Pharmacokinetics and Exposure-Response of Tofacitinib in a Phase 3 Maintenance Study in Ulcerative Colitis Patients

Mukherjee, Arnab; D’Haens, Geert R.; Sandborn, William J.; Tsuchiwata, Shinichi; Vong, Camille; Deng, Chonghai; Xie, Ruiqin; Hazra, Anasuya; Martin, Steven W.; Friedman, Gary S.; Niezychowski, Wojciech; Su, Chinyu

doi:10.1016/s0016-5085(17)32133-9

Cited by 4 publications

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“…Previous E‐R analyses of the 8‐week, phase II induction study characterized the relationship between tofacitinib dose and plasma concentration, and provided the basis for selection of tofacitinib 10 mg b.i.d. in the phase III induction studies (OCTAVE Induction 1 and 2) 12,16 . Induction efficacy estimates for remission in patients without prior TNFi failure indicated overall consistency between the phase II study and the phase III program, despite some differences between study populations.…”

Section: Discussionmentioning

confidence: 92%

“…in the phase III induction studies (OCTAVE Induction 1 and 2). 12,16 Induction efficacy estimates for remission in patients without prior TNFi failure indicated overall consistency between the phase II study and the phase III program, despite some differences between study populations. Results from our E-R modeling analysis suggest clinically meaningful induction efficacy may be achieved with tofacitinib 5 mg b.i.d.…”

Section: Discussionmentioning

confidence: 92%

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Exposure‐Response Characterization of Tofacitinib Efficacy in Moderate to Severe Ulcerative Colitis: Results From Phase II and Phase III Induction and Maintenance Studies

Mukherjee

Tsuchiwata

Nicholas

et al. 2022

Clin Pharma and Therapeutics

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Tofacitinib is an oral small molecule JAK inhibitor for the treatment of ulcerative colitis. Relationships between plasma tofacitinib concentration and efficacy were characterized using exposure‐response (E‐R) models, with demographic and disease covariates evaluated as potential predictors of efficacy. Data were from phase II and III (OCTAVE Induction 1 and 2) induction studies, and a phase III maintenance study (OCTAVE Sustain). Induction studies included 1,355 patients (tofacitinib 0.5, 3, 10, or 15 mg b.i.d. or placebo). The maintenance study included 592 patients (tofacitinib 5 or 10 mg b.i.d. or placebo). E‐R models, including induction patients predicted placebo‐adjusted remission rates of 6.4% and 12.7% at week 8 for tofacitinib 5 and 10 mg b.i.d., respectively; corresponding rates in patients without prior tumor necrosis factor inhibitor (TNFi) failure were 12.8% and 20.4%. Estimates to achieve/maintain remission at week 52 of maintenance were 29% and 18% (tofacitinib 5 mg b.i.d.), and 41% and 26% (tofacitinib 10 mg b.i.d.), for patients in remission or not following induction, respectively. During maintenance, patients with prior TNFi failure had lower probability of remission on 5 mg b.i.d. (24.9%) than 10 mg b.i.d. (35.0%). Results indicated tofacitinib 10 mg b.i.d. was an appropriate induction dose but suggested efficacy with 5 mg b.i.d. in patients without prior TNFi failure. Tofacitinib 5 mg b.i.d. was efficacious for maintenance, although patients with prior TNFi failure might see additional benefit on 10 mg b.i.d. Per product labeling, recommended tofacitinib induction dose is 10 mg b.i.d., then maintenance at 5 mg b.i.d. For patients who lose response during maintenance, 10 mg b.i.d. may be considered, limited to the shortest duration. Clinicaltrials.gov: NCT00787202; NCT01465763; NCT01458951; and NCT01458574.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 92%

Exposure‐Response Characterization of Tofacitinib Efficacy in Moderate to Severe Ulcerative Colitis: Results From Phase II and Phase III Induction and Maintenance Studies

Mukherjee

Tsuchiwata

Nicholas

et al. 2022

Clin Pharma and Therapeutics

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“…Using a fixed C avg as the exposure metric in the E-R analyses tends to underestimate the E-R relationship or lead to an inverse E-R relationship for efficacy end points, as demonstrated here; on the contrary, it could also lead to the overestimation of the E-R relationship for safety end points for drugs with frequent dose modifications. 11 Thus, although fixed exposure metrics (ie, only 1 value for each patient), such as C avg , minimum concentration, maximum concentration, and area under the concentration-time curve, which are routinely used in E-R analyses, are considered appropriate for drugs without significant dose modification during treatment, [12][13][14] for drugs associated with frequent dose modification, a dynamic time-varying exposure metric (eg, C avg,t ) should be used instead. 15 The results of these analyses support the use of the maximum tolerated dose of 1 mg once daily as the starting dose for talazoparib treatment to ensure optimal exposure and efficacy.…”

