ObjectivePatients with rheumatoid arthritis (RA) are at increased risk of herpes zoster, and vaccination is recommended for patients ages 50 years and older, prior to starting treatment with biologic agents or tofacitinib. Tofacitinib is an oral JAK inhibitor for the treatment of RA. We evaluated its effect on the immune response and safety of live zoster vaccine (LZV).MethodsIn this phase II, 14‐week, placebo‐controlled trial, patients ages 50 years and older who had active RA and were receiving background methotrexate were given LZV and randomized to receive tofacitinib 5 mg twice daily or placebo 2–3 weeks postvaccination. We measured humoral responses (varicella zoster virus [VZV]–specific IgG level as determined by glycoprotein enzyme‐linked immunosorbent assay) and cell‐mediated responses (VZV‐specific T cell enumeration, as determined by enzyme‐linked immunospot assay) at baseline and 2 weeks, 6 weeks, and 14 weeks postvaccination. End points included the geometric mean fold rise (GMFR) in VZV‐specific IgG levels (primary end point) and T cells (number of spot‐forming cells/106 peripheral blood mononuclear cells) at 6 weeks postvaccination.ResultsOne hundred twelve patients were randomized to receive tofacitinib (n = 55) or placebo (n = 57). Six weeks postvaccination, the GMFR in VZV‐specific IgG levels was 2.11 in the tofacitinib group and 1.74 in the placebo group, and the VZV‐specific T cell GMFR was similar in the tofacitinib group and the placebo group (1.50 and 1.29, respectively). Serious adverse events occurred in 3 patients in the tofacitinib group (5.5%) and 0 patients (0.0%) in the placebo group. One patient, who lacked preexisting VZV immunity, developed cutaneous vaccine dissemination 2 days after starting tofacitinib (16 days postvaccination). This resolved after tofacitinib was discontinued and the patient received antiviral treatment.ConclusionPatients who began treatment with tofacitinib 2–3 weeks after receiving LZV had VZV‐specific humoral and cell‐mediated immune responses to LZV similar to those in placebo‐treated patients. Vaccination appeared to be safe in all of the patients except 1 patient who lacked preexisting VZV immunity.
This study evaluated the short-term effects of tofacitinib treatment on peripheral blood leukocyte phenotype and function, and the reversibility of any such effects following treatment withdrawal in healthy volunteers. Cytomegalovirus (CMV)-seropositive subjects received oral tofacitinib 10 mg twice daily for 4 weeks and were followed for 4 weeks after drug withdrawal. There were slight increases in total lymphocyte and total T-cell counts during tofacitinib treatment, and B-cell counts increased by up to 26%. There were no significant changes in granulocyte or monocyte counts, or granulocyte function. Naïve and central memory T-cell counts increased during treatment, while all subsets of activated T cells were decreased by up to 69%. T-cell subsets other than effector memory cluster of differentiation CD4 +, activated naïve CD4 + and effector CD8 + T-cell counts and B-cell counts, normalized 4 weeks after withdrawal. Following ex vivo activation, measures of CMV-specific T-cell responses, and antigen non-specific T-cell-mediated cytotoxicity and interferon (IFN)-γ production, decreased slightly. These T-cell functional changes were most pronounced at Day 15, partially normalized while still on tofacitinib and returned to baseline after drug withdrawal. Total natural killer (NK)-cell counts decreased by 33%, returning towards baseline after drug withdrawal. NK-cell function decreased during tofacitinib treatment, but without a consistent time course across measured parameters. However, markers of NK-cell-mediated cytotoxicity, antibody-dependent cellular cytotoxicity and IFN-γ production were decreased up to 42% 1 month after drug withdrawal. CMV DNA was not detectable in whole blood, and there were no cases of herpes zoster reactivation. No new safety concerns arose. In conclusion, the effect of short-term tofacitinib treatment on leukocyte composition and function in healthy CMV+ volunteers is modest and largely reversible 4weeks after withdrawal.
Background and Objective Abrocitinib is a Janus kinase 1-selective inhibitor for the treatment of moderate-to-severe atopic dermatitis. Abrocitinib is eliminated primarily by metabolism involving cytochrome P450 (CYP) enzymes. Abrocitinib pharmacologic activity is attributable to the unbound concentrations of the parent molecule and 2 active metabolites, which are substrates of organic anion transporter 3 (OAT3). The sum of potency-adjusted unbound exposures of abrocitinib and its 2 active metabolites is termed the abrocitinib active moiety. We evaluated effects of CYP inhibition, CYP induction, and OAT3 inhibition on the pharmacokinetics of abrocitinib, its metabolites, and active moiety. Methods Three fixed-sequence, open-label, phase I studies in healthy adult volunteers examined the drug-drug interactions (DDIs) of oral abrocitinib with fluvoxamine and fluconazole, rifampin, and probenecid. Results Co-administration of abrocitinib with fluvoxamine or fluconazole increased the area under the plasma concentration-time curve from time 0 to infinity (AUC inf ) of the unbound active moiety of abrocitinib by 91% and 155%, respectively. Co-administration with rifampin decreased the unbound active moiety AUC inf by 56%. The OAT3 inhibitor probenecid increased the AUC inf of the unbound active moiety by 66%. Conclusions It is important to consider the effects of DDIs on the abrocitinib active moiety when making dosing recommendations. Co-administration of strong CYP2C19/2C9 inhibitors or CYP inducers impacted exposure to the abrocitinib active moiety. A dose reduction by half is recommended if abrocitinib is co-administered with strong CYP2C19 inhibitors, whereas co-administration with strong CYP2C19/2C9 inducers is not recommended. No dose adjustment is required when abrocitinib is administered with OAT3 inhibitors.
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