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Effect of Vemurafenib on the Pharmacokinetics of a Single Dose of Tizanidine (a CYP1A2 Substrate) in Patients With BRAF V600 Mutation–Positive Malignancies
Author(s) -
Zhang Weijiang,
McIntyre Christine,
Riehl Todd,
Forbes Harper,
Bertran Enric,
Choi Hye Jin,
Lee Dae Ho,
Lee Jeeyun
Publication year - 2020
Publication title -
clinical pharmacology in drug development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.711
H-Index - 22
eISSN - 2160-7648
pISSN - 2160-763X
DOI - 10.1002/cpdd.788
Subject(s) - tizanidine , medicine , pharmacokinetics , vemurafenib , pharmacology , dosing , urology , anesthesia , cancer , metastatic melanoma , spasticity
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.