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. 2013 Oct;40(5):597-607.
doi: 10.1007/s10928-013-9332-2. Epub 2013 Aug 31.

Second-generation minimal physiologically-based pharmacokinetic model for monoclonal antibodies

Yanguang Cao  1 , Joseph P Balthasar, William J Jusko
Affiliations

Second-generation minimal physiologically-based pharmacokinetic model for monoclonal antibodies

Yanguang Cao et al. J Pharmacokinet Pharmacodyn. 2013 Oct.

Abstract

Minimal physiologically-based pharmacokinetic (mPBPK) models provide a sensible modeling approach when fitting only plasma (or blood) data yielding physiologically-relevant PK parameters that may provide more practical value than parameters of mammillary models. We propose a second-generation mPBPK model specifically for monoclonal antibodies (mAb) by including (lumping) several essential components of mAb PK used in full PBPK models. These components include convection as the primary mechanism of antibody movement from plasma into tissues and return to plasma with interstitial fluid as the major extravascular distribution space. The model divides tissue spaces into two groups according to their vascular endothelial structure, leaky and tight, which consequently allows discernment of two types and general sites of distribution. This mPBPK model was applied to two mAbs in mice and ten mAbs with linear kinetics in humans. The model captured their plasma PK profiles well with predictions of concentrations in interstitial fluid for two types of tissues. Predictions of tissue concentrations for mAb 7E3 and 8C2 were consistent with actual measurements in mice, indicating the feasibility of this model in assessing extravascular distribution in the two categories of tissues. The vascular reflection coefficients (σ₁) of tight tissues (V(tight)) ranged 0.883-0.987 and coefficients (σ₂) for leaky tissues (V(leaky)) ranged 0.311 to 0.837. The plasma clearance (CL(p)) varied among the mAbs in humans from 0.0054 to 0.03 L/h. In addition, applying this model generates parameters for mAb transcapillary escape rates and assesses major sites of elimination. Four of ten mAbs exhibited better fitting statistics premised on elimination from interstitial fluid than from plasma. This approach allows comparisons of mAb PK when only plasma data are available, provides more realistic parameters and predictions than mammillary models, and may provide an intermediate step towards utilizing full PBPK models for mAbs.

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Figures

Figure 1
Figure 1
Second-generation minimal-PBPK model for monoclonal antibody pharmacokinetics Symbols and physiological restrictions are defined with Eq (1–7) Clearance is applied either to plasma (Model A) or to interstitial fluid (Model B). The plasma compartment in the left box represents the venous plasma as in full PBPK models, but is not applied in the present model.
Figure 2
Figure 2
A. Plasma and total tissue profiles of 7E3 in mice; B. Predicted interstitial fluid (Vleaky and Vtight) profiles based on estimates using only plasma data. Symbols are observations and curves are model fittings or predictions.
Figure 3
Figure 3
Pharmacokinetic profiles of 8C2 in mice. Symbols are observations and curves are model fittings or predictions.
Figure 4
Figure 4
Simulated tissue and interstitial fluid (Vleaky and Vtight) profiles of 8C2 in mice. The simulated tissue and interstitial fluid concentrations were for a dose of 8 mg/kg. Symbols are observations and curves are model fittings or predictions.
Figure 5
Figure 5
Pharmacokinetic profiles of 10 monoclonal antibodies in human subjects. Symbols are observations and curves are model fittings or predictions.
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