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Simultaneous Exposure-Response Modeling of ACR20, ACR50, and ACR70 Improvement Scores in Rheumatoid Arthritis Patients With Certolizumab Pegol
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. (Pharmacometrics)
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. (Pharmacometrics)
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. (Pharmacometrics)
2014 (Engelska)Ingår i: CPT Pharmacometrics and Systems Pharmacology, ISSN 2163-8306, Vol. 3, nr 10, s. 1-11Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The Markovian approach has been proposed to model ACR response (ACR20, ACR50 or ACR70) reported in rheumatoid arthritis clinical trials to account for the dependency of the scores over time. However, dichotomizing the composite ACR assessment discards much information. Here we propose a new approach for modeling together the 3 thresholds: a continuous-time Markov exposure-response model was developed, based on data from 5 placebo-controlled certolizumab pegol clinical trials. This approach allows adequate prediction of individual ACR20/50/70 time-response, even for non-periodic observations. An exposure-response was established over a large range of licensed and unlicensed doses including phase II dose-ranging data. Simulations from the model (50 to 400 mg every other week) illustrated the range and sustainability of response (ACR20: 56 to 68%, ACR50: 27 to 42%, ACR70: 11 to 22% at week 24) with maximum clinical effect achieved at the recommended maintenance dose of 200 mg every other week.

Ort, förlag, år, upplaga, sidor
Nature Publishing Group, 2014. Vol. 3, nr 10, s. 1-11
Nyckelord [en]
Rheumatoid arthritis, ACR, ACR20, ACR50, ACR70, exposure-response modeling, Markov, certolizumab pegol
Nationell ämneskategori
Farmaceutiska vetenskaper
Forskningsämne
Farmakokinetik och läkemedelsterapi; Farmaceutisk vetenskap; Farmakologi
Identifikatorer
URN: urn:nbn:se:uu:diva-247891DOI: 10.1038/psp.2014.41OAI: oai:DiVA.org:uu-247891DiVA, id: diva2:797898
Tillgänglig från: 2015-03-25 Skapad: 2015-03-25 Senast uppdaterad: 2018-01-11Bibliografiskt granskad
Ingår i avhandling
1. Pharmacometric Modeling in Rheumatoid Arthritis
Öppna denna publikation i ny flik eller fönster >>Pharmacometric Modeling in Rheumatoid Arthritis
2015 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Biologic therapies have revolutionized the treatment of rheumatoid arthritis, a common chronic inflammatory disease, mainly characterized by the chronic inflammation of the joints. The activity and progression of the disease are highly variable, both between subjects and between the successive assessments for the same subject. Standardized assessments of clinical variables have been developed to reflect the disease activity and evaluate new therapies. Pharmacokinetics-pharmacodynamic (PKPD) models and methods for analyzing the generated time-course data are needed to improve the interpretation of the clinical trials’ outcomes, and to describe the variability between subjects, including patients characteristics, disease factors and the use of concomitant treatments that may affect the response to treatment. In addition, good simulation properties are also desirable for predicting clinical responses for various populations or for different dosing schedules. The aim of this thesis was to develop methods and models for analyzing pharmacokinetic and pharmacokinetic-pharmacodynamic (PKPD) data from rheumatoid arthritis patients, illustrated by treatment with a new anti-TNFα biologic drug under clinical development, certolizumab pegol.

Two models were developed that characterized the relationship between the exposure to the drug and the efficacy ACR variables that represent improvement of the disease; a logistic-type Markov model for 20% improvement (ACR20) and a continuous-type Markov model for simultaneous analysis of 20% (ACR20), 50% (ACR50) and 70% (ACR70) improvement. Both models accounted for the within-subjects correlation in the successive clinical assessments and were able to capture the observed ACR responses over time. Simulations from these models of the ACR20 response rate supported dosing regimens of 400 mg at weeks 0, 2 and 4 to achieve a rapid onset of response to the treatment, followed by 200 mg every 2 weeks, or alternative maintenance regimen of 400 mg every 4 weeks.

The immunogenicity induced by the biologic drug was characterized by a time to event model describing the time to appearance of antibodies directed against the drug. The immunogenicity was predicted to appear mainly during the first 3 months following the start of the treatment and to be reduced at higher trough concentrations of CZP, as well as with concomitant administration of MTX.

The full time-course of sequential events, such as dose-exposure-efficacy relations, is most accurately described by a simultaneous analysis of all data. However, due to the complexity and runtime limitations of such an analysis, alternatives are often used. In this thesis, a method, IPPSE, was developed and compared to the reference simultaneous method and to existing alternative methods. The IPPSE method was shown to provide accuracy and precision of estimates similar to the simultaneous method, but with easier implementation and shorter run times.

In conclusion, two PKPD models and one immunogenicity model were developed for evaluation of the response of a biologic drug against rheumatoid arthritis that allowed accurate analysis and simulation of clinical trial data, as well as serving as examples for how a model-informed basis for decisions about biological drugs can be created.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2015. s. 68
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 199
Nyckelord
rheumatoid arthritis, PKPD, immunogenicity, ACR, IPPSE, certolizumab pegol
Nationell ämneskategori
Farmaceutiska vetenskaper
Identifikatorer
urn:nbn:se:uu:diva-247917 (URN)978-91-554-9221-2 (ISBN)
Disputation
2015-05-22, B42, BMC, Uppsala, 13:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2015-04-28 Skapad: 2015-03-25 Senast uppdaterad: 2018-01-11

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Lacroix, BrigitteKarlsson, MatsFriberg, Lena

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