Population pharmacokinetics: model-free approach and nonlinear mixed-effects modelling

The work is devoted to the application and further development of modern statistical methods to study pharmacokinetics of drugs. Specifically, it deals with applications and development of repeated measures analysis, so called 'population approach' methods, in the field of pharmacokinetics. hi the first part of the thesis, a new, model-free approach is developed and tested. It introduces a model-free measure of patient's exposure to drugs, and then investigates the relationships between the exposure level and covariates using various statistical techniques. Classification tree models (CART) and regression analysis are used to study various subpopulations of interest. It is shown, via simulations, that the model-free method is capable to identify predictors of exposure in a wide range of variability in the data. The non-linear mixed effect modelling is used to confirm the results of the model-free investigation. Model-free approach is successfully applied to several drugs. Non-linear Mixed Effects population models developed for the same data agree with its results. Limits of the new method are also identified. Specifically, it does not allow the estimation of the variability: either the within-subject (intra-individual) variability in response, or between-subject (inter-individual) variability of the pharmacokinetic parameters in the population. The second part of the thesis is devoted to applications of the Non-linear Mixed Effect methodology to population pharmacokinetics and dose-response analysis. Population pharmacokinetic and dose-response models of several drugs are developed. Pharmacokinetic models allow for complete characterisation of the drug's pharmacokinetics and its relationships to safety and efficacy. The developed models are used to explore the relationships between the exposure (individual Bayes estimates) and demographic predictors of exposure, and safety and efficacy of the drug. Finally, the developed models are used in simulations to guide the design of new studies

Role of obinutuzumab exposure on clinical outcome of follicular lymphoma treated with first-line immunochemotherapy

Aims: Obinutuzumab (G) is a humanized type II, Fc-glycoengineered anti-CD20 monoclonal antibody used in various indications, including patients with previously untreated front-line follicular lymphoma. We investigated sources of variability in G exposure and association of progression-free survival (PFS) with average concentration over induction (C meanIND ) in front-line follicular lymphoma patients treated with G plus chemotherapy (bendamustine, CHOP, or CVP) in the GALLIUM trial. Methods: Individual exposures (C meanIND ) were obtained from a previously established population pharmacokinetic model updated with GALLIUM data. Multivariate Cox proportional hazard models and univariate Kaplan–Meier plots investigated relationships of PFS with exposure and other potential prognostic factors. Results: Overall, G exposure was lower in high body-weight patients and in males, and slightly lower in patients with high baseline tumour burden. Analysis of clinical outcomes showed that variability in G exposure did not impact PFS in G-bendamustine-treated patients; PFS was inferior in males and patients with FCGR2a/2b T232 T low-affinity receptor variant, and superior in patients with FCGR2a/2b I232T variant. In G-CHOP/CVP arms, PFS improved with increasing C meanIND (hazard ratio = 1.74 and 0.394 at 5 th and 95 th percentile compared to median C meanIND ) and was inferior in patients with high baseline tumour size and B symptoms. Conclusions: It remains unclear whether for G-CHOP/CVP patients lower G exposure is a consequence of adverse disease biology and/or resistance to chemotherapy backbone (higher clearance in nonresponder patients, as demonstrated for rituximab) rather than being the cause of poorer clinical outcome. A study with &gt;1 dose level of G could help resolve this uncertainty. </p

Ocrelizumab in relapsing and primary progressive multiple sclerosis: Pharmacokinetic and pharmacodynamic analyses of OPERA I, OPERA II and ORATORIO

AimsOcrelizumab is a humanized monoclonal antibody that selectively targets CD20-positive B cells and is indicated for treatment of patients with relapsing forms of multiple sclerosis (RMS) or primary progressive multiple sclerosis (PPMS). The pharmacokinetics and pharmacodynamics of ocrelizumab in patients with RMS or PPMS were assessed.MethodsA population pharmacokinetic model was developed based on data from the Phase II study and the Phase III studies OPERA I and OPERA II in patients with RMS. Data from the ORATORIO Phase III study in patients with PPMS became available after model finalization and was used for external model evaluation.ResultsThe ocrelizumab serum concentration vs time course was accurately described by a 2-compartment model with time-dependent clearance. Body weight was found to be the main covariate. The area under the concentration-time curve over the dosing interval was estimated to be 26% higher for patients with RMS weighing &lt;60&nbsp;kg and 21% lower for patients weighing &gt;90&nbsp;kg when compared with the 60-90&nbsp;kg group. The terminal half-life of ocrelizumab was estimated as 26&nbsp;days. The extent of B-cell depletion in blood, as the pharmacodynamic marker, was greater with increasing ocrelizumab exposure.ConclusionThe pharmacokinetics of ocrelizumab was described with pharmacokinetic parameters typical for an immunoglobulin G1 monoclonal antibody, with body weight as the main covariate. The pharmacokinetics and B-cell depletion in blood were comparable across the RMS and PPMS trials, and the extent of blood B-cell depletion was greater with higher exposure

Ocrelizumab in relapsing and primary progressive multiple sclerosis: Pharmacokinetic and pharmacodynamic analyses of OPERA I, OPERA II and ORATORIO.

AimsOcrelizumab is a humanized monoclonal antibody that selectively targets CD20-positive B cells and is indicated for treatment of patients with relapsing forms of multiple sclerosis (RMS) or primary progressive multiple sclerosis (PPMS). The pharmacokinetics and pharmacodynamics of ocrelizumab in patients with RMS or PPMS were assessed.MethodsA population pharmacokinetic model was developed based on data from the Phase II study and the Phase III studies OPERA I and OPERA II in patients with RMS. Data from the ORATORIO Phase III study in patients with PPMS became available after model finalization and was used for external model evaluation.ResultsThe ocrelizumab serum concentration vs time course was accurately described by a 2-compartment model with time-dependent clearance. Body weight was found to be the main covariate. The area under the concentration-time curve over the dosing interval was estimated to be 26% higher for patients with RMS weighing &lt;60&nbsp;kg and 21% lower for patients weighing &gt;90&nbsp;kg when compared with the 60-90&nbsp;kg group. The terminal half-life of ocrelizumab was estimated as 26&nbsp;days. The extent of B-cell depletion in blood, as the pharmacodynamic marker, was greater with increasing ocrelizumab exposure.ConclusionThe pharmacokinetics of ocrelizumab was described with pharmacokinetic parameters typical for an immunoglobulin G1 monoclonal antibody, with body weight as the main covariate. The pharmacokinetics and B-cell depletion in blood were comparable across the RMS and PPMS trials, and the extent of blood B-cell depletion was greater with higher exposure