Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Population pharmacokinetics of cladribine in patients with multiple sclerosis
Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, USA.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Pharmacometrics group)ORCID iD: 0000-0003-0665-6484
Persson Ekblom Sarl, St-Prex, Switzerland.
Merck Institute of Pharmacometrics, Lausanne, Switzerland.
Show others and affiliations
2017 (English)In: Clinical Pharmacokinetics, ISSN 0312-5963, E-ISSN 1179-1926, Vol. 56, no 10, p. 1245-1253Article in journal (Refereed) Published
Abstract [en]

The aims of this study were to characterize the concentration-time course of cladribine (CdA) and its main metabolite 2-chloroadenine (CAde), estimate interindividual variability in pharmacokinetics (PK), and identify covariates explaining variability in the PK of CdA. This population PK analysis was based on the combined dataset from four clinical studies in patients with multiple sclerosis (MS): three phase I studies, including one food and one drug-drug interaction study, and one phase III clinical study. Plasma and urine concentration data of CdA and CAde were modeled simultaneously. The analysis comprised a total of 2619 CdA and CAde plasma and urine concentration observations from 173 patients with MS who received an intravenous infusion or oral tablet doses of CdA as a single agent or in combination with interferon (IFN) beta-1a. CdA PK data were best described by a three-compartment model, while a one-compartment model best described the PK of CAde. CdA renal clearance (CLR) was correlated with creatinine clearance (CLCR), predicting a decrease in the total clearance of 19%, 30% and 40% for patients with mild (CLCR = 65 ml/min), moderate (CLCR = 40 ml/min) and severe (CLCR = 20 ml/min) renal impairment, respectively. Food decreased the extent of CdA absorption by 11.2% and caused an absorption delay. Coadministration with IFN beta-1a was found to increase non-CLR (CLNR) by 21%, resulting in an increase of 11% in total clearance. Both CdA and CAde displayed linear PK after intravenous and oral administration of CdA, with CdA renal function depending on CLCR.

Place, publisher, year, edition, pages
2017. Vol. 56, no 10, p. 1245-1253
Keywords [en]
cladribine, multiple sclerosis, population pharmacokinetics
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-315633DOI: 10.1007/s40262-017-0516-6ISI: 000410264900012PubMedID: 28255849OAI: oai:DiVA.org:uu-315633DiVA, id: diva2:1078238
Available from: 2017-03-03 Created: 2017-03-03 Last updated: 2018-01-13Bibliographically approved
In thesis
1. Longitudinal Models for Quantifying Disease and Therapeutic Response in Multiple Sclerosis
Open this publication in new window or tab >>Longitudinal Models for Quantifying Disease and Therapeutic Response in Multiple Sclerosis
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. p. 71
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 225
Keywords
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
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-316562 (URN)978-91-554-9836-8 (ISBN)
Public defence
2017-04-21, B42, Biomedicinskt Centrum, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2017-03-30 Created: 2017-03-03 Last updated: 2018-01-13

Open Access in DiVA

fulltext(972 kB)86 downloads
File information
File name FULLTEXT01.pdfFile size 972 kBChecksum SHA-512
e517332280b0185c7f4f056ecf84ff39bca9d4f0989e1b5da2425256b7aa32147ee517b1daf7d0d19d864cebaf2ea4e6ee9dc60ac9567279dc61e51301ba31b1
Type fulltextMimetype application/pdf

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Novakovic, Ana M.Karlsson, Mats O.
By organisation
Department of Pharmaceutical Biosciences
In the same journal
Clinical Pharmacokinetics
Pharmaceutical Sciences

Search outside of DiVA

GoogleGoogle Scholar
Total: 86 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 513 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf