Tofacitinib, an oral Janus kinase inhibitor: analysis of malignancies across the rheumatoid arthritis clinical development programme.

OBJECTIVES: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). To further assess the potential role of Janus kinase inhibition in the development of malignancies, we performed an integrated analysis of data from the tofacitinib RA clinical development programme. METHODS: Malignancy data (up to 10 April 2013) were pooled from six phase II, six Phase III and two long-term extension (LTE) studies involving tofacitinib. In the phase II and III studies, patients with moderate-to-severe RA were randomised to various tofacitinib doses as monotherapy or with background non-biological disease-modifying antirheumatic drugs (DMARDs), mainly methotrexate. The LTE studies (tofacitinib 5 or 10 mg twice daily) enrolled patients from qualifying prior phase I, II and III index studies. RESULTS: Of 5671 tofacitinib-treated patients, 107 developed malignancies (excluding non-melanoma skin cancer (NMSC)). The most common malignancy was lung cancer (n=24) followed by breast cancer (n=19), lymphoma (n=10) and gastric cancer (n=6). The rate of malignancies by 6-month intervals of tofacitinib exposure indicates rates remained stable over time. Standardised incidence ratios (comparison with Surveillance, Epidemiology and End Results) for all malignancies (excluding NMSC) and selected malignancies (lung, breast, lymphoma, NMSC) were within the expected range of patients with moderate-to-severe RA. CONCLUSIONS: The overall rates and types of malignancies observed in the tofacitinib clinical programme remained stable over time with increasing tofacitinib exposure.

The role of training in effective simulated self-injection of subcutaneous depot medroxyprogesterone acetate: observations from a usability study.

OBJECTIVES: The need for quarterly clinic visits is a barrier to use of subcutaneous depot medroxyprogesterone acetate (DMPA-SC) contraception. The ability to self-inject at home may enhance method acceptance. Since efficacy depends on proper administration, we evaluated whether women could correctly perform simulated injections of DMPA-SC in a Uniject™ injection system using printed Instructions for Use (IFU), with and without hands-on training. STUDY DESIGN: Adult female volunteers (N=120) injected DMPA-SC into a rubber trainer at two visits, 3 months apart. Women were randomly assigned to receive hands-on training before the first injection or no training. The primary outcome was the proportion of women who successfully operated the injection system. An attempt was defined as successful if the participant correctly performed all critical steps in the injection procedure (getting ready, selecting an injection area, preparing the injector, mixing the medicine, activating the injector, injecting the dose) and expelled the dose without unexpected interruption. The success rate at month 3 was considered the primary endpoint. A one-sided 95% confidence limit >80% was used to declare the delivery system and IFU "fit for purpose." RESULTS: With training, the success rate (one-sided 95% confidence limit) was 90.0% (81.8%) at day 1 and 96.7% (90.4%) at month 3; without training, rates were 76.7% (66.7%) and 88.3% (79.8%), respectively. The trained (96.4%) and untrained (92.2%) groups successfully completed injecting into the trainer at first injection, the final critical step of the injection procedure, despite the fact that about one third of participants considered expelling depot medroxyprogesterone acetate (one component of this step) to be difficult. CONCLUSION: Most participants understood the IFU and successfully operated the injection system. Initial hands-on training improved success rates at both visits. For women interested in self-injection, providers should review all steps of the IFU, provide a demonstration, supervise initial injection(s) and ensure that the patient is aware of future injection dates. The potential for self-injection to improve adherence should be studied. IMPLICATIONS: After initial training, women performed simulated self-injections of DMPA-SC in the Uniject system proficiently using printed instructions. Women who are motivated and demonstrate competent injection technique during training can be relied upon to self-inject correctly at home. DMPA-SC users not suitable for self-injection should continue receiving injections at the clinic.

Effects of tofacitinib and other DMARDs on lipid profiles in rheumatoid arthritis: implications for the rheumatologist.

Cardiovascular (CV) morbidity and mortality are increased in patients with active, untreated rheumatoid arthritis (RA), despite lower levels of total and low-density lipoprotein cholesterol reported in individuals with active RA compared with those without RA. Alterations in non-traditional lipid assessments, such as high-density lipoprotein (HDL) function and HDL-associated proteins, have been described in patients with active RA, including elevated HDL-associated serum amyloid A and decreased paraoxonase-1 activity. We review changes in both traditional lipoprotein concentrations and non-traditional lipoprotein assessments in multiple studies of treatment with disease-modifying antirheumatic drugs (DMARDs), including non-biologic and biologic DMARDs and tofacitinib. In addition, data from a recently published clinical trial with tofacitinib that describe a potential mechanism for suppression of cholesterol levels in active RA patients are reviewed. Finally, CV event data from various studies of DMARDs are presented, and the current management of RA patients with regard to the CV risk is reviewed.

Potential mechanisms leading to the abnormal lipid profile in patients with rheumatoid arthritis versus healthy volunteers and reversal by tofacitinib.

OBJECTIVE: Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). Systemic inflammation is proposed to play a fundamental role in the altered lipid metabolism associated with RA; however, the underlying mechanisms are unknown. We undertook this study to compare cholesterol and lipoprotein kinetics in patients with active RA with those in matched healthy volunteers. METHODS: This was a phase I open-label mechanism-of-action study. Cholesterol and lipoprotein kinetics were assessed with (13) C-cholesterol and (13) C-leucine infusions. RA patients were reevaluated after receiving oral tofacitinib 10 mg twice daily for 6 weeks. RESULTS: Levels of high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, total cholesterol, and apolipoprotein A-I (Apo A-I) as well as HDL cholesterol particle number were lower in RA patients (n = 36) than in healthy volunteers (n = 33). In contrast, the cholesterol ester fractional catabolic rate was higher in RA patients, but no differences were observed in cholesterol ester transfer protein, cholesterol ester production rate, HDL-associated Apo A-I fractional catabolic rate, or LDL-associated Apo B fractional catabolic rate. Following tofacitinib treatment in RA patients, the cholesterol ester fractional catabolic rate decreased and cholesterol levels increased. The decrease in cholesterol ester fractional catabolic rate correlated significantly with the increase in HDL cholesterol. Additionally, HDL cholesterol particle number increased and markers of HDL cholesterol function improved. CONCLUSION: This is the first study to assess cholesterol and lipoprotein kinetics in patients with active RA and matched healthy volunteers. The data suggest that low cholesterol levels in patients with active RA may be driven by increases in cholesterol ester catabolism. Tofacitinib treatment reduced cholesterol ester catabolism, thereby increasing cholesterol levels toward those in healthy volunteers, and markers of antiatherogenic HDL function improved.

Immediate early gene expression in the visual cortex of normal and dark reared cats: differences between fos and egr-1.

Northern blotting indicated that the level of induced fos was higher in normal than dark reared cat visual cortex (VC) at 5 weeks of age, comparable at 10 weeks, and higher in dark reared than normal cat visual cortex at 20 weeks. Fos egr-1, induction was higher in dark reared visual cortex at all ages. Thus, dark rearing has similar effects on fos, but not egr-1, expression as it has on physiological neuronal plasticity during the VC critical period.

Evaluation of the effect of fluconazole and ketoconazole on the pharmacokinetics of tofacitinib in healthy adult subjects.

Tofacitinib is a novel, oral JAK inhibitor that is being investigated as a targeted immunomodulator. Tofacitinib is predominantly metabolized by cytochrome P450 (CYP) 3A4 and to a lesser extent by CYP2C19. Two Phase 1, randomized, open-label, single sequence studies in 24 healthy subjects (12 per study) characterized the effects of fluconazole (moderate CYP3A4/potent CYP2C19 inhibitor) and ketoconazole (potent CYP3A4 inhibitor) on tofacitinib pharmacokinetics. In the fluconazole study, subjects received a single tofacitinib 30 mg dose. After 72 hours, subjects received fluconazole 400 mg, followed by 200 mg once daily (QD; days 2-7) plus tofacitinib 30 mg on day 5. In the ketoconazole study, a single tofacitinib 10 mg dose was administered. After 24 hours, subjects received ketoconazole (400 mg QD; days 1-3) plus tofacitinib 10 mg on day 3. Treatment comparisons were made using mixed-effect models. Tofacitinib area under the curve and maximal plasma concentration increased by 79% and 27%, respectively, with fluconazole co-administration and by 103% and 16%, respectively, with ketoconazole co-administration. Tofacitinib half-life increased by approximately 1 hour during co-administration with fluconazole or ketoconazole. Co-administration of moderate to potent CYP3A4 inhibitors is likely to increase the systemic exposure of tofacitinib and thus may warrant dosage adjustments or restrictions.

