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Title:	Evaluation of immunoglobulin therapy and population pharmacokinetic model development
Authors:	Lee Jian Lynn (P93201)
Supervisor:	Noraida Mohamed Shah, Assoc. Prof. Dr.
Keywords:	Immunization Passive Pharmacokinetics Universiti Kebangsaan Malaysia -- Dissertations Dissertations, Academic -- Malaysia
Issue Date:	22-Jun-2022
Description:	Rational use of immunoglobulin therapy should attempt to optimize its clinical utilization while improving patient outcomes. Intravenous immunoglobulin (IVIG) therapy is used in the management of immunodeficiency states and a wide range of other medical conditions. The high between-subject variability in the pharmacokinetics of IVIG therapy indicates that dose individualization should be practised in order to optimize IVIG use. The general objectives of this study were to evaluate the prescribing practice and to explore the potential of dose individualization for IVIG therapy. The initial study was an evaluation on the prescribing patterns of IVIG in two hospitals. It was found that 42.5% of the IVIG prescriptions was used for licensed indications whereas 57.5% was for off-label indications. Close to a quarter of the IVIG prescriptions (23.6%) were for the antibody replacement therapy in patients with primary immunodeficiency (PI). For this indication, dose individualization is possible as IgG levels are routinely measured to monitor its treatment outcome. However, despite the long history of IVIG use in PI, the optimal IgG trough level, remains unclear. A systematic review and meta-regression analysis showed that, increasing IgG trough level up to 960 mg/dL progressively reduced rate of infections with minimal additional benefit beyond that level. Apart from having a target concentration, factors for the high pharmacokinetic variability need to be identified in order to develop a dosing algorithm that can accurately calculate the dose required to achieve the desired IgG level. Hence, another systematic review was conducted to examine the potential factors influencing the pharmacokinetic of IgG. The review which included six studies that uses the nonlinear mixed effects modeling approach showed that only weight and disease type were significant covariates. Genetic polymorphism of the FCGRT gene encoding the promoter region of the neonatal Fc receptor (FcRn) that was hypothesized to affect the efficacy of IgG therapy were not evaluated in any studies previously. The subsequent study estimated the prevalence of this genetic polymorphism and the genotypes detected were VNTR3/3 (84.8%), VNTR2/3 (13.9%) and VNTR3/4 (1.3%). Using MonolixTM software, population pharmacokinetic (popPK) models of IVIG was developed, with demographic, clinical, and genetic factors evaluated as potential covariates. Genetic polymorphism of the FCGRT gene was found to have no impact on pharmacokinetics of IVIG. In the replacement therapy for population with PI, the final model only identified total body weight as a significant predictor for the pharmacokinetics of IVIG. With the availability of a target IgG level and popPK model, individualizing doses is possible for patients with PI. In the overall population, which also included the patients with inflammatory diseases and auto-immune diseases, the final model identified total body weight and disease type as significant predictors for the pharmacokinetics of IVIG. Overall, findings from this research highlighted the possibility of improving the efficient use of IVIG through evidence-based prescribing and dose individualization. The findings on IVIG prescribing practice are able to guide future drug policies while the developed popPK models are able to enrich the opportunity for dose individualization by adding to the knowledge of model-informed precision dosing for IVIG,Ijazah Doktor Falsafah
Notes:	e-thesis
Pages:	348
Publisher:	UKM, Kuala Lumpur
Appears in Collections:	Faculty of Pharmacy / Fakulti Farmasi

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