Section: Discussionmentioning

confidence: 99%

Talazoparib Exposure‐Efficacy Analysis in Patients With Advanced Breast Cancer and Germline BRCA1/2 Mutations in the EMBRACA Trial

Elmeliegy

Litton

et al. 2020

The Journal of Clinical Pharma

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In the phase 3 EMBRACA trial, treatment with the poly(ADP‐ribose) polymerase inhibitor, talazoparib, led to significantly improved progression‐free survival (PFS) compared with chemotherapy (hazard ratio, 0.54; 95% confidence interval, 0.41‐0.71; P < .0001). We conducted an exposure‐efficacy analysis using EMBRACA data from 285 patients who were treated with talazoparib and had available pharmacokinetic parameters to evaluate the effect of talazoparib exposure (time‐varying average talazoparib concentration [Cavg,t]) and other baseline variables on PFS. Graphical examination of the relationship between Cavg,t and PFS and a Cox proportional model were used. Exposure‐response analyses showed that higher talazoparib exposure, absence of visceral disease, lower baseline lactate dehydrogenase levels, and disease‐free interval >12 months were independent covariates associated with longer PFS. The association of talazoparib exposure with PFS (higher exposure, longer PFS) suggests the recommended starting dose of 1 mg once daily (the maximum tolerated dose) is appropriate.

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“…In the OCTAVE trials, there was no decrease in plasma concentrations of tofacitinib in individual patients with ulcerative colitis with either the 5 mg bid or 10 mg bid doses during treatment (up to 52 wk), as shown in Figure 3 . 111 Baseline disease activity (albumin levels, Mayo score) was not significantly associated with plasma concentrations of tofacitinib during induction or maintenance, 107 indicating that tofacitinib concentration is not expected to be lower in patients with the highest disease activity, in contrast to biologic agents. 112 Tofacitinib plasma concentration is not a meaningful determinant of efficacy, and no loss of efficacy due to low plasma concentration was identified in clinical trials.…”

Section: Approved and Investigational Small-molecule Treatmentsmentioning

confidence: 99%

“… 112 Tofacitinib plasma concentration is not a meaningful determinant of efficacy, and no loss of efficacy due to low plasma concentration was identified in clinical trials. 107 , 111 …”

Section: Approved and Investigational Small-molecule Treatmentsmentioning

confidence: 99%

Therapeutic Drug Monitoring for Current and Investigational Inflammatory Bowel Disease Treatments

Lee

Shivashankar

Quirk

et al. 2020

Journal of Clinical Gastroenterology

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This article reviews therapeutic drug monitoring (TDM) use for current inflammatory bowel disease (IBD) treatments. IBD comprises Crohn’s disease and ulcerative colitis-chronic gastrointestinal inflammatory disorders. Treatment options for moderate to severe IBD include thiopurines; methotrexate; biologic agents targeting tumor necrosis factor, α 4 β 7 integrin or interleukins 12 and 23; and Janus kinase inhibitors. TDM is recommended to guide treatment decisions for some of these agents. Published literature concerning TDM for IBD treatments was reviewed. S.D.L., R.S., and E.V.L. drew on their clinical experiences. Polymorphisms resulting in altered enzymatic activity inactivating thiopurine metabolites can lead to myelotoxicity and hepatotoxicity. Increased elimination of biologic agents can result from immunogenicity or higher disease activity, leading to low drug concentration and consequent nonresponse or loss of response. TDM may aid treatment and dose decisions for individual patients, based on monitoring metabolite levels for thiopurines, or serum drug trough concentration and antidrug antibody levels for biologic agents. Challenges remain around TDM implementation in IBD, including the lack of uniform assay methods and guidance for interpreting results. The Janus kinase inhibitor tofacitinib is not impacted by enzyme polymorphisms or disease activity, and is not expected to stimulate the formation of neutralizing antidrug antibodies. TDM is associated with implementation challenges, despite the recommendation of its use for guiding many IBD treatments. Newer small molecules with less susceptibility to patient variability factors may fulfill the unmet need of treatment options that do not require TDM, although further study is required to confirm this.

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Pharmacokinetics and Exposure-Response of Tofacitinib in a Phase 3 Maintenance Study in Ulcerative Colitis Patients

Cited by 4 publications

References 0 publications

Exposure‐Response Characterization of Tofacitinib Efficacy in Moderate to Severe Ulcerative Colitis: Results From Phase II and Phase III Induction and Maintenance Studies

Exposure‐Response Characterization of Tofacitinib Efficacy in Moderate to Severe Ulcerative Colitis: Results From Phase II and Phase III Induction and Maintenance Studies

Talazoparib Exposure‐Efficacy Analysis in Patients With Advanced Breast Cancer and Germline BRCA1/2 Mutations in the EMBRACA Trial

Therapeutic Drug Monitoring for Current and Investigational Inflammatory Bowel Disease Treatments

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