Selection between Michaelis–Menten and target-mediated drug disposition pharmacokinetic models

Abstract

Target-mediated drug disposition (TMDD) models have been applied to describe the pharmacokinetics of drugs whose distribution and/or clearance are affected by its target due to high binding affinity and limited capacity. The Michaelis–Menten (M–M) model has also been frequently used to describe the pharmacokinetics of such drugs. The purpose of this study is to investigate conditions for equivalence between M–M and TMDD pharmacokinetic models and provide guidelines for selection between these two approaches. Theoretical derivations were used to determine conditions under which M–M and TMDD pharmacokinetic models are equivalent. Computer simulations and model fitting were conducted to demonstrate these conditions. Typical M–M and TMDD profiles were simulated based on literature data for an anti-CD4 monoclonal antibody (TRX1) and phenytoin administered intravenously. Both models were fitted to data and goodness of fit criteria were evaluated for model selection. A case study of recombinant human erythropoietin was conducted to qualify results. A rapid binding TMDD model is equivalent to the M–M model if total target density Rtot is constant, and RtotKD/(KD + C)2 ≪ 1 where KD represents the dissociation constant and C is the free drug concentration. Under these conditions, M–M parameters are defined as: Vmax = kintRtotVc and Km = KD where kint represents an internalization rate constant, and Vc is the volume of the central compartment. Rtot is constant if and only if kint = kdeg, where kdeg is a degradation rate constant. If the TMDD model predictions are not sensitive to kint or kdeg parameters, the condition of RtotKD/(KD + C)2 ≪ 1 alone can preserve the equivalence between rapid binding TMDD and M–M models. The model selection process for drugs that exhibit TMDD should involve a full mechanistic model as well as reduced models. The best model should adequately describe the data and have a minimal set of parameters estimated with acceptable precision.

Population pharmacokinetic and pharmacodynamic analysis of BIIB023, an anti‐TNF‐like weak inducer of apoptosis (anti‐TWEAK) monoclonal antibody

“…Similar pharmacokinetic properties were observed for BIIB023 in the previous phase 1 clinical study [14]. Whether the observed nonlinearity in clearance of BIIB023 is due to target-mediated drug disposition could not be confirmed due to insufficient information on the pharmacokinetics of soluble TWEAK and soluble TWEAK: BIIB023 complex [29,30]. The BIIB023 population pharmacokinetic results reported here are consistent with results of the noncompartmental analysis of subjects in study 211HV102 and suggest that no dose adjustments would be required for Chinese or Japanese patients relative to Caucasian patients.…”

“…Baseline assessments were performed prior to dosing on Day 1. Follow-up occurred through the final study visit on Day 71, with assessments on Days 3, 4, 6 (±6 hours), and on Days 8,11,15,22,29,35,43, 57 and 71 (±2 days).…”

“…Blood samples were collected for the determination of BIIB023 serum concentrations on Day 1 (predose and 5 minutes, 2 hours and 8 hours after the end of the 1 hour infusion), Day 2 (24 hours postdose), Day 3 (48 hours postdose), Day 4 (72 hours postdose), Day 6 (120 hours postdose), Days 8,11,15,22,29,35,43,57 and Day 71 (final study visit or early withdrawal from the study visit). All BIIB023 concentrations reported as below the limit of quantification (BLQ; <0.1 μg ml À1 ) were set equal to zero (i.e., they were not treated as 'missing').…”

Monoclonal Antibodies for Therapeutic Use: Specific Characteristics of Clinical Development, Evaluation by the Agencies, and Long-term Monitoring of Safety

“…This two-way relationship should ideally be described by a target-mediated drug disposition (TMDD) model, which describes both the pharmacokinetic profile and PK-PD relationship. [23] As discussed above, patient immunization will be responsible for reduced MoAb concentrations. This immunisation is in itself dependent on the concentrations of the therapeutic antibody since, for example, the risk of developing anti-infliximab antibodies has been shown to be higher the lower the infliximab concentrations.…”

Anticorps monoclonaux à usage thérapeutique : spécificités du développement clinique, évaluation par les agences, suivi de la tolérance à long terme

“…Cette relation à double sens doit idéalement être décrite par un modèle de type « élimination liée à la cible » (target-mediated drug disposition ou TMDD), qui permet de décrire de façon conjointe la pharmacocinétique et la relation PK-PD. [23] Comme nous l'avons vu plus haut, l'immunisation des patients va être responsable d'une diminution des concentrations de l'AcMo. Cette immunisation est elle-même dépendante des concentrations de l'anticorps thérapeutique.…”