Intra-patient variability in adalimumab drug levels within and between cycles in Crohn's disease

M. G. Ward, Peter A Thwaites, L. Beswick, Andrew J Hogg, G. Rosella, D. Van Langenberg, J. Reynolds, P. R. Gibson, M. P. Sparrow

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Abstract

Background: Whether therapeutic drug monitoring for adalimumab needs to be performed at trough has not been defined. Aim: To determine intra-patient adalimumab drug-level variation and to identify modulating patient and disease factors. Methods: In this prospective observational study, adult patients with Crohn's disease established on maintenance adalimumab had drug levels measured repeatedly according to pre-defined schedules (visit 1: day 4–6, visit 2: day 7–9, trough: day 13–14) across two consecutive fortnightly cycles. Disease activity was assessed using Harvey–Bradshaw Index, C-reactive protein and faecal calprotectin. For this analysis, trough levels ≥4.9 μg/mL were considered therapeutic. Results: Nineteen patients underwent 111 evaluations. Mean intra-patient drug levels from paired visits between cycles did not differ (visit1 cycle1: 4.81, cycle2: 5.21 μg/mL, P = 0.24, visit2 cycle1: 4.86, cycle2: 4.82, P = 0.91 and trough cycle1: 3.95, cycle2: 3.95, P = 0.99), irrespective of disease activity. Drug levels were stable over the first 9 days (visit 1–2), but declined to trough by a mean 1.06 and 0.89 μg/mL between visit 1 or 2, respectively (P < 0.001). Models using nontemporal factors (smoking, syringe delivery device) and levels at earlier visits accounted for 66–80% of the variance in trough levels. On receiver-operating curve analysis, thresholds identified in the first 9 days that predicted a therapeutic trough level were similar to the trough threshold itself, with high sensitivity but modest specificity. Conclusion: While therapeutic drug monitoring should be performed at trough, a drug level ≥4.9 μg/mL obtained during the first 9 days predicts a therapeutic trough drug level with reasonable confidence.

Original languageEnglish
Pages (from-to)1135-1145
Number of pages11
JournalAlimentary Pharmacology and Therapeutics
Volume45
Issue number8
DOIs
Publication statusPublished - 1 Apr 2017

Cite this

@article{7bb6233b46394881afd3bdb928c01b6c,
title = "Intra-patient variability in adalimumab drug levels within and between cycles in Crohn's disease",
abstract = "Background: Whether therapeutic drug monitoring for adalimumab needs to be performed at trough has not been defined. Aim: To determine intra-patient adalimumab drug-level variation and to identify modulating patient and disease factors. Methods: In this prospective observational study, adult patients with Crohn's disease established on maintenance adalimumab had drug levels measured repeatedly according to pre-defined schedules (visit 1: day 4–6, visit 2: day 7–9, trough: day 13–14) across two consecutive fortnightly cycles. Disease activity was assessed using Harvey–Bradshaw Index, C-reactive protein and faecal calprotectin. For this analysis, trough levels ≥4.9 μg/mL were considered therapeutic. Results: Nineteen patients underwent 111 evaluations. Mean intra-patient drug levels from paired visits between cycles did not differ (visit1 cycle1: 4.81, cycle2: 5.21 μg/mL, P = 0.24, visit2 cycle1: 4.86, cycle2: 4.82, P = 0.91 and trough cycle1: 3.95, cycle2: 3.95, P = 0.99), irrespective of disease activity. Drug levels were stable over the first 9 days (visit 1–2), but declined to trough by a mean 1.06 and 0.89 μg/mL between visit 1 or 2, respectively (P < 0.001). Models using nontemporal factors (smoking, syringe delivery device) and levels at earlier visits accounted for 66–80{\%} of the variance in trough levels. On receiver-operating curve analysis, thresholds identified in the first 9 days that predicted a therapeutic trough level were similar to the trough threshold itself, with high sensitivity but modest specificity. Conclusion: While therapeutic drug monitoring should be performed at trough, a drug level ≥4.9 μg/mL obtained during the first 9 days predicts a therapeutic trough drug level with reasonable confidence.",
author = "Ward, {M. G.} and Thwaites, {Peter A} and L. Beswick and Hogg, {Andrew J} and G. Rosella and {Van Langenberg}, D. and J. Reynolds and Gibson, {P. R.} and Sparrow, {M. P.}",
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Intra-patient variability in adalimumab drug levels within and between cycles in Crohn's disease. / Ward, M. G.; Thwaites, Peter A; Beswick, L.; Hogg, Andrew J; Rosella, G.; Van Langenberg, D.; Reynolds, J.; Gibson, P. R.; Sparrow, M. P.

