Models for drugs exhibiting target-mediated drug disposition (TMDD) play an important role in the investigation of biological products (Mager and Jusko 2001). These models are often overparameterized and difficult to converge. A simpler quasi-equilibrium (QE) approximation of the general model has been suggested (Mager and Krzyzanski 2005), but even this simpler form can be overparameterized when, for example, drug target level is not available. This work (a) introduces quasi-steady-state (QSS) and Michaelis-Menten (MM) approximations of the TMDD model, (b) derives the relationships between the parameters of the TMDD, QE, QSS and MM models, (c) investigates the parameter ranges where the simplified approximations are equivalent to the TMDD model, (d) proposes an algorithm for establishing identifiability of these models, and (e) tests this algorithm on simulated datasets. The proposed QSS approximation is more general than the QE approximation: it degenerates into the QE approximation when the internalization rate of the drug-target complex is much smaller than its dissociation rate. The proposed identifiability analysis algorithm may be applied to provide justification for use of simplified approximations, avoiding use of incorrect parameter estimates of over-parameterized TMDD models while simultaneously saving time and resources required for the pharmacokinetics analysis of drugs with TMDD. The utility of the derived approximations and of the identifiability algorithm was demonstrated on the examples of the simulated data sets. The simulation examples indicated that the QSS model may be preferable to the QE model when the internalization rate of the drug-target complex significantly exceeds its dissociation rate. The MM approximation may be adequate when the drug concentration significantly exceeds the target concentrations or when the target occupancy is close to 100%.

Models for drugs exhibiting target-mediated drug disposition (TMDD) describe biological processes in which drug-target binding significantly influences both pharmacodynamics (PD) and pharmacokinetics (PK). TMDD models are often over-parameterized and their parameters are difficult to estimate based on available data. Approximations of the general model have been suggested, but even these simpler forms can be over-parameterized when, for example, target and drug-target complex concentrations are not available. This work i) reviews TMDD equations, their approximations and methods to study identifiability of model parameters; ii) reviews the publications that used TMDD equations to describe PK and PD of biologics; and iii) discusses issues of identifiability of the TMDD model parameters related to study design and data analysis. Examples demonstrate that use of the TMDD equations for the population PK and PD modeling is most successful when the target and drug-target complex concentrations are available in addition to the drug concentration data. TMDD parameter estimates can be trusted only when they are identifiable, that is, can be estimated from the available data with sufficient precision. Parameter identifiability analysis should be an integral part of the TMDD system investigation. It also should be used prospectively for optimal study design.

Background and aims: To evaluate the safety and efficacy of the intercellular adhesion molecule 1 (ICAM-1) antisense phosphorothioate oligonucleotide alicaforsen (ISIS 2302) in Crohn's disease. Methods: Active (Crohn's disease activity index (CDAI) 200-350), steroid dependent (prednisone 10-40 mg) Crohn's patients were randomised into three treatment groups: placebo versus ISIS 2302 (2 mg/kg intravenously three times a week) for two or four weeks. Patients were treated in months 1 and 3, with steroid withdrawal attempted by week 10. The primary end point (steroid free remission) was a CDAI <150 off steroids at the end of week 14. Results: A total of 299 patients were enrolled, with a mean baseline CDAI of 276 and steroid dose of 23 mg/day. Rates of steroid free remission were equivalent for the two and four week ISIS 2302 groups (20.2% and 21.2%) and the placebo group (18.8%). At week 14, steroid withdrawal was successful in more ISIS 2302 patients compared with placebo treated patients (78% v 64%; p=0.032). Steroid free remission was highly correlated with exposure (p=0.0064). Other clinical responses were correlated with exposure, with significant results versus placebo being observed in the highest area under the curve subgroup. CDAI scores decreased by 136 (112) at week 14 versus 52 (107) for placebo (p=0.027) and inflammatory bowel disease score questionnaire improved by 43 (31) versus 15 (36) for placebo (p=0.027). Conclusions: Although the primary outcomes failed to demonstrate efficacy, pharmacodynamic modelling suggests that alicaforsen (ISIS 2302) may be an effective therapy for steroid dependent Crohn's disease.

Treatment regimens involving obinutuzumab (GA101) demonstrated increased efficacy to rituximab in clinical trials for non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). However, the pharmacokinetic (PK) properties and the exposure–response relationships of obinutuzumab still need to be fully described. Data from four clinical trials of obinutuzumab were analyzed to describe the PK properties in patients with NHL or CLL and the pharmacodynamic (PD) properties in patients with CLL. A population PK model with linear time-dependent clearance described the obinutuzumab concentration–time course. Diagnosis, baseline tumor size (BSIZ), body weight, and gender were the main covariates affecting obinutuzumab exposure. In patients with CLL, exposure was not associated with safety but showed positive trends of correlation with efficacy. Although efficacy correlated positively with exposure, since both efficacy and exposure correlated negatively with BSIZ, it was not possible to determine with certainty whether it would be beneficial to adjust the dose according to BSIZ.

The population pharmacokinetics of eltrombopag were characterized in healthy subjects (n = 111) and patients with idiopathic thrombocytopenic purpura (ITP) (n = 88) using nonlinear mixed-effects modeling. The final model was evaluated via graphical diagnostics and through predictive check and nonparametric bootstrap procedures. A 2-compartment model with dual sequential first-order absorption, absorption lag time, and interoccasion variability in absorption adequately described the data. For a typical 70-kg Caucasian male ITP patient not taking corticosteroids, estimated parameters were apparent clearance (CL/F) = 0.668 L/h, apparent volume of the central compartment (Vc/F) = 8.76 L, apparent volume of the peripheral compartment (Vp/F) = 11.3 L, and distributional clearance (Q/F) = 0.399 L/h. Eltrombopag CL/F, Vc/F, Q/F, and Vp/F increased with body weight. For the range of weights included (43-122 kg), the parameters ranged from 26% lower to 41% higher than for a 70-kg individual. The typical eltrombopag CL/F was 33% lower in East Asians compared with other races, 26% lower in patients taking corticosteroids concomitantly, 19% lower in females compared with males, and 17% higher in healthy subjects compared with ITP patients. There was also a dose effect, with CL/F and Vc/F estimated to be respectively 68% and 55% higher for doses 20 mg or less. In conclusion, East Asian race had the largest impact on eltrombopag exposure with a lower initial dose being recommended.