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

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Abstract

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.

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ACKNOWLEDGMENTS

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

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, University at Buffalo, Kapoor Hall, Buffalo, New York, USA

    Aman P. Singh & Wojciech Krzyzanski

  2. Global Clinical Pharmacology, Pfizer, Inc, Cambridge, Massachusetts, USA

    Steven W. Martin

  3. Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc, Cambridge, Massachusetts, USA

    Gregory Weber, Alison Betts, Anson Abraham, Anup Zutshi & Pratap Singh

  4. BioTx Clinical Research, Pfizer, Inc, Cambridge, Massachusetts, USA

    Alaa Ahmad

  5. Rinat Experimental Medicine, San Francisco, California, USA

    John Lin

  6. 700 Main St, Cambridge, Massachusetts, 02139, USA

    Pratap Singh

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  1. Aman P. Singh
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Correspondence to Pratap Singh.

Electronic supplementary material

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Figure S1

mAb-1 (Efalizumab) pharmacokinetics and %CD11a receptor modulation in chimpanzees fitted with a rapid-binding approximation of TMDD model. (DOCX 35 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)

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)

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)

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)

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)

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)

Figure S8

mAb-5 pharmacokinetics in cynomolgus monkeys and in humans fitted with a rapid-binding approximation of a TMDD model. (DOCX 163 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)

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)

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)

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)

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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Singh, A.P., Krzyzanski, W., Martin, S.W. et al. Quantitative Prediction of Human Pharmacokinetics for mAbs Exhibiting Target-Mediated Disposition. AAPS J 17, 389–399 (2015). https://doi.org/10.1208/s12248-014-9690-8

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  • DOI: https://doi.org/10.1208/s12248-014-9690-8

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