Background/Purpose: Tofacitinib is an oral Janus kinase
inhibitor for the treatment of RA. A modified-release (MR) formulation has been
designed to enable once daily (QD) dosing and achieve a comparable clinical profile
to the approved 5 mg twice daily (BID) immediate-release formulation (IR). Two
key clinical pharmacology studies have been conducted to evaluate
pharmacokinetic (PK) performance of the MR formulation.

Methods: Two randomized, open-label, cross-over, Phase 1 studies were conducted
in healthy volunteers (HV). HV were randomly assigned 1:1 to one of two
treatment sequences in each study. In study A (Pfizer study A3921212), HV were
given tofacitinib MR 11 mg QD or tofacitinib IR 5 mg BID under both single- and
multiple-dose conditions to assess relative bioavailability (BA) of the MR
formulation compared with the IR formulation. Duration of multiple-dose phase
was 5 days. In study B (NCT0208475, Pfizer study A3921180) tofacitinib MR 11 mg
single dose was given under fed and fasted conditions to evaluate the impact of
a high-fat meal on BA. HV were aged 18-55 years, with body mass index 17.5‑30.5
kg/m², total body weight >50 kg, and no evidence of active or
latent tuberculosis infection.

Results: In study A (N=24), MR and IR achieved maximum plasma concentration (C_max) at 4 hours and 0.5 hours post-dose,
respectively; mean terminal half-life (t_1/2) was 5.9 and 3.2 hours,
respectively. Area under the plasma-concentration time profile (AUC) and C_max after both single- and multiple-dose
administrations were equivalent between MR and IR (Table 1); minimum plasma
concentration was 29% lower for the MR formulation. In study B (N=24), maximum
plasma concentrations were achieved 1 hour later in the presence of food. Mean
t_1/2 was 4.4 and 5.5 hours, under fed and fasted conditions,
respectively. AUC was essentially the same under fed and fasted conditions
(Table 2). C_max increased by 27% under fed
conditions (Table 2), and peak concentrations were achieved 1 hour later in the
presence of food. Tofacitinib MR, under fasted and fed conditions, was well
tolerated in both studies. Most reported adverse events (AEs) were mild and
related to study treatment; AEs were similar in frequency and type for
tofacitinib MR and IR.

Conclusion: The tofacitinib MR formulation given QD has equivalent
AUC and C_max to the IR formulation given
BID; C_min for MR is ~29% lower. Food does
not impact the BA of tofacitinib from the MR formulation. Tofacitinib was well
tolerated in both studies.