Evaluation of the potential interaction between tofacitinib and drugs that undergo renal tubular secretion using metformin, an in vivo marker of renal organic cation transporter 2.

Tofacitinib is a novel, oral Janus kinase inhibitor. The potential for drug-drug interactions (DDIs) between tofacitinib and drugs that undergo renal tubular secretion was evaluated using metformin as a probe transporter substrate, and genotyping for organic cation transporter (OCT) 1, OCT2 and multidrug and toxin extrusion 1 polymorphisms. Twenty-four healthy male subjects completed this open-label, fixed-sequence study. Subjects were administered a single oral metformin 500 mg dose on Days 1 and 4, and multiple oral tofacitinib 30 mg twice daily doses on Days 2, 3, and 4. Subjects underwent serial blood and urine samplings (Days 1 and 4) to estimate metformin pharmacokinetics. A single blood sample for tofacitinib was collected 2 hours after the morning dose (Day 4). The 90% confidence intervals for the ratios of maximum plasma concentration, area under the curve and renal clearance of metformin, with and without tofacitinib, were contained within the 80-125% acceptance range commonly used to establish a lack of DDI. No deaths, serious adverse events (AEs), severe AEs or discontinuations due to AEs were reported. The study confirms tofacitinib is unlikely to impact the pharmacokinetics of drugs that undergo renal tubular secretion, and concurs with its weak in vitro OCT2 inhibitory profile.

Central nervous system pharmacokinetics of the Mdr1 P-glycoprotein substrate CP-615,003: intersite differences and implications for human receptor occupancy projections from cerebrospinal fluid exposures.

The central nervous system (CNS) distribution and transport mechanisms of the investigational drug candidate CP-615,003 (N-[3-fluoro-4-[2-(propylamino)ethoxy]phenyl]-4,5,6,7-tetrahydro-4-oxo-1H-indole-3-carboxamide) and its active metabolite CP-900,725 have been characterized. Brain distribution of CP-615,003 and CP-900,725 was low in rats and mice (brain-to-serum ratio < 0.2). Cerebrospinal fluid (CSF)-to-serum ratios of CP-615,003 were 6- to 8-fold lower than the plasma unbound fraction in rats and dogs. In vitro, CP-615,003 displayed quinidine-like efflux in MDR1-expressing Madin-Darby canine kidney II cells. The brain-to-serum ratio of CP-615,003 in mdr1a/1b (-/-) mice was approximately 7 times that in their wild-type counterparts, confirming that impaired CNS distribution was explained by P-gp efflux transport. In contrast, P-gp efflux did not explain the impaired CNS penetration of CP-900,725. Intracerebral microdialysis was used to characterize rat brain extracellular fluid (ECF) distribution. Interestingly, the ECF-to-serum ratio of the P-gp substrate CP-615,003 was 7-fold below the CSF-to-serum ratio, whereas this disequilibrium was not observed for CP-900,725. In a clinical study, steady-state CSF exposures were measured after administration of 100 mg of CP-615,003 b.i.d. The human CSF-to-plasma ratios of CP-615,003 and CP-900,725 were both approximately 10-fold below their ex vivo plasma unbound fractions, confirming impaired human CNS penetration. Preliminary estimates of CNS receptor occupancy from human CSF concentrations were sensitive to assumptions regarding the magnitude of the CSF-ECF gradient for CP-615,003 in humans. In summary, this case provides an example of intersite differences in CNS pharmacokinetics of a P-gp substrate and potential implications for projection of human CNS receptor occupancy of transporter substrates from CSF pharmacokinetic data when direct imaging-based approaches are not feasible.