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A population pharmacokinetic model was developed using data from healthy subjects and patients with moderate‐to‐severe asthma receiving intravenous or subcutaneous dupilumab doses. A total of nine phase I to phase III studies were pooled (202 healthy subjects and 1912 patients with asthma including 68 adolescents) in the model development. The best model was a two‐compartment model with parallel linear and nonlinear Michaelis–Menten elimination with first order absorption. The PK parameter estimates were distribution volume of central compartment 2.76 L, linear elimination rate 0.0418 1/day, and subcutaneous bioavailability 60.9%. Pharmacokinetics (PK) properties of dupilumab in patients with asthma were determined to be comparable to those of healthy subjects and patients with atopic dermatitis. Only body weight exerts a notable effect explaining between‐subject variability in dupilumab PK, but dose adjustment for weight is not warranted based on results from clinical studies. There is no PK difference between adolescent and adult patients with asthma after correction for body weight.

We evaluated interleukin-6 (IL-6) receptor-α subunit (IL-6Rα) signaling inhibition with sarilumab and tocilizumab, the association between IL-6Rα receptor occupancy (RO) and C-reactive protein (CRP), and the potential clinical relevance of any differences. For this, we measured IL-6Rα binding and signaling inhibition with sarilumab and tocilizumab in vitro, simulated soluble IL-6Rα RO over time for approved sarilumab subcutaneous (SC) and tocilizumab intravenous (IV) and SC doses, and assessed associations between calculated RO and CRP reduction, 28-joint Disease Activity Score based on CRP, and 20%/50%/70% improvement in American College of Rheumatology responses from clinical data. Sarilumab binds IL-6Rα in vitro with 15- to 22-fold higher affinity than tocilizumab, and inhibits IL-6–mediated classical and trans signaling via membrane-bound and soluble IL-6Rα. Sarilumab 200 and 150 mg SC every 2 weeks achieved >90% RO after first and second doses, respectively, maintained throughout the treatment period. At steady-state trough, RO was greater with sarilumab 200 mg (98%) and 150 mg SC every 2 weeks (94%), and tocilizumab 162 mg SC weekly (>99%) and 8 mg/kg IV every 4 weeks (99%), vs tocilizumab 162 mg SC every 2 weeks (84%) and 4 mg/kg IV every 4 weeks (60%). Higher RO was associated with greater CRP reduction and 28-joint Disease Activity Score based on CRP reduction, and more sarilumab patients achieving 20%/50%/70% improvement in American College of Rheumatology responses. The greatest reduction in CRP levels was observed with sarilumab (both doses) and tocilizumab 8 mg/kg IV every 4 weeks (reductions proportionally smaller with 4 mg/kg IV every 4 weeks). Higher IL-6Rα binding affinity translated into higher RO with sarilumab vs tocilizumab 4 mg/kg every 4 weeks or 162 mg every 2 weeks; tocilizumab required the higher dose or increased frequency to maintain the same degree of RO and CRP reduction. Higher RO was associated with clinical parameter improvements.

Fedratinib is an oral and selective kinase inhibitor with activity against wild type and mutationally activated Janus kinase 2 and FMS-like tyrosine kinase 3, for the treatment of adult patients with intermediate-2 or high-risk primary or secondary myelofibrosis. This open-label mass balance study in healthy subjects investigated the excretion balance and systemic exposure of radioactivity after oral administration of [14C]-fedratinib; and the pharmacokinetics of fedratinib and its contribution to overall exposure of radioactivity. Six healthy males received a single oral dose of 200 mg [14C]-fedratinib base (2.775 MBq, 75 μCi) as a solution. Blood, urine and feces samples were collected for up to 35 day postdose. Urine and feces samples were collected until the 24-h excretion of radioactivity fell below 0.5% of administered dose (at least 14 day postdose). Expired air was collected up to 8-h postdose. Total radioactivity (blood, plasma, urine, feces, and expired air) and fedratinib concentrations (plasma) were measured. Approximately 77% (23% unchanged) of fedratinib derived radioactivity was excreted in feces and 5% (3% unchanged) was excreted in urine. Excretion via expired air was negligible. The time to maximum concentration for both total radioactivity and parent drug was similar, with unchanged drug representing the majority of the circulating radioactivity. The ratio of blood to plasma concentration of radioactivity ranged from 0.615 to 0.753 indicating limited distribution of fedratinib and/or its metabolites into red blood cells. Fedratinib derived radioactivity was primarily excreted in feces following a single oral dose of radiolabeled fedratinib to healthy subjects.

