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P386. Pharmacokinetics of laquinimod in patients with active moderate to severe Crohn's disease

G. D'Haens1, W.J. Sandborn2, P. Rutgeerts3, J.F. Colombel4, D. Mimrod5, O. Spiegelstein5, K. Brown6, B. Feagan7, 1University of Amsterdam, Academic Medical Center, Amsterdam, Netherlands, 2University of California, UCSD Inflammatory Bowel Disease Center, San Diego CA, United States, 3Catholic University of Leuven, Department of Internal Medicine and Endoscopy, Leuven, Belgium, 4Icahn School of Medicine at Mount Sinai, Gastroenterology, New York, United States, 5Teva Pharmaceuticals, Phase-1 & Clinical Pharmacology Research and Development, Netanya, Israel, 6Teva Pharmaceuticals, Clinical Development Research and Development, Frazer, United States, 7University of Western Ontario, Robarts Clinical Trials Robarts Research Institute, Ontario, Canada


Laquinimod is an oral therapy in development for the treatment of Crohn's disease (CD). An exploratory multicenter double-blind dose-ranging phase 2 study (NCT00737932) found that laquinimod at doses of 0.5 mg and 1.0 mg safely induced clinical remission in patients with active moderate–severe CD while higher doses of laquinimod showed effects similar to placebo. We evaluated the pharmacokinetics of multiple doses of laquinimod in patients with active moderate to severe CD.


Patients (N = 180) with active moderate-to-severe CD were randomly assigned to one of 4 laquinimod doses (0.5, 1.0, 1.5, 2 mg/day) or placebo in sequential dose-escalating cohorts. A loading dose regimen of twice the intended daily dose was given during the first two days of study drug treatment. Treatment was administered daily for 8 weeks with a 4-week follow-up visit. Stable concomitant therapies and prior anti-TNF medications were allowed. Blood samples were collected from all patients on week 4 before dosing and at 0.25, 0.5, 1, 1.5, 2, 3, 6, and 24 h postdose. Noncompartmental PK analysis was done using Phoenix WinNonlin and the following pharmacokinetic parameters were derived: Cmax, Tmax, AUC, Cmin, and % Fluctuation. Assessment of dose-proportionality was done using a multiple linear regression model.


Plasma concentration-time data were available from a total of 26 patients receiving placebo (n = 6), 0.5 mg (n = 5), 1 mg (n = 2), 1.5 mg (n = 8) and 2 mg (n = 4). Plasma concentrations reached maximum levels within 1 hour of dosing with little decline over the 24h dosing interval (Table 1).

Pre-dose concentrations were similar at Week 1 and Week 4, suggesting that steady state was reached with loading regimen within first week of dosing. Laquinimod plasma exposure increased with dose, with dose-normalized Cmax and AUC comparable across the 0.5 to 2.0 mg dose range. Statistical analyses indicated that the systemic exposure of laquinimod was proportional to dose in the 0.5 to 2 mg range.

Table 1 (abstract P386) a
DosenTmax (h)Cmax (ng/mL)AUC0–last (h·ng/mL)Cmin (ng/mL)Cmax/DAUC0–last/D
0.5 mg53.03376(112)6996(2063)249(74.6)752(223)13993(4126)
1.5 mg71.25885(155)17552(3514)622(127)590(103)11701(2343)
2.0 mg41.031447(435)28883(10475)970(316)724(218)14442(5238)
a Values are mean(SD), except for Tmax (median); NC, not calculated. Cmax/D and AUC0–last/D are dose normalized values.
b The 1 mg dose group included only two subjects and therefore mean values were not calculated.


Laquinimod reached its maximum concentration levels within approximately 1 hour of administration and maintained steady state conditions with little fluctuation of plasma levels throughout the 24 hour dosing interval. The pharmacokinetics of laquinimod in CD patients appears to be linear across the dose range of 0.5 to 2.0 mg and similar to that seen in healthy volunteers and in patients with multiple sclerosis. The pharmacokinetics of laquinimod does not explain the improved clinical symptoms seen in patients with CD with lower but not higher laquinimod doses.