Background/Purpose: Tofacitinib is a novel oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). It has a short pharmacokinetic (PK) half-life of 3 hours, with systemic concentrations falling below pharmacologically active levels within 24 hours after cessation of therapy. This analysis investigated the reversibility of the pharmacodynamic (PD) effects of tofacitinib over a range of biomarkers. Phosphorylation of signal transducer and activator of transcription (STAT)5 was measured as a direct read-out of JAK1/3 dependent signaling. In addition, changes reflecting downstream events such as interferon-inducible protein-10 (IP-10), lymphocyte subsets (natural killer (NK) and B cells), neutrophils, C-reactive protein (CRP), and clinical efficacy were monitored.

Methods: Data following discontinuation (dc) of tofacitinib from 2 randomized Phase 2 (P2) studies of 4-6 weeks’ treatment duration, and temporary withdrawal from 1 long-term extension (LTE), were assessed. In P2 study A (NCT00976599), tofacitinib 10 mg twice daily (BID) or placebo were administered to 29 RA patients (pts) on stable methotrexate for 4 weeks and blood samples were collected during therapy and ≤1 week post-dc. In P2 study B (NCT00147498), tofacitinib 5, 15, or 30 mg BID or placebo were administered to 264 RA pts as monotherapy for 6 weeks and blood samples were collected during therapy and 2 and 6 weeks after dc. In the LTE study (NCT00413699), after a median of approximately 22 months of exposure, CRP, disease activity score defined using 28 joint counts (DAS28) and Health Assessment Questionnaire Disability Index (HAQ-DI) were assessed in pts in whom tofacitinib was administered continuously throughout the study or in whom tofacitinib was withdrawn for a 2-week period.

Results: After short-term tofacitinib treatment (4-6 weeks), mean and median pSTAT5 levels fully reversed to baseline within 24 hours after dc, while serum IP-10 levels and NK and B cell counts completely reversed to baseline levels 1-2 weeks after dc; mean CRP and neutrophil counts partially reversed over 2-4 weeks after dc. After temporary withdrawal from longer-term tofacitinib treatment, B cell counts decreased and CRP, DAS28 and HAQ-DI values increased after 1-2 weeks (Table).

Table. Reversibility of Pharmacodynamic Endpoints After Tofacitinib Treatment is Discontinued
	Biomarker	Change during treatment	Time to reversal (weeks)
Phase 2 RCT	pSTAT5a	↓	<1
	IP-10a	↓	1
	CRPb	↓	2
	B cellsb	↑	2
	NK cellsb	↓	2
	Neutrophilsb	↓	4
LTE*	B cells	↑	1
	CRP	↓	1
	DAS28-4(ESR)	↓	1
	HAQ-DI	↓	2
RCT, randomized controlled trial; aP2 study A (4 weeks); bP2 study B (6 weeks); *LTE, long-term extension study (median 22 months)

Conclusion: The PD effects of short- or long-term tofacitinib treatment are reversible, after approximately 2 weeks of dc. These data provide a scientific basis for a 2-week dc of tofacitinib to reverse many of the pharmacologic effects of the agent.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/reversibility-of-pharmacodynamic-effects-after-short-and-long-term-treatment-with-tofacitinib-in-patients-with-rheumatoid-arthritis/