Background Sarilumab is a human monoclonal antibody blocking the interleukin-6 receptor alpha (IL-6Rɑ) approved for the treatment of moderately to severely active rheumatoid arthritis in adults with inadequate response or intolerance to other disease-modifying antirheumatic drugs. Objective The aim of the current analysis was to describe sarilumab exposure–response relationships. Methods Population pharmacokinetic/pharmacodynamic (PopPK/PD) models were developed describing the time course of the 28-joint disease activity score by C-reactive protein (DAS28-CRP) and absolute neutrophil count (ANC) using data from phase I–III studies (NCT01011959, NCT01061736, NCT01709578, NCT01768572) after subcutaneous sarilumab 50–150 mg every week or 100–200 mg every 2 weeks. Results The time course of DAS28-CRP and ANC after sarilumab administration was described by semi-mechanistic, indirect-response models. Drug effect was predicted to be numerically greater at median exposure for the 200 mg every 2 weeks regimen versus the 150 mg every 2 weeks regimen, for both DAS28-CRP (50% vs. 47%) and ANC reduction from baseline (39% vs. 31%), with the latter showing less fluctuations within a dosing interval. Four covariates were retained in the final models: body weight, baseline rheumatoid factor status, anti-cyclic citrullinated peptide status, and concomitant methotrexate. There was no clinically meaningful influence of investigated covariates for either model. Conclusion The PopPK/PD models showed numerically greater reductions in DAS28-CRP and ANC with sarilumab 200 mg every 2 weeks than with 150 mg every 2 weeks. There was no clinically meaningful influence of investigated covariates. These data contribute to the totality of evidence that supports a sarilumab subcutaneous starting dose of 200 mg every 2 weeks, with a subsequent reduction to 150 mg every 2 weeks in the event of laboratory abnormalities such as neutropenia.

Fedratinib is an orally administered Janus kinase 2-selective inhibitor that is indicated for the treatment of adult patients with intermediate-2 or high-risk myelofibrosis in the United States. Fedratinib is metabolized by multiple cytochrome P450s (CYPs) in vitro, with the predominant contribution from CYP3A4. The primary objective of this study was to evaluate the effects of 14-day repeated 200 mg twice daily (BID) oral doses of a strong CYP3A4 inhibitor, ketoconazole, on a sequential ascending single oral dose of fedratinib in healthy male subjects. An open-label, fixed-sequence, two-treatment cross-over study was conducted. Two cohorts of healthy adult males received two single doses of fedratinib (50 mg in Cohort 1 and 300 mg in Cohort 2) with one dose administered alone on Day 1 of Period 1 and the other dose coadministered with ketoconazole in the morning of Day 6 of Period 2. Subjects in both cohorts received 200-mg BID (Days 1–14) ketoconazole during Period 2. Coadministration of repeated 200-mg BID oral doses of ketoconazole for 14 days increased fedratinib exposure by 3.85- and 3.06-fold for area under the plasma concentration–time curve from time zero to infinity following a single oral dose of fedratinib of 50 and 300 mg, respectively. Oral administration of a single dose of 50 or 300 mg of fedratinib, administered alone or coadministered with steady-state ketoconazole, was safe and tolerable in the healthy male subjects. These results serve as the basis for fedratinib dose reduction when fedratinib is coadministered with strong CYP3A4 inhibitors.

Dupilumab, a human monoclonal antibody against interleukin-4 receptor alpha, has demonstrated efficacy and an acceptable safety profile in adult and pediatric patients with moderate-to-severe atopic dermatitis (AD) and other type 2 inflammatory diseases. Dupilumab is available in 200- and 300-mg strengths as a prefilled syringe with a needle shield (PFS-S), and more recently as an autoinjector (AI) device. This study was designed to assess the pharmacokinetic (PK) comparability of a single subcutaneous (SC) dose of dupilumab 200 mg, delivered by 2 different devices, AI (test) versus PFS-S (reference). A total of 130 healthy male and female participants were enrolled in this phase 1 parallel design study, with 128 evaluable for PK. Following dupilumab 200-mg SC injection, dupilumab exposure in serum was similar for both AI and PFS-S. The geometric mean ratios of PK parameters with 90% confidence intervals were 1.08 (0.97-1.21) for maximum serum concentration (C

