Predicting the F(ab)-mediated effect of monoclonal antibodies in vivo by combining cell-level kinetic and pharmacokinetic modelling

Cell-level kinetic models for therapeutically relevant processes increasingly benefit the early stages of drug development. Later stages of the drug development processes, however, rely on pharmacokinetic compartment models while cell-level dynamics are typically neglected. We here present a systematic approach to integrate cell-level kinetic models and pharmacokinetic compartment models. Incorporating target dynamics into pharmacokinetic models is especially useful for the development of therapeutic antibodies because their effect and pharmacokinetics are inherently interdependent. The approach is illustrated by analysing the F(ab)-mediated inhibitory effect of therapeutic antibodies targeting the epidermal growth factor receptor. We build a multi-level model for anti-EGFR antibodies by combining a systems biology model with in vitro determined parameters and a pharmacokinetic model based on in vivo pharmacokinetic data. Using this model, we investigated in silico the impact of biochemical properties of anti-EGFR antibodies on their F(ab)-mediated inhibitory effect. The multi-level model suggests that the F(ab)-mediated inhibitory effect saturates with increasing drug-receptor affinity, thereby limiting the impact of increasing antibody affinity on improving the effect. This indicates that observed differences in the therapeutic effects of high affinity antibodies in the market and in clinical development may result mainly from Fc-mediated indirect mechanisms such as antibody-dependent cell cytotoxicity

Concordance of DSM-IV alcohol and drug use disorder criteria and diagnoses as measured by AUDADIS-ADR, CIDI and SCAN

This study was designed to examine the agreement of DSM-IV alcohol and drug use disorder diagnoses generated by three WHO/NIH diagnostic instruments, the AUDADIS-ADR, the CIDI, and the SCAN. This substudy, conducted in three countries, Greece; Luxembourg, and the United States: was parr of the larger joint project on diagnosis and classification of mental disorders and alcohol and drug-related problems, which was initiated to evaluate the cross-cultural applicability of the instruments and the criteria. Overall, concordance among the three assessments was good for alcohol and opiate dependence, fair to good for cocaine and sedative dependence, and low for amphetamine dependence. Cannabis dependence concordance was significantly more discrepant than any other substance. Agreement on abuse was low for all substances examined. In addition, the concordance of DSM-IV criteria for each substance was examined. Finally, reasons for discrepancies in responses among assessments were examined: based on discrepancy interview protocol methodology. Further investigation will help to refine these instruments in order to provide a more thorough understanding of alcohol and drug abuse diagnoses. (C) 1997 Elsevier Science Ireland Ltd