as a Pharmacokinetic/Pharmacodynamic Summer Intern at PDM Department in Pfizer and partially supported by the NIH grant GM 57980

Supplementary material

12248_2014_9690_MOESM1_ESM.docx (36 kb)
Figure S1 mAb-1 (Efalizumab) pharmacokinetics and %CD11a receptor modulation in chimpanzees fitted with a rapid-binding approximation of TMDD model. (DOCX 35 kb)
12248_2014_9690_MOESM2_ESM.docx (102 kb)
Figure S2 mAb-1 (Efalizumab) pharmacokinetics and %CD11a receptor modulation in Psoriatic patients fitted with a rapid-binding approximation of a TMDD model. (DOCX 101 kb)
12248_2014_9690_MOESM3_ESM.docx (108 kb)
Figure S3 mAb-2 (TRX-1) pharmacokinetics, free and total % CD4+ cells modulation in healthy baboons fitted with a rapid-binding approximation of TMDD model. (DOCX 108 kb)
12248_2014_9690_MOESM4_ESM.docx (104 kb)
Figure S4 mAb-2 (TRX-1) pharmacokinetics, free and total % CD4+ cells modulation in healthy volunteers in phase 1 clinical trial fitted with a rapid-binding approximation of TMDD model. (DOCX 104 kb)
12248_2014_9690_MOESM5_ESM.docx (60 kb)
Figure S5 mAb-3 (MTRX-1) pharmacokinetics, free and total %CD4+ cells modulation in baboons fitted with a rapid-binding approximation of TMDD model. (DOCX 60 kb)
12248_2014_9690_MOESM6_ESM.docx (67 kb)
Figure S6 mAb-3 (MTRX-1) pharmacokinetics, free and total %CD4+ cells modulation fitted with a rapid-binding approximation of TMDD model. (DOCX 67 kb)
12248_2014_9690_MOESM7_ESM.docx (353 kb)
Figure S7 mAb-4 pharmacokinetics in cynomolgus monkeys and healthy volunteers in phase 1 trial fitted with a rapid-binding approximation of a TMDD model. (DOCX 353 kb)
12248_2014_9690_MOESM8_ESM.docx (163 kb)
Figure S8 mAb-5 pharmacokinetics in cynomolgus monkeys and in humans fitted with a rapid-binding approximation of a TMDD model. (DOCX 163 kb)
12248_2014_9690_MOESM9_ESM.docx (51 kb)
Figure S9 mAb-6 pharmacokinetics and total %target modulation in cynomolgus monkeys fitted with a rapid-binding approximation of TMDD model. (DOCX 50 kb)
12248_2014_9690_MOESM10_ESM.docx (52 kb)
Figure S10 mAb-6 pharmacokinetics and total %target modulation in healthy volunteers in a phase-1 trial fitted with a rapid-binding approximation of TMDD model. (DOCX 52 kb)
12248_2014_9690_MOESM11_ESM.docx (104 kb)
Figure S11 TMDD model based predictions for the test drug (mAb-7) PK in a phase-1 clinical trial in healthy volunteers. Note that most of the PK data (except for one subject) for 3 mg SC dose was below the limit of quantification of the assay and could not be presented in Figure 6. Consistent with these findings, model predictions for 3mg SC group were below LLOQ. (DOCX 103 kb)
12248_2014_9690_MOESM12_ESM.docx (106 kb)
Figure S12 Vmax/Km model based predictions for the test drug (mAb-7) PK in a phase-1 clinical trial in healthy volunteers. (DOCX 105 kb)
12248_2014_9690_MOESM13_ESM.docx (218 kb)
Figure S13 Comparative performance of translation rule based predictions vs. empirical (V max/K m) approach. Predicted AUC (A) and Cmax (B) at each dose (3-120mg SC) are shown for the two approaches and compared against the observed data. Solid diagonal line represents perfect agreement. (DOCX 217 kb)


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Copyright information

© American Association of Pharmaceutical Scientists 2014

Authors and Affiliations

  • Aman P. Singh
    • 1
  • Wojciech Krzyzanski
    • 1
  • Steven W. Martin
    • 2
  • Gregory Weber
    • 3
  • Alison Betts
    • 3
  • Alaa Ahmad
    • 4
  • Anson Abraham
    • 3
  • Anup Zutshi
    • 3
  • John Lin
    • 5
  • Pratap Singh
    • 3
    • 6
  1. 1.Department of Pharmaceutical SciencesUniversity at BuffaloBuffaloUSA
  2. 2.Global Clinical Pharmacology, Pfizer, IncCambridgeUSA
  3. 3.Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer IncCambridgeUSA
  4. 4.BioTx Clinical Research, Pfizer, IncCambridgeUSA
  5. 5.Rinat Experimental MedicineSan FranciscoUSA
  6. 6.CambridgeUSA

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