Xin Zhang

Background Baricitinib is approved for the treatment of adults with moderate-to-severe atopic dermatitis (AD) who are candidates for systemic therapy and has received regulatory authorization in Europe for moderate-to-severe AD in patients 2 to ® (vIGA-AD) score of 0 or 1 (clear to almost clear skin) with ≥2-point improvement from baseline at week 16. Baricitinib pharmacokinetics were characterized from 393 pediatric patients using a 2-compartment model with allometric scaling on clearance and volume of distribution. Results The age-based and subsequent weight-based dosing (2 mg for patients 10 to <30 kg and 4 mg for patients ≥30 kg) was comparable to the 4-mg adult exposure. A clear E-R relationship was observed for the primary endpoint when sorted for age or weight groups. Conclusion The population PK model developed using baricitinib concentrations from adult patients, with allometric scaling for weight on clearance and volume, adequately predicted exposures in the pediatric population. The PK modeling, with E-R analysis, informed an appropriate weight-based dosing regimen.

Introduction Mirikizumab, a humanized anti-interleukin-23p19 monoclonal antibody, is approved for the treatment of moderate-to-severe ulcerative colitis (UC) and Crohn’s disease (CD). Two phase 1, open-label, two-arm, randomized studies compared pharmacokinetics and safety of mirikizumab (200 mg, Study AMBW; 300 mg, Study AMBX) to establish bioequivalence. Mirikizumab was administered subcutaneously using an autoinjector or a prefilled syringe (PFS) as a single dose in healthy participants. Methods Participants (male and female) were randomized 1:1 to mirikizumab by a PFS (reference) and an autoinjector (test). Participants were sub-randomized (1:1:1) to one of three injection sites (abdomen, arm, thigh) and stratified into one of three weight groups. Primary endpoints were maximum observed drug concentration (C_max), and area under concentration versus time curves (time zero to infinity [AUC_0–∞]; time to last time point with measurable concentration [AUC_0–tlast]). Secondary objectives were safety and immunogenicity. Results In Study AMBW, 90% confidence intervals (CIs) for the ratios (autoinjector to PFS) of geometric least squares mean values for C_max, AUC_0–∞, and AUC_0–tlast were within prespecified bioequivalence limits (0.80–1.25). Similar results were observed in Study AMBX, after administration of mirikizumab 300 mg, with bioequivalence achieved for AUC_0–tlast and AUC_0–∞, while the upper bound of the 90% CI of the geometric least squares mean ratio for C_max was slightly above the bioequivalence upper threshold. Overall safety of mirikizumab was similar between devices in both studies. Immunogenicity was similar overall in Study AMBW, but slightly higher (autoinjector versus PFS) in Study AMBX. Conclusion Mirikizumab administered by autoinjector or PFS was considered bioequivalent at the 200-mg UC maintenance dose and the 300-mg CD maintenance dose. Safety and immunogenicity profiles were comparable between autoinjector and PFS. Availability of an autoinjector option may be preferred by some patients and may help improve patient adherence to treatment. Clinical Trial Registration ClinicalTrials.gov NCT04607733; NCT05069896.

Mirikizumab is a humanized anti–interleukin‐23‐p19 monoclonal antibody approved for both moderately‐to‐severely active ulcerative colitis and moderately‐to‐severely active Crohn's disease (CD). We characterized pharmacokinetics (PK) and exposure‐response (ER) of mirikizumab in relation to efficacy and safety in CD using data from randomized phase 2 SERENITY (NCT02891226) and phase 3 VIVID‐1 (NCT03926130) trials. Patients received 12‐week mirikizumab induction (200, 600, or 1000 mg [SERENITY] or 900 mg [VIVID‐1] intravenously [IV]) or placebo, every 4 weeks (Q4W), then maintenance (200, 600, or 1000 mg IV [SERENITY], 300 mg subcutaneously (SC) [SERENITY and VIVID‐1], or placebo, Q4W) to Week 52. PK and ER for efficacy were analyzed using population PK and logistic regression models for Weeks 12 and 52 endpoints, respectively, and included analyses of covariate effects. Mirikizumab PK was best described by a two‐compartment model, with first‐order absorption for SC maintenance doses. Body weight, body mass index, serum albumin concentration, C‐reactive protein, and disease severity had statistically significant effects on PK, while body weight and disease severity affected ER; these effects were not considered clinically relevant. Efficacy results of 900 mg mirikizumab in VIVID‐1 aligned with SERENITY, which observed near‐maximal efficacy at Week 12 with 600–1000 mg mirikizumab IV. Efficacy at Week 52 did not vary markedly with exposure during maintenance. There was no significant association between exposure and adverse events. These results support the selection of 900 mg mirikizumab IV Q4W for induction and 300 mg SC Q4W for maintenance in patients with CD, with no dose adjustment for patient factors required.

