Tillmann, C. (Christiane)

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    Modelling the Anti-Migraine Effects of BIBN 4096 BS
    (Adis Press, 2006) Troconiz, I.F. (Iñaki F.); Schaefer, H. (Hans); Tillmann, C. (Christiane); Roth, W. (Willy); Wolters, J.M. (Jan Markus)
    Migraine attacks are associated with release of the calcitonin gene-related peptide (CGRP) from trigeminal nerves. BIBN 4096 BS is the first CGRP receptor antagonist tested in humans showing response rates similar to those reported for triptans, together with very good safety and tolerability profiles. The objective of the current study is to develop a population pharmacokinetic/pharmacodynamic model resembling the mechanism of action of BIBN 4096 BS, and to extract by model-based simulations dosage formulations and pharmacodynamic properties that can assist in the development of CGRP receptor antagonists. METHODS: 126 patients with an acute moderate to severe migraine attack lasting not more than 6 hours were enrolled in this phase IIa study. BIBN 4096 BS was given as a single intravenous 10-minute infusion at different dose levels ranging from 0.25 to 10 mg. Severity of headache was measured up to 24 hours. Patients who did not show pain relief by 2 hours were allowed to take rescue medication. Severity of headache and time to rescue medication measurements were fitted simultaneously using logistic regression and time-to-event analysis with nonlinear mixed-effect modelling software NONMEM version V. RESULTS: Severity of headache and time to rescue medication were described as a function of the fraction of the CGRP receptors blocked by BIBN 4096 BS, and controlled by the second- and first-order rate constants representing the onset (k(on)) and offset (k(off)) of the anti-migraine effects. The model predicted a slow rate of offset of the anti-migraine effect (half-life of k(off) = 21 hours). The model developed described the data well and was validated properly. DISCUSSION: A semi-mechanistic population pharmacokinetic/pharmacodynamic model has been developed for the anti-migraine effects of BIBN 4096 BS, characterised by the severity of headache and time to rescue medication. Simulations exploring the effect of the rate of absorption, bioavailability after an extravascular administration and the rate of activation/inactivation of the anti-migraine effect were performed. The rate of absorption seems to play a minor role; however, at least bioavailability fractions of 0.2-0.3 should be obtained. With regard to the kinetics of the anti-migraine effect, and to achieve a response rate of 60% at 2 hours, values of k(on) should be > 0.081 mL/ng/h. At later times after administration higher values of k(off) are associated with faster offset of the response. The simulations showed that molecules with high k(on) and low k(off) values are the most promising.
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    Effects of the direct thrombin inhibitor dabigatran on ex vivo coagulation time in orthopaedic surgery patients: a population model analysis
    (British pharmacological society, 2006) Troconiz, I.F. (Iñaki F.); Liesenfeld, K.H. (K.H.); Tillmann, C. (Christiane); Eriksson, B.I. (B. I.); Stangier, J. (J.); Schäfer, G.H. (G.H.)
    Aims To describe the pharmacokinetic–pharmacodynamic (PK–PD) characteristics of the direct thrombin inhibitor dabigatran in hip replacement patients by assessing coagu- lation parameters activated partial thromboplastin time (aPTT) and ecarin clotting time (ECT), interindividual variability and factors affecting PD responses. Methods BISTRO I patients received oral dabigatran etexilate postsurgery for 6–10 days. Dabig- atran plasma concentrations and aPTT/ECT were measured on the day of surgery, on subsequent days and at steady state. PK–PD characteristics of the dabigatran–aPTT/ ECT relationships were evaluated using NONMEM V. Results The dabigatran concentration–aPTT relationship was described combining a linear and an Emax model. Mean baseline aPTT was 33.4 s and Emax (maximum increase in aPTT contributed by the Emax model) was 26.9 s. The dabigatran concentration needed to attain 50% of maximum effect (EC50) was 94.7 ng ml−1 and the mean slope of the linear concentration–response relationship (SLOP) was 0.0509 s ng−1 ml−1. Base- line aPTT and Emax were highest following surgery and declined with time. The dabigatran concentration–ECT relationship fitted a linear model. Mean baseline ECT was 28 s and decreased with time; 50% of the maximum effect was observed after 2.9 days. SLOP decreased from 0.38 to 0.27 s ng−1 ml−1 with a half-life of 1.1 day, indicating greater PD effects on the day of surgery. Interindividual and residual variability was low. Covariates could not explain variability of this model. Conclusions aPTT and ECT prolongation were directly correlated with dabigatran concentrations. Blood coagulation prolongation was most pronounced following surgery. Data suggest that ECT provides a more precise description of the anticoagulant effect than aPTT.