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A longitudinal model linking absolute lymphocyte count and volume of T2 lesions to expanded disability status scale in relapse-remitting multiple sclerosis patients
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. (Pharmacometrics group)ORCID-id: 0000-0003-0665-6484
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
Merck Institute of Pharmacometrics, Lausanne, Switzerland.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
(engelsk)Manuskript (preprint) (Annet vitenskapelig)
HSV kategori
Identifikatorer
URN: urn:nbn:se:uu:diva-315641OAI: oai:DiVA.org:uu-315641DiVA, id: diva2:1078241
Tilgjengelig fra: 2017-03-03 Laget: 2017-03-03 Sist oppdatert: 2018-01-13
Inngår i avhandling
1. Longitudinal Models for Quantifying Disease and Therapeutic Response in Multiple Sclerosis
Åpne denne publikasjonen i ny fane eller vindu >>Longitudinal Models for Quantifying Disease and Therapeutic Response in Multiple Sclerosis
2017 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Treatment of patients with multiple sclerosis (MS) and development of new therapies have been challenging due to the disease complexity and slow progression, and the limited sensitivity of available clinical outcomes. Modeling and simulation has become an increasingly important component in drug development and in post-marketing optimization of use of medication. This thesis focuses on development of pharmacometric models for characterization and quantification of the relationships between drug exposure, biomarkers and clinical endpoints in relapse-remitting MS (RRMS) following cladribine treatment.

A population pharmacokinetic model of cladribine and its main metabolite, 2-chloroadenine, was developed using plasma and urine data. The renal clearance of cladribine was close to half of total elimination, and was found to be a linear function of creatinine clearance (CRCL).

Exposure-response models could quantify a clear effect of cladribine tablets on absolute lymphocyte count (ALC), burden of disease (BoD), expanded disability status scale (EDSS) and relapse rate (RR) endpoints. Moreover, they gave insight into disease progression of RRMS.

This thesis further demonstrates how integrated modeling framework allows an understanding of the interplay between ALC and clinical efficacy endpoints. ALC was found to be a promising predictor of RR. Moreover, ALC and BoD were identified as predictors of EDSS time-course. This enables the understanding of the behavior of the key outcomes necessary for the successful development of long-awaited MS therapies, as well as how these outcomes correlate with each other.

The item response theory (IRT) methodology, an alternative approach for analysing composite scores, enabled to quantify the information content of the individual EDSS components, which could help improve this scale. In addition, IRT also proved capable of increasing the detection power of potential drug effects in clinical trials, which may enhance drug development efficiency.

The developed nonlinear mixed-effects models offer a platform for the quantitative understanding of the biomarker(s)/clinical endpoint relationship, disease progression and therapeutic response in RRMS by integrating a significant amount of knowledge and data.

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis, 2017. s. 71
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 225
Emneord
nonlinear mixed-effects models, pharmacometrics, NONMEM, multiple sclerosis, cladribine, EDSS, item response theory, relapse rate, absolute lymphocyte count, total volume T2 lesions, burden of disease, power, sample size
HSV kategori
Forskningsprogram
Farmaceutisk vetenskap
Identifikatorer
urn:nbn:se:uu:diva-316562 (URN)978-91-554-9836-8 (ISBN)
Disputas
2017-04-21, B42, Biomedicinskt Centrum, Husargatan 3, Uppsala, 09:15 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2017-03-30 Laget: 2017-03-03 Sist oppdatert: 2018-01-13

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