Effect of Vemurafenib on the Pharmacokinetics of a Single Dose of Tizanidine (a CYP1A2 Substrate) in Patients With BRAF V600 Mutation-Positive Malignancies.

Autor: Zhang W; F. Hoffmann-La Roche Ltd., New York, New York, USA., McIntyre C; pRED Roche Innovation Centre Welwyn, Roche Products Ltd., Welwyn Garden City, UK., Riehl T; Genentech, Inc., South San Francisco, California, USA., Forbes H; F. Hoffmann-La Roche Ltd., Mississauga, Ontario, Canada., Bertran E; pRED Roche Innovation Centre Basel, Roche Products Ltd., Basel, Switzerland., Choi HJ; Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea., Lee DH; Asan Medical Center, Seoul, Republic of Korea., Lee J; Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Jazyk: angličtina
Zdroj: Clinical pharmacology in drug development [Clin Pharmacol Drug Dev] 2020 Jul; Vol. 9 (5), pp. 651-658. Date of Electronic Publication: 2020 Apr 20.
DOI: 10.1002/cpdd.788
Abstrakt: This phase 1 open-label, multicenter, 3-period, fixed-sequence study evaluated the effect of multiple doses of vemurafenib on the pharmacokinetics of 1 dose of tizanidine, a probe CYP1A2 substrate, in patients with BRAF V600 mutation-positive metastatic malignancy. Patients received 1 dose of tizanidine 2 mg on day 1 (period A), vemurafenib 960 mg twice daily on days 2-21 (period B), and 1 dose of tizanidine 2 mg and vemurafenib 960 mg twice daily on day 22 (period C). Log-transformed area under the concentration-time curve (AUC) and maximum plasma concentration (C max ) values for tizanidine in 16 patients were compared between periods A (tizanidine alone) and C (tizanidine plus vemurafenib) using an analysis of variance model. Multiple doses of vemurafenib increased plasma exposure of 1 dose of tizanidine, with geometric mean ratios (period C/period A) for C max , AUC inf , and AUC last of 2.15 (90%CI, 1.71-2.71), 4.22 (90%CI, 3.37-5.28), and 4.74 (90%CI, 3.55-6.33), respectively; 90%CIs were all outside predefined limits for lack of drug-drug interaction (0.82-1.22). This study confirmed vemurafenib as a moderate inhibitor of CYP1A2 in vivo, with a statistically significant drug-drug interaction with tizanidine. Caution should be exercised when dosing vemurafenib concurrently with CYP1A2 substrates.
(© 2020, The American College of Clinical Pharmacology.)
Databáze: MEDLINE
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