| Lack of effect of tofacitinib (CP-690,550) on the pharmacokinetics of the CYP3A4 substrate midazolam in healthy volunteers: confirmation of in vitro data. | |
| | |
MedLine Citation:
|
PMID: 22233204 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: • Tofacitinib (CP-690,550) is a novel, oral Janus kinase inhibitor being investigated as a targeted immunomodulator and disease-modifying therapy in rheumatoid arthritis. • Non-renal elimination accounts for 70% of the total clearance of tofacitinib and the metabolism is primarily mediated by cytochrome P450 (CYP) 3A4. • This study was required to determine the effect of tofacitinib on the in vivo pharmacokinetics of a sensitive CYP3A4 substrate. WHAT THIS STUDY ADDS: • The pharmacokinetics of midazolam, a sensitive CYP3A4 substrate, are not altered when co-administered with tofacitinib in healthy subjects. • Tofacitinib is unlikely to affect the clearance of drugs metabolized by CYP enzymes. • There is no need for dose adjustments of CYP substrates when co-administered with tofacitinib. AIMS: To investigate inhibitive and inductive effects of tofacitinib (CP-690,550), a Janus kinase inhibitor, on CYP3A4 function via in vitro and in vivo studies. METHODS: In vitro experiments were conducted to assess the inhibition and induction potential of tofacitinib for major drug metabolizing enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4). A phase 1, randomized, open-label, two-way crossover study (NCT00902460) was conducted to confirm the lack of inhibitive/inductive effect on a sensitive CYP3A4 substrate, midazolam, in healthy subjects. Midazolam pharmacokinetics were assessed over 24 h following single dose 2 mg administration prior to administering tofacitinib and after twice daily dosing of tofacitinib 30 mg for 6 days. The primary endpoint was midazolam area under the concentration-time profile, from time 0 to infinity (AUC(0,∞)). RESULTS: In vitro studies demonstrated low potential for CYP inhibition (IC(50) estimates tofacitinib > 30 µm), CYP3A4 mRNA induction (observed at tofacitinib concentrations ≥ 25 µm) and no effect on enzymatic activity of CYP substrates. In the human study, AUC(0,∞) adjusted geometric mean ratio for midazolam plus tofacitinib to midazolam alone was 103.97% [90% confidence interval (CI) 95.57, 113.12], wholly within the pre-specified acceptance region (80, 125). The 90% CI for the ratio of adjusted geometric means of maximum plasma concentration (C(max) ) (95.98, 108.87) was also wholly within this acceptance region. CONCLUSIONS: These data confirm a lack of an inhibitive or inductive effect of tofacitinib on CYP3A activity in humans and, in conjunction with in vitro data, support the conclusion that tofacitinib is unlikely to influence the CYP enzyme system as a whole. |
| | |
Authors:
|
Pankaj Gupta; Christine Alvey; Rong Wang; Martin E Dowty; Odette A Fahmi; Robert L Walsky; Richard J Riese; Sriram Krishnaswami |
Related Documents
:
|
10225354 - Changes in somatosensory evoked potentials following forebrain ischemia in the gerbils:... 16671474 - Effects of 2,4-dinitrophenol on ischemia-induced blood-brain barrier disruption. 18277344 - Different flavonoids present in the micronized purified flavonoid fraction (daflon 500 ... 15782554 - Effects of intracarotid injection of methylprednisolone on cellular oedema after osmoti... 7515474 - Radioprotective effect of stobadine in the mouse micronucleus test. 20215554 - Anti-cd22 immunotoxin rfb4(dsfv)-pe38 (bl22) for cd22-positive hematologic malignancies... |
Publication Detail:
|
Type: Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't |
Journal Detail:
|
Title: British journal of clinical pharmacology Volume: 74 ISSN: 1365-2125 ISO Abbreviation: Br J Clin Pharmacol Publication Date: 2012 Jul |
Date Detail:
|
Created Date: 2012-06-11 Completed Date: 2012-11-19 Revised Date: 2013-04-16 |
Medline Journal Info:
|
Nlm Unique ID: 7503323 Medline TA: Br J Clin Pharmacol Country: England |
Other Details:
|
Languages: eng Pagination: 109-15 Citation Subset: IM |
Copyright Information:
|
© 2012 Pfizer Inc. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society. |
Affiliation:
|
Pfizer Inc., Groton, CT 06340-8012, USA. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Adult Cross-Over Studies Cytochrome P-450 CYP3A / metabolism* Drug Interactions Female GABA Modulators / pharmacokinetics* Half-Life Humans Janus Kinases / antagonists & inhibitors* Male Metabolic Clearance Rate Midazolam / pharmacokinetics* Middle Aged Pyrimidines / pharmacology* Pyrroles / pharmacology* Young Adult |
| Chemical | |
Reg. No./Substance:
|
0/GABA Modulators; 0/Pyrimidines; 0/Pyrroles; 0/tofacitinib; 59467-70-8/Midazolam; EC 1.14.13.67/CYP3A4 protein, human; EC 1.14.14.1/Cytochrome P-450 CYP3A; EC 2.7.10.2/Janus Kinases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Hypericin-mediated Photodynamic Antimicrobial Effect on Clinically Isolated Pathogens(†).
Next Document: Ginsenoside-Rd improves outcome of acute ischaemic stroke - a randomized, double-blind, placebo-cont...