Dataset Information

Pharmacokinetics and concentration-effect relationship of adalimumab in rheumatoid arthritis.

ABSTRACT: This study aimed at describing adalimumab pharmacokinetics (PK) and the concentration-effect relationship of adalimumab using pharmacokinetic-pharmacodynamic (PK-PD) modelling in patients with rheumatoid arthritis (RA).Adalimumab PK and PK-PD data were obtained from a multicentric observational study. Adalimumab (40?mg) was administered subcutaneously every other week, and its pharmacokinetics was described using a one-compartment model. The relationship between adalimumab concentration and C-reactive protein (CRP) concentration was described using an indirect response model with inhibition of CRP input, whereas the relationship between adalimumab concentration and disease activity score in 28 joints (DAS28) was described using a direct inhibition model. Dose regimens that included a loading dose of adalimumab were simulated.Thirty patients treated for RA were analysed. The following pharmacokinetic and PK-PD parameters were estimated (interidividual coefficient of variation): apparent volume of distribution (Vd /F)?=?10.8?l (92%); apparent clearance (CL/F)?=?0.32?l?day(-1) (17%); first-order absorption rate (ka )?=?0.28 day(-1) ; CRP input (kin )?=?22.0?mg?l(-1) ?day(-1) (65%); adalimumab concentration leading to a 50% decrease in kin (C50 )?=?3.6?mg?l(-1) (88%); baseline DAS28 (DAS0 )?=?5.5?mg?l(-1) (11%); and adalimumab concentration leading to 50% decrease of DAS0 (IC50 )?=?11.0?mg?l(-1) (71%). Simulations showed that a 160?mg loading dose should reduce the time to reach efficacy in terms of both CRP and DAS28 after the first injection.This is the first study to describe adalimumab pharmacokinetics and the concentration-effect relationship in RA. A 160?mg loading dose may lead to an increased benefit from treatment in RA patients.

SUBMITTER: Ternant D

PROVIDER: S-EPMC4309634 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Pharmacokinetics and concentration-effect relationship of adalimumab in rheumatoid arthritis.

Ternant David D Ducourau Emilie E Fuzibet Piéra P Vignault Céline C Watier Hervé H Lequerré Thierry T Le Loët Xavier X Vittecoq Olivier O Goupille Philippe P Mulleman Denis D Paintaud Gilles G

British journal of clinical pharmacology 20150201 2

<h4>Aims</h4>This study aimed at describing adalimumab pharmacokinetics (PK) and the concentration-effect relationship of adalimumab using pharmacokinetic-pharmacodynamic (PK-PD) modelling in patients with rheumatoid arthritis (RA).<h4>Methods</h4>Adalimumab PK and PK-PD data were obtained from a multicentric observational study. Adalimumab (40 mg) was administered subcutaneously every other week, and its pharmacokinetics was described using a one-compartment model. The relationship between adal ...[more]

PMID: 25223394

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Project description:Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). The aim of this study was to explore the safety and efficacy of open-label tofacitinib following blinded treatment with adalimumab or tofacitinib for moderate to severe RA.Analyses included patients treated with adalimumab 40 mg once every 2 weeks or tofacitinib 10 mg twice daily (BID) with background methotrexate (MTX) in a 12-month randomized study (NCT00853385), who subsequently received tofacitinib 10 mg BID (with/without background MTX) in an open-label extension (NCT00413699). Patients with treatment-related serious adverse events (AEs) and serious or recurrent infections in the index study were excluded from the extension study. Exposure-adjusted incidence rates of safety-related events were assessed in 3-month and 12-month periods in the year before and in the year after switching. Efficacy was assessed 3 months before, at the time of, and 3 months after switching.There were 233 (107 adalimumab to tofacitinib 10 mg BID, 126 blinded to open-label tofacitinib 10 mg BID) patients included in these analyses. Patients in both treatment sequences had similar incidence rates (per 100 patient-years) of discontinuation due to AEs, serious AEs, and serious infections in the year before and in the year after switching. Incidence rates of AEs were increased in the first 3 months after switching compared with the last 3 months before switching in both treatment groups. Switching from either blinded adalimumab or tofacitinib to open-label tofacitinib resulted in numerically higher incidence of responders for signs and symptoms of disease and improved physical function.Treatment can be directly switched from adalimumab to tofacitinib. A similar safety and efficacy profile was seen when patients received open-label tofacitinib after receiving either blinded adalimumab or tofacitinib.ClinicalTrials.gov Identifiers: NCT00853385 , registered 27 February 2009; NCT00413699 , registered 18 December 2006.

Project description:IntroductionThe treatment of rheumatoid arthritis (RA) patients with anti-tumor necrosis factor alpha (TNF?) biological drugs has dramatically improved the prognosis of these patients. However, a third of the treated patients do not respond to this therapy. Thus, the search for biomarkers of clinical response to these agents is currently highly active. Our aim is to analyze the number and distribution of circulating monocytes, and of their CD14?highCD16?, CD14?highCD16? and CD14?lowCD16+ subsets in methotrexate (MTX) non-responder patients with RA, and to determine their value in predicting the clinical response to adalimumab plus MTX treatment.MethodsThis prospective work investigated the number of circulating monocytes, and of their CD14?highCD16?, CD14?highCD16? and CD14?lowCD16? subsets, in 35 MTX non-responder patients with RA before and after three and six months of anti-TNF? treatment using multiparametric flow cytometry. The number of circulating monocytes in an age- and sex-matched healthy population was monitored as a control.ResultsNon-responder patients with RA show an increased number of monocytes and of their CD14?highCD16?, CD14?highCD16? and CD14?lowCD16? subsets after three months of adalimumab plus MTX treatment that remained significantly increased at six months. In contrast, significant normalization of the numbers of circulating monocytes was found in responders at three months of adalimumab plus MTX treatment that lasts up to six months. CX3CR1 expression is increased in monocytes in non-responders. At three months of anti-TNF? treatment the number of circulating monocytes and their subsets was associated with at least 80% sensitivity, 84% specificity and an 86% positive predictive value (PPV) in terms of discriminating between eventual early responders and non-responders.ConclusionsThe absolute number of circulating monocytes and of their CD14?highCD16?, CD14?highCD16? and CD14?lowCD16? subsets at three months of adalimumab plus MTX treatment, have a predictive value (with high specificity and sensitivity) in terms of the clinical response after six months of anti-TNF? treatment in patients with RA.

Dataset Information

Pharmacokinetics and concentration-effect relationship of adalimumab in rheumatoid arthritis.

Publications

Pharmacokinetics and concentration-effect relationship of adalimumab in rheumatoid arthritis.

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