Background and Objective Sarilumab binds to the interleukin-6 receptor with high affinity, inhibiting cis and trans signaling by interleukin-6. Sarilumab has demonstrated efficacy and safety in patients with rheumatoid arthritis. The objective of this study was to develop a population-pharmacokinetic model using data from 1770 patients with rheumatoid arthritis across phase I–III studies. Methods Potential covariates were identified using a stepwise forward-addition and backward-deletion strategy, and the final model was evaluated by visual predictive check and bootstrap methods. Results Sarilumab pharmacokinetics is described by a two-compartment model with first-order absorption and parallel linear and nonlinear Michaelis–Menten elimination. A subcutaneous dose of sarilumab 200 mg every 2 weeks resulted in more pronounced saturation of the nonlinear clearance pathway over the dosing interval than 150 mg every 2 weeks. Steady-state exposure (area under the plasma concentration–time curve from day 0 to day 14) increased twofold with dose escalation from 150 to 200 mg every 2 weeks. Body weight, anti-drug antibody status, sarilumab drug product, sex, creatinine clearance, albumin, and baseline C-reactive protein levels were identified as significant covariates according to the predefined statistical significance criteria in stepwise covariate searches. The main intrinsic source of pharmacokinetic variability in exposure was body weight. Compared with a typical 71-kg patient, the area under the plasma concentration–time curve from day 0 to day 14 was 20–23% lower for an 83-kg patient and 20–25% higher for a 62-kg patient. Conclusions These findings, combined with the safety and efficacy data, indicated limited clinical relevance of body-weight effect on sarilumab exposure. No adjustment in sarilumab dose is required for body weight or any other demographics assessed. Electronic supplementary material The online version of this article (10.1007/s40262-019-00765-1) contains supplementary material, which is available to authorized users.

Dupilumab demonstrated efficacy with an acceptable safety profile in two randomized, double-blind, placebo-controlled, parallel-group, phase III trials in adolescents (12-17 years; LIBERTY AD ADOL) and children (6-11 years; LIBERTY AD PEDS) with atopic dermatitis (AD) treated for 16 weeks. Here, we present the pharmacokinetic profiles and exposure-response relationships of dupilumab that guided the posology in these populations. A total of 251 adolescent patients with moderate-to-severe AD were randomized to subcutaneous dupilumab monotherapy every 2 weeks (q2w) (200 mg q2w, baseline weight

