A mathematical analysis of rebound in a target-mediated drug disposition model: II. With feedback.
We consider the possibility of free receptor (antigen/cytokine) levels rebounding to higher than the baseline level after the application of an antibody drug using a target-mediated drug disposition model. It is assumed that the receptor synthesis rate experiences homeostatic feedback from the receptor levels. It is shown for a very fast feedback response, that the occurrence of rebound is determined by the ratio of the elimination rates, in a very similar way as for no feedback. However, for a slow feedback response, there will always be rebound. This result is illustrated with an example involving the drug efalizumab for patients with psoriasis. It is shown that slow feedback can be a plausible explanation for the observed rebound in this example.
Department of Mathematics, University of Surrey, Guildford, GU2 7XH, UK.
Philip J
PJ
Aston
Department of Mathematics, University of Surrey, Guildford, GU2 7XH, UK. G.Derks@surrey.ac.uk.
Gianne
G
Derks
MedImmune, Pharmacokinetics/Dynamics and Bioanalysis, Cambridge, CB21 6GH, UK.
Balaji M
BM
Agoram
Leiden Academic Centre for Drug Research (LACDR), 2300 RA, Leiden, The Netherlands.|Certara QSP, Canterbury, CT2 7FG, UK.
Piet H
PH
van der Graaf
D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D016503:Drug Delivery Systems; D025461:Feedback, Physiological / Q000187:drug effects*; D006801:Humans; D008954:Models, Biological; D011565:Psoriasis / Q000188:drug therapy
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C472181:efalizumab
Antibody; Feedback; Pharmacodynamics; Pharmacokinetics; Receptor rebound; Systems pharmacology