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Model-based assessment of dosing strategies in children for monoclonal antibodies exhibiting target-mediated drug disposition.

ABSTRACT: Body weight/body surface area-based and/or tiered fixed dosing strategies are widely utilized for monoclonal antibodies with linear clearance to scale adult clinical doses to children. However, there is limited knowledge on whether or not body weight-based dosing strategies also yield comparable dose-concentration-response relationships in adults and children for monoclonal antibodies that exhibit target-mediated drug disposition. Our findings indicate that it is important to interpret pharmacokinetics information in a pharmacokinetics/pharmacodynamics context as similar systemic drug exposure in adults and children may not be reflective of the corresponding target occupancy. They further indicate that BW-based dosing is superior to fixed dosing for the same target concentration, whereas the opposite holds true for the same target amount in adults and children. Michaelis-Menten approximations yielded similar profiles compared to the full target-mediated drug disposition model for all simulation scenarios and may be used to guide the selection of appropriate dosing regimens in children.

SUBMITTER: Zheng S

PROVIDER: S-EPMC4474168 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Model-based assessment of dosing strategies in children for monoclonal antibodies exhibiting target-mediated drug disposition.

Zheng S S Gaitonde P P Andrew M A MA Gibbs M A MA Lesko L J LJ Schmidt S S

CPT: pharmacometrics & systems pharmacology 20141001

Body weight/body surface area-based and/or tiered fixed dosing strategies are widely utilized for monoclonal antibodies with linear clearance to scale adult clinical doses to children. However, there is limited knowledge on whether or not body weight-based dosing strategies also yield comparable dose-concentration-response relationships in adults and children for monoclonal antibodies that exhibit target-mediated drug disposition. Our findings indicate that it is important to interpret pharmacok ...[more]

PMID: 25271939

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Project description:Target-mediated drug disposition (TMDD) usually accounts for nonlinear pharmacokinetics (PK) of drugs whose distribution and/or clearance are affected by their targets owing to high affinity and limited capacity. TMDD is frequently reported for monoclonal antibodies (mAb) for such reason. Minimal physiologically-based pharmacokinetic models (mPBPK), which accommodate the unique PK behaviors of mAb, provide a general approach for analyzing mAbs PK and predicting mAb interstitial concentrations in two groups of tissues. This study assessed the feasibility of incorporating TMDD into mPBPK models to consider target-binding in either plasma (cTMDD) or interstitial fluid (ISF) (pTMDD). The dose-related signature profiles of the pTMDD model reveal a parallel early decay phase, in contrast with the cTMDD model that exhibits a faster initial decline for low doses. The parallel early phase in the pTMDD model is associated with the slow perivascular extravasation of mAb, which restricts the initial decline regardless of interstitial target-mediated elimination. The cTMDD and pTMDD models both preserve the long terminal phase that is typically perceived in conventional two-compartment (2CM) and TMDD models. Having TMDD in ISF impacts the typical relationships between plasma concentrations and receptor occupancy, and between saturation of apparent nonlinear clearance and saturation of receptors. The vascular reflection coefficient (? v ) was found to affect receptor occupancy in ISF. In the cTMDD model, saturation of nonlinear clearance is equivalent to saturation of receptors. However, in the pTMDD model, they are no longer equal and all parameters pertaining to receptors or receptor binding (R total , K D , K ss , k int ) shifts such relationships. Different TMDD models were utilized in analyzing PK for seven mAbs from digitized literature data. When the target is in plasma, the cTMDD model performed similarly to the 2CM and TMDD models, but with one less system parameter. When the target exists in ISF, the pTMDD functioned well in analyzing only plasma data to reflect interstitial target binding properties. Assigning TMDD consistent with target-expressing tissues is important to obtain reliable characterizations of receptors and receptor binding. The mPBPK model exhibits excellent feasibility in integrating TMDD not only in plasma but also in ISF.

Project description:Most monoclonal antibodies in oncology are administered in body-size-based dosing schedules. This is believed to correct for variability in both drug distribution and elimination between patients. However, monoclonal antibodies typically distribute to the blood plasma and extracellular fluids only, which increase less than proportionally with the increase in body weight. Elimination takes place via proteolytic catabolism, a nonspecific immunoglobulin G elimination pathway, and intracellular degradation after binding to the target. The latter is the primary route of elimination and is related to target expression levels rather than body size. Taken together, the minor effects of body size on distribution and elimination of monoclonal antibodies and their usually wide therapeutic window do not support body-size-based dosing. We evaluated effects of body weight on volume of distribution and clearance of monoclonal antibodies in oncology and show that a fixed dose for most of these drugs is justified based on pharmacokinetics. A survey of the savings after fixed dosing of monoclonal antibodies at our hospital showed that fixed dosing can reduce costs of health care, especially when pooling of preparations is not possible (which is often the case in smaller hospitals). In conclusion, based on pharmacokinetic parameters of monoclonal antibodies, there is a rationale for fixed dosing of these drugs in oncology. Therefore, we believe that fixed dosing is justified and can improve efficiency of the compounding. Moreover, drug spillage can be reduced and medication errors may become less likely. IMPLICATIONS FOR PRACTICE:The currently available knowledge of elimination of monoclonal antibodies combined with the publicly available data from clinical trials and extensive population pharmacokinetic (PopPK) modeling justifies fixed dosing. Interpatient variation in exposure is comparable after body weight and fixed dosing and most monoclonal antibodies show relatively flat dose-response relationships. For monoclonal antibodies, this results in wide therapeutic windows and no reduced clinical efficacy after fixed dosing. Therefore, we believe that fixed dosing at a well-selected dose can increase medication safety and help in reduction of costs of health care without the loss of efficacy or safety margins.

Dataset Information

Model-based assessment of dosing strategies in children for monoclonal antibodies exhibiting target-mediated drug disposition.

Publications

Model-based assessment of dosing strategies in children for monoclonal antibodies exhibiting target-mediated drug disposition.

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