Introduction Mirikizumab, a p19-directed antibody against interleukin-23 (IL-23), is administered by subcutaneous (SC) injection. Injection site pain (ISP) associated with citrate buffers may negatively affect patient adherence to SC-administered treatments. We assessed the bioequivalence and safety of the citrate-free (CF) and original formulations of mirikizumab. Methods The formulations were assessed in three phase 1, two-arm, randomized, single-dose, parallel design studies in healthy participants: study A (NCT04548219), study B (NCT05515601), and study C (NCT05644353). Participants were randomized 1:1 to either formulation, then further randomized to injection site locations of abdomen, arm, or thigh. The relative bioavailability (RBA) study A had a primary objective of assessing the RBA of a single 200 mg dose. Bioequivalence (BE) studies B and C had the primary objective of assessing the BE of a 200 and 300 mg dose, respectively. In all studies, the primary endpoints were C_max, AUC(0–∞), and AUC(0–t_last). The secondary objective was to assess safety and tolerability by treatment-emergent adverse events and serious adverse events. In study A, ISP was quantified prospectively using the 100-mm validated visual analogue scale (VAS) assessment form. Results The primary objective was met in all studies. The RBA study found no significant difference in exposure between the formulations. BE was demonstrated between CF and original mirikizumab in both BE studies, with the 90% confidence intervals of the ratios of geometric least squares means within the pre-specified equivalence limits of 0.80 and 1.25. The frequency of ISP and injection site reactions (ISRs) was lower for CF than original mirikizumab in all studies. Furthermore, a significant difference in mean VAS score was observed in study A. Conclusion Mirikizumab CF and original formulations were bioequivalent. The CF formulation was associated with less pain and fewer ISRs, with no other notable differences in safety profiles. Trial Registration ClinicalTrials.gov identifier NCT04548219, NCT05515601, NCT05644353.

Mirikizumab is a p19‐directed anti‐interleukin‐23 antibody approved for the treatment of adults with moderate‐to‐severe ulcerative colitis (UC). Here, we report the first data of mirikizumab pharmacokinetics (PK) and exposure–response (E/R) relationships in pediatric participants (aged 2 to 10 kg) with moderate‐to‐severe UC from the phase II, open‐label study SHINE‐1 (NCT04004611). PK parameters were analyzed using a model developed previously in adults with fixed‐exponent allometry for body weight. Serum samples collected from 26 participants during the 12‐week induction and 40‐week maintenance periods of SHINE‐1 were analyzed. Estimated body weight‐adjusted systemic clearance, volume of distribution, and subcutaneous bioavailability were 0.021 L/h, 0.069 L/kg, and 49.8%, respectively. Covariate analysis identified no clinically significant covariates other than body weight. In the exposure range studied, E/R analysis using post hoc grouping by average concentration quartile and comparison of observed change from baseline in modified Mayo Score (MMS) at Week 12 with the adult model prediction revealed no obvious E/R relationship in clinical response, clinical remission, or endoscopic response, consistent with observations in adults. The E/R relationship for observed change from baseline in MMS at Week 12 is also similar to the adult model prediction. The PK modeling and E/R analyses suggested optimal doses of intravenous mirikizumab 300 mg for weight >40 kg, 5 mg/kg for weight ≤40 kg every 4 weeks (Q4W) during induction, and subcutaneous mirikizumab 200 mg (>40 kg), 100 mg (>20 to ≤40 kg), or 50 mg (≤20 kg) Q4W during maintenance therapy for pediatric patients with moderate‐to‐severe UC.

Baricitinib is approved for the treatment of rheumatoid arthritis (RA) in more than 70 countries, and juvenile idiopathic arthritis (JIA) in the European Union. Population pharmacokinetic (PK) models were developed in a phase 3 trial to characterize PK in pediatric patients with JIA and identify weight‐based dosing regimens. The phase 3, randomized, double‐blind, placebo‐controlled withdrawal, efficacy and safety trial, JUVE‐BASIS, enrolled patients (aged 2 to <18 years) with polyarticular course JIA. During a safety/PK period, baricitinib concentration data from age‐based dose cohorts were compared to concentrations from adult patients receiving 4‐mg QD. PK data were used to develop a population PK model with allometric scaling to determine a weight‐based posology in pediatric patients with JIA that matched the adult 4‐mg exposure. Baricitinib plasma concentrations from 217 pediatric patients were used to characterize PK. Based on the adult model, pediatric PK was best described using a 2‐compartment model with allometric scaling on clearance and volume of distribution and renal function (estimated with glomerular filtration rate [GFR], a known covariate affecting PK of baricitinib) on clearance. The PK modeling suggested the optimal dosing regimen based on weight for pediatric patients as: 2‐mg QD for patients 10 to <30 kg and 4‐mg QD for patients ≥30 kg. The use of a population PK model of baricitinib treatment in adult patients with RA, with the addition of allometric scaling for weight on clearance and volume terms, was useful to predict exposures and identify weight‐based dosing in pediatric patients with JIA.

