Following oral administration of XELJANZ (tablets and oral solution), peak plasma concentrations were reached within 0.5 hour - 1 hour, elimination half-life was about 3 hours and a dose-proportional increase in systemic exposure was observed in the therapeutic dosage range. Steady state concentrations were achieved in 24-48 hours with negligible accumulation after twice daily administration.

Following oral administration of XELJANZ XR (extended-release tablets), peak plasma concentrations were reached at 4 hours and half-life was about 6 to 8 hours. Steady state concentrations were achieved within 48 hours with negligible accumulation after once daily administration.

Table 8 describes the pharmacokinetic parameters of XELJANZ and XELJANZ XR.

Absorption

Distribution

After intravenous administration, the volume of distribution was 87 L. The protein binding of tofacitinib is approximately 40%. Tofacitinib binds predominantly to albumin and does not appear to bind to α1-acid glycoprotein. Tofacitinib distributes equally between red blood cells and plasma.

Metabolism and Excretion

Clearance mechanisms for tofacitinib are approximately 70% hepatic metabolism and 30% renal excretion of the parent drug. The metabolism of tofacitinib is primarily mediated by CYP3A4 with minor contribution from CYP2C19. In a human radiolabeled study, more than 65% of the total circulating radioactivity was accounted for by unchanged tofacitinib, with the remaining 35% attributed to 8 metabolites, each accounting for less than 8% of total radioactivity. The pharmacologic activity of tofacitinib is attributed to the parent molecule.

Pharmacokinetics in Patients with RA, PsA, AS, and UC

Population pharmacokinetic (PK) analyses indicated that PK characteristics were similar between patients with RA, PsA, ankylosing spondylitis, and UC. The coefficient of variation (%) in AUC of tofacitinib were generally similar across different disease patients, ranging from 22% to 34% (Table 9).

Specific Populations

Covariate evaluation as part of population PK analyses in adult patient populations indicated no clinically relevant change in tofacitinib exposure, after accounting for differences in renal function (i.e., creatinine clearance) between patients, based on age, weight, biological sex and race (Figure 1). An approximately linear relationship between body weight and volume of distribution was observed, resulting in higher peak (Cmax) and lower trough (Cmin) concentrations in lighter patients. However, this difference is not considered to be clinically relevant.

Covariate evaluation as part of population PK analyses in pediatric patients with pcJIA, including PsA, identified body weight significantly impacting tofacitinib exposure, which supports weight-based dosing in this population. There were no identified clinically significant differences in tofacitinib exposure with different age, biological sex, racial, or pcJIA or PsA disease severity groups.

The effect of renal and hepatic impairment and other intrinsic factors on the PK of tofacitinib is shown in Figure 1.

Figure 1: Impact of Intrinsic Factors on Tofacitinib Pharmacokinetics

Note: Reference values for weight, age, biological sex, and race comparisons are 70 kg, 55 years, male, and white, respectively; reference groups for renal and hepatic impairment data are patients with normal renal and hepatic function. Renal function was estimated using creatinine clearance by Cockcroft-Gault method and hepatic function was estimated using Child-Pugh scoring method.

In patients with end-stage renal disease maintained on hemodialysis, mean AUC was approximately 40% higher compared with historical healthy subject data, consistent with approximately 30% contribution of renal clearance to the total clearance of tofacitinib [see Dosage and Administration (2.3, 2.4, 2.5) and Use in Specific Populations (8.6)].

Drug Interaction Studies

Potential for XELJANZ/XELJANZ XR to Influence the PK of Other Drugs

In vitro studies indicate that tofacitinib does not significantly inhibit or induce the activity of the major human drug-metabolizing CYPs (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at concentrations corresponding to the steady state Cmax of a 10 mg twice daily dose. These in vitro results were confirmed by a human drug interaction study showing no changes in the pharmacokinetics of midazolam, a highly sensitive CYP3A4 substrate, when concomitantly administered with XELJANZ.

In vitro studies indicate that tofacitinib does not significantly inhibit the activity of the major human drug-metabolizing uridine 5'-diphospho-glucuronosyltransferases (UGTs) [UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7] at concentrations exceeding 250 times the steady state Cmax of a 10 mg twice daily dose.

In patients with RA, the oral clearance of tofacitinib does not vary with time, indicating that tofacitinib does not normalize CYP enzyme activity in patients with RA. Therefore, concomitant use with XELJANZ/XELJANZ XR is not expected to result in clinically relevant increases in the metabolism of CYP substrates in patients with RA.

In vitro data indicate that the potential for tofacitinib to inhibit transporters such as P-glycoprotein, organic anionic or cationic transporters at therapeutic concentrations is low.

The impact of tofacitinib on the PK of other drugs for the concomitant drugs are shown in Figure 2.

Figure 2: Impact of Tofacitinib on the Pharmacokinetics of Other Drugs

Note: Reference group is administration of concomitant medication alone; OCT = Organic Cationic Transporter; MATE = Multidrug and Toxic Compound Extrusion.

Potential for Other Drugs to Influence the Pharmacokinetics of Tofacitinib

Since tofacitinib is metabolized by CYP3A4, interaction with drugs that inhibit or induce CYP3A4 is likely. Inhibitors of CYP2C19 alone or P-glycoprotein are unlikely to substantially alter the pharmacokinetics of tofacitinib (see Figure 3).

Figure 3: Impact of Other Drugs on the Pharmacokinetics of Tofacitinib

Note: Reference group is administration of XELJANZ alone.