In: Alimentary Pharmacology and Therapeutics, Vol. 45, No. 8, 01.04.2017, p. 1135-1145.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Intra-patient variability in adalimumab drug levels within and between cycles in Crohn's disease

AU - Ward, M. G.

AU - Thwaites, Peter A

AU - Beswick, L.

AU - Hogg, Andrew J

AU - Rosella, G.

AU - Van Langenberg, D.

AU - Reynolds, J.

AU - Gibson, P. R.

AU - Sparrow, M. P.

PY - 2017/4/1

Y1 - 2017/4/1

N2 - Background: Whether therapeutic drug monitoring for adalimumab needs to be performed at trough has not been defined. Aim: To determine intra-patient adalimumab drug-level variation and to identify modulating patient and disease factors. Methods: In this prospective observational study, adult patients with Crohn's disease established on maintenance adalimumab had drug levels measured repeatedly according to pre-defined schedules (visit 1: day 4–6, visit 2: day 7–9, trough: day 13–14) across two consecutive fortnightly cycles. Disease activity was assessed using Harvey–Bradshaw Index, C-reactive protein and faecal calprotectin. For this analysis, trough levels ≥4.9 μg/mL were considered therapeutic. Results: Nineteen patients underwent 111 evaluations. Mean intra-patient drug levels from paired visits between cycles did not differ (visit1 cycle1: 4.81, cycle2: 5.21 μg/mL, P = 0.24, visit2 cycle1: 4.86, cycle2: 4.82, P = 0.91 and trough cycle1: 3.95, cycle2: 3.95, P = 0.99), irrespective of disease activity. Drug levels were stable over the first 9 days (visit 1–2), but declined to trough by a mean 1.06 and 0.89 μg/mL between visit 1 or 2, respectively (P < 0.001). Models using nontemporal factors (smoking, syringe delivery device) and levels at earlier visits accounted for 66–80% of the variance in trough levels. On receiver-operating curve analysis, thresholds identified in the first 9 days that predicted a therapeutic trough level were similar to the trough threshold itself, with high sensitivity but modest specificity. Conclusion: While therapeutic drug monitoring should be performed at trough, a drug level ≥4.9 μg/mL obtained during the first 9 days predicts a therapeutic trough drug level with reasonable confidence.

AB - Background: Whether therapeutic drug monitoring for adalimumab needs to be performed at trough has not been defined. Aim: To determine intra-patient adalimumab drug-level variation and to identify modulating patient and disease factors. Methods: In this prospective observational study, adult patients with Crohn's disease established on maintenance adalimumab had drug levels measured repeatedly according to pre-defined schedules (visit 1: day 4–6, visit 2: day 7–9, trough: day 13–14) across two consecutive fortnightly cycles. Disease activity was assessed using Harvey–Bradshaw Index, C-reactive protein and faecal calprotectin. For this analysis, trough levels ≥4.9 μg/mL were considered therapeutic. Results: Nineteen patients underwent 111 evaluations. Mean intra-patient drug levels from paired visits between cycles did not differ (visit1 cycle1: 4.81, cycle2: 5.21 μg/mL, P = 0.24, visit2 cycle1: 4.86, cycle2: 4.82, P = 0.91 and trough cycle1: 3.95, cycle2: 3.95, P = 0.99), irrespective of disease activity. Drug levels were stable over the first 9 days (visit 1–2), but declined to trough by a mean 1.06 and 0.89 μg/mL between visit 1 or 2, respectively (P < 0.001). Models using nontemporal factors (smoking, syringe delivery device) and levels at earlier visits accounted for 66–80% of the variance in trough levels. On receiver-operating curve analysis, thresholds identified in the first 9 days that predicted a therapeutic trough level were similar to the trough threshold itself, with high sensitivity but modest specificity. Conclusion: While therapeutic drug monitoring should be performed at trough, a drug level ≥4.9 μg/mL obtained during the first 9 days predicts a therapeutic trough drug level with reasonable confidence.

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U2 - 10.1111/apt.13992

DO - 10.1111/apt.13992

M3 - Article

VL - 45

SP - 1135

EP - 1145

JO - Alimentary Pharmacology and Therapeutics

JF - Alimentary Pharmacology and Therapeutics

SN - 0269-2813

IS - 8

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