Background and Objective Mirikizumab is a humanized anti-interleukin-23-p19 monoclonal antibody being developed for ulcerative colitis and Crohn’s disease. This analysis characterized mirikizumab pharmacokinetics using phase II and III trial data from patients with moderately to severely active ulcerative colitis. Methods Serum pharmacokinetic data in patients receiving mirikizumab 50–1000 mg intravenously every 4 weeks as induction treatment and mirikizumab 200 mg subcutaneously every 4 or 12 weeks as maintenance treatment across three trials (N = 1362) were analyzed using non-linear mixed-effects modeling. Covariate effects on mirikizumab exposure were evaluated using simulation-based estimations. Results Mirikizumab pharmacokinetics was best described by a linear two-compartment model with first-order absorption. Clearance, volume of distribution for central and peripheral compartments, and half-life were estimated at approximately 0.022 L/h (linear), 3.11 L and 1.69 L, and 9.5 days, respectively. Statistically significant effects of body weight and serum albumin levels on clearance, body weight on central and peripheral volumes of distribution, and body mass index on bioavailability were observed but effects were small relative to random inter-individual variability (% coefficient of variation: 18–64%). The subcutaneous bioavailability of mirikizumab was 48%. Conclusions Mirikizumab displayed pharmacokinetic characteristics typical of a monoclonal antibody where clearance increased with body weight and decreased with the albumin level, and bioavailability decreased with body mass index. These effects were small relative to random variability, indicating that a dose adjustment for patient factors is not required. Clinical Trial Registration ClinicalTrials.gov: NCT02589665 (28 October, 2015), NCT03518086 (8 May, 2018), NCT03524092 (14 May, 2018).

The in vitro pharmacology of baricitinib, upadacitinib, and tofacitinib was evaluated to understand differences among these JAK inhibitors (JAKis) at the cellular level. Peripheral blood mononuclear cells from healthy donors were incubated with different JAKis, levels of phosphorylated signal transducer and activator of transcription (pSTAT) were measured following cytokine stimulation, and half maximum inhibitory concentration (IC50) values were calculated in phenotypically gated leukocyte subpopulations. Therapeutic dose relevance of the in vitro analysis was assessed using calculated mean concentration-time profiles over 24 h obtained from JAKi-treated subjects. Time above IC50 and average daily percent inhibition of pSTAT formation were calculated for each JAKi, cytokine, and cell type. Distinct JAKis displayed different in vitro pharmacologic profiles. For example, tofacitinib and upadacitinib were the most potent inhibitors of the JAK1/3-dependent cytokines tested (interleukin [IL]-2, IL-4, IL-15, and IL-21) with lower IC50 values and increased time above IC50 translating to a greater overall inhibition of STAT signaling during the dosing interval. All JAKis tested inhibited JAK1/2-dependent cytokines (e.g., IL-6 and interferon [IFN]-γ), the JAK1/tyrosine kinase 2 (TYK2)-dependent cytokines IL-10 and IFN-α, the JAK2/2-dependent cytokines IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF), and the JAK2/TYK2-dependent cytokine granulocyte colony-stimulating factor (G-CSF), but often to significantly differing degrees. Different JAKis modulated distinct cytokine pathways to varying degrees, and no agent potently or continuously inhibited an individual cytokine signaling pathway throughout the dosing interval. Notably, baricitinib inhibited JAK1/3 signaling to a lesser extent than upadacitinib and tofacitinib, while upadacitinib, baricitinib, and tofacitinib inhibited the signaling of JAK2/2-dependent cytokines, including GM-CSF and IL-3, as well as the signaling of the JAK2/TYK2-dependent cytokine G-CSF.

Baricitinib is an oral inhibitor of Janus kinases (JAKs), selective for JAK1 and 2. It demonstrated dose‐dependent efficacy in patients with moderate‐to‐severe rheumatoid arthritis (RA) in a phase IIb study up to 24 weeks. Population pharmacokinetic/pharmacodynamic (PopPK/PD) models were developed to characterize concentration‐time profiles and dose/exposure‐response (D/E‐R) relationships for the key efficacy (proportion of patients achieving American College of Rheumatology 20%, 50%, or 70% response rate) and safety endpoints (incidence of anemia) for the phase IIb study. The modeling suggested that 4 mg q.d. was likely to offer the optimum risk/benefit balance, whereas 2 mg q.d. had the potential for adequate efficacy. In addition, at the same total daily dose, a twice‐daily regimen is not expected to provide an advantage over q.d. dosing for the efficacy or safety endpoints. The model‐based simulations formed the rationale for key aspects of dosing, such as dose levels and dosing frequency for phase III development.