Background Objectives The in vitro binding affinity of sarilumab (KD 61.9 pM) for the human interleukin-6 receptor (IL-6R) is 15- to 22-fold higher than tocilizumab.1 We explored the relationship between IL-6R RO, relevant pharmacodynamic (PD) variables (eg CRP), and potential clinical relevance of the differences between sarilumab and tocilizumab. Methods Binding to total soluble IL-6R (sIL-6R) in vivo translates into the quasi-steady-state target-mediated drug disposition pharmacokinetics (PK) and indirect-response PD model with inhibition of elimination of sIL–6R and unbound sIL-6R concentration for both sarilumab and tocilizumab.2–5 PK/PD models were used to simulate sIL-6R RO dynamic profiles (% RO over time) for: sarilumab after subcutaneous (SC) doses of 200 and 150 mg once every 2 wks (q2w); tocilizumab after SC doses of 162 mg q2w and once every wk (qw); and tocilizumab after intravenous (IV) doses of 4 and 8 mg/kg once every 4 wks (q4w). In addition, RO profiles were compared with changes in observed CRP levels in patients with RA following administration of sarilumab SC and tocilizumab IV (ASCERTAIN study; NCT01768572). In this study, 60.8% of patients required an increase in tocilizumab dose from 4 to 8 mg/kg IV during the study period, based on clinical response. Results Sarilumab SC 200 mg q2w achieved >90% RO after the first dose, which was maintained over the dosing interval throughout the 24-wk treatment course; at the lower dose of 150 mg q2w, RO was >90% from the second dose onwards. RO for tocilizumab SC, at 162 mg q2w, was >90% immediately after the first dose but dropped below 50% prior to the second dose. Similarly, for tocilizumab IV at 4 mg/kg q4w, the RO was high immediately after the first dose (>99% at Wk 1) but decreased over the dosing interval. At trough steady-state (Wk 24), RO was greater with sarilumab SC 200 mg q2w (98%) and 150 mg q2w (94%) compared with tocilizumab SC 162 mg q2w (84%) and IV 4 mg/kg q4w (60%). The higher doses of tocilizumab SC 162 mg qw and tocilizumab IV 8 mg/kg q4w were able to maintain RO ≥99% at steady state, similar to sarilumab SC 200 mg at steady state. CRP levels in patients with RA were inversely associated with RO at trough; the greatest suppression in CRP was seen in patients who received sarilumab SC (at either dose) or the higher IV tocilizumab dose (Fig). However, proportionally smaller reductions in CRP levels were observed with the lower IV tocilizumab dose (4 mg/kg q4w), consistent with the lower RO of tocilizumab. Conclusion The higher binding affinity of sarilumab to IL-6R compared with tocilizumab translated into higher RO and greater reduction in CRP levels for sarilumab than tocilizumab, confirming the expected association between RO and PD effect. Sarilumab SC 200 mg q2w led to a rapid and sustained suppression of CRP over the 24-wk interval investigated; however, a higher dose (IV) or frequency of administration (SC) of tocilizumab was required to maintain the same degree of RO and CRP suppression. CRP may be a useful tool in clinical practice for patients treated with an IL-6R blocker. References [1] Rafique A, et al. Ann Rheum Dis 2013;72: Abstr 797. [2] Xu C, et al. PAGE Meeting 2017; Abstr 7283. [3] Huizinga T, et al. Ann Rheum Dis 2014;73:1626–34. [4] Gibiansky L, et al. J Pharmacokinet Pharmacodyn 2012;39:5–16. [5] FDA Clinical Pharmacology Review for tocilizumab, 2013. Acknowledgement Study funding and editorial support (Helen Johns, Adelphi) provided by Sanofi and Regeneron Pharmaceuticals, Inc. Disclosure of Interests Christine Xu Shareholder of: Sanofi, Employee of: Sanofi, Patrick Nolain Shareholder of: Sanofi, Employee of: Sanofi, Qiang Lu Shareholder of: Sanofi, Employee of: Sanofi, Anne Paccaly Shareholder of: Regeneron, Amgen, Employee of: Regeneron, Sanofi, Amgen, Melitza Iglesias-Rodriguez Shareholder of: Sanofi Genzyme, Employee of: Sanofi Genzyme, Gregory St John Shareholder of: Regeneron Pharmaceuticals Inc, Employee of: Regeneron Pharmaceuticals Inc, Chad Nivens Shareholder of: Regeneron, Employee of: Regeneron, Rafael Maldonado Grant/research support from: Sanofi, Esteve, Almirall, GSK, Boehringer, Lundbeck, Grunenthal, UPSA, Uphjon, Uriach, Ferrer, Janus, Aelis, Spherium, Pharmaleads, BRAINco, Phytoplant, Rhodes and GW Pharma., Consultant for: Sanofi, Esteve, Almirall, GSK, Boehringer, Lundbeck, Grunenthal, UPSA, Uphjon, Uriach, Ferrer, Janus, Aelis, Spherium, Pharmaleads, BRAINco, Phytoplant, Rhodes and GW Pharma., Tomonori Ishii Grant/research support from: GSK, Janssen, Consultant for: GSK, Janssen, Speakers bureau: Mitsubishi-Tanabe, Janssen, Chugai, Ono, Sanofi, Abbvie, Eisai, Astellas, UCB, Teijin, Daiichi-Sankyo, Pfizer, Takeda, Asahi, and Kasei Pharma, Ernest Choy Grant/research support from: Amgen, Bio-Cancer, Chugai Pharma, Ferring Pharmaceuticals, Novimmune, Pfizer, Roche, and Union Chimique Belge, Consultant for: Abbvie, Amgen, AstraZeneca, Biogen, BMS, Boehringer Ingelheim, Celgene, Chelsea Therapeutics, Chugai Pharma, Daiichi Sankyo, Eli Lilly, Ferring Pharmacuetical, GlaxoSmithKline, Hospita, ISIS, Jazz Pharmaceuticals, Janssen, MedImmune, Merrimack Pharmaceutical, Merck Sharp & Dohme, Napp, Novimmune, Novartis, ObsEva, Pfizer, Regeneron, Roche, R-Pharm, SynAct Pharma, Sanofi-Genzyme, Tonix and Union Chimique Belge, Speakers bureau: Amgen, BMS, Boehringer Ingelheim, Chugai Pharma, Eli Lilly, Hospira, Merck Sharp & Dohme, Novartis, Pfizer, Regeneron, Roche, Sanofi-Aventis, and Union Chimique Belge, Vanaja Kanamaluru Shareholder of: Sanofi, Employee of: Sanofi

An open-label, nonrandomized study was conducted to assess the effect of ravuconazole on the pharmacokinetics of concomitantly administered nelfinavir. Healthy volunteers received 750 mg nelfinavir on day 1, 750 mg nelfinavir and 400 mg ravuconazole on day 2, 400 mg ravuconazole on days 3 to 28, and 750 mg nelfinavir and 400 mg ravuconazole on day 29. The geometric means of C(max) and area under the curve of nelfinavir coadministered with ravuconazole were 30.7% and 31.9% higher on day 2 and 7.9% and 16.2% lower on day 29, respectively, compared to the corresponding values on day 1. These findings are consistent with the potential for ravuconazole to both inhibit and induce CYP3A isozymes. The alterations in the systemic exposure to nelfinavir were within the range defined by the 90% confidence interval. The study data indicate that coadministration of ravuconazole did not result in a clinically significant change in the plasma levels of nelfinavir.