Xuejun Chen

The Pharmacokinetics, Pharmacodynamics, and Safety of Orally Dosed INCB018424 Phosphate in Healthy Volunteers

INCB018424 phosphate, a potent inhibitor of JAK enzymes with selectivity for JAK1&2, is in development for the treatment of myelofibrosis (MF). The oral dose pharmacokinetics, pharmacodynamics, safety, and tolerability of INCB018424 were evaluated in healthy volunteers in 2 double‐blind, randomized, and placebo‐controlled studies. The first study evaluated single ascending doses of 5 to 200 mg INCB018424 and the effect of food, whereas the second study evaluated multiple ascending doses, including both once‐ and twice‐daily dosing for 10 days. As a Biopharmaceutical Classification System class I drug, INCB018424 exhibited good oral bioavailability and dose‐proportional systemic exposures. INCB018424 showed low oral dose clearance and a small volume of distribution, with an approximate 3‐hour plasma half‐life and insignificant accumulation following repeat dosing. A high‐fat meal reduced INCB018424 Cmax by 24% but had little effect on INCB018424 AUC. INCB018424 was cleared primarily by metabolism with negligible renal excretion. The pharmacodynamics of INCB018424, evaluated by the inhibition of phosphorylated STAT3 following cytokine stimulation in whole blood, showed good correlation with INCB018424 plasma concentrations. INCB018424 was generally safe and well tolerated, with 25 mg bid and 100 mg qd established as the maximum tolerated doses in healthy volunteers.

The Effect of CYP3A4 Inhibition or Induction on the Pharmacokinetics and Pharmacodynamics of Orally Administered Ruxolitinib (INCB018424 Phosphate) in Healthy Volunteers

Ruxolitinib, a selective Janus kinase (JAK) 1&2 inhibitor in development for the treatment of myeloproliferative neoplasms, is primarily metabolized by CYP3A4. The effects of inhibition or induction of CYP3A4 on single oral dose ruxolitinib pharmacokinetics (PK) and pharmacodynamics (PD) were evaluated in healthy volunteers. Coadministration of ketoconazole (a potent CYP3A4 inhibitor) and erythromycin (a moderate CYP3A4 inhibitor) increased total ruxolitinib plasma exposure (AUC0‐∞) by 91% and 27%, respectively, and ruxolitinib PD, as measured by the inhibition of interleukin (IL)–6‐stimulated STAT3 phosphorylation in whole blood, was generally consistent with the PK observed. Pretreatment with rifampin, a potent CYP3A4 inducer, decreased ruxolitinib AUC0‐∞ by 71% while resulting in only a 10% decrease in the overall PD activity. This apparent PK/PD discrepancy may be explained, in part, by an increase in the relative abundance of ruxolitinib active metabolites with the rifampin coadministration. The collective PK/PD data suggest that starting doses of ruxolitinib should be reduced by 50% if coadministered with a potent CYP3A4 inhibitor, whereas adjustments in ruxolitinib starting doses may not be needed when coadministered with inducers or mild/moderate inhibitors of CYP3A4. All study doses of ruxolitinib were generally safe and well tolerated when given alone and in combination with ketoconazole, erythromycin, or rifampin.

The pharmacokinetics, pharmacodynamics, and safety of baricitinib, an oral JAK 1/2 inhibitor, in healthy volunteers.

Baricitinib (also known as LY3009104 or INCB028050), a novel and potent small molecule inhibitor of Janus kinase family of enzymes (JAKs) with selectivity for JAK1 and JAK2, is currently in clinical development for the treatment of rheumatoid arthritis (RA) and other inflammatory disorders. Two double‐blind, randomized, and placebo‐controlled studies were conducted to evaluate single ascending doses of 1–20 mg and multiple ascending doses of 2–20 mg QD and 5 mg BID for 10 or 28 days in healthy volunteers. Following oral administration, baricitinib plasma concentration typically attains its peak value within 1.5 hours postdose and subsequently declines in a bi‐exponential fashion. Baricitinib demonstrates dose‐linear and time‐invariant pharmacokinetics, with low oral‐dose clearance (17 L/h) and minimal systemic accumulation observed following repeat dosing. The mean renal clearance of baricitinib was determined to be ∼12 L/h. [Correction added after publication 12 November 2014: in the preceding sentence, “2 L/h” was changed to “12 L/h.”] The effect of a high‐fat meal on baricitinib pharmacokinetics was insignificant. The pharmacodynamics of baricitinib, evaluated by the inhibition of STAT3 phosphorylation following cytokine stimulation in the whole blood ex vivo, was well correlated with baricitinib plasma concentrations. Baricitinib was generally safe and well tolerated, with no serious treatment‐related adverse events (AEs) reported from either of the studies. An expected rapidly reversible, dose‐related decline in absolute neutrophil count was seen with baricitinib.

A randomized, double-blind, placebo-controlled, dose-escalation study of the safety and efficacy of INCB039110, an oral janus kinase 1 inhibitor, in patients with stable, chronic plaque psoriasis

Abstract Background: Chronic plaque psoriasis is partially mediated by elevation of proinflammatory cytokines, including several within the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Objective: To evaluate the safety and efficacy of the oral selective JAK1 inhibitor INCB039110 in stable, chronic plaque psoriasis. Methods: This was a phase 2, randomized, double-blind, placebo-controlled, dose-escalation study of INCB039110 (100 mg once daily, 200 mg once daily, 200 mg twice daily and 600 mg once daily) for 28 days. The primary endpoint was mean percent change from baseline in the static Physician Global Assessment (sPGA) at day 28. The protocol was institutional review board approved. Results: Of 50 patients, 48 completed the study. At day 28, mean percent reduction from baseline in sPGA was 22.2% for INCB039110 100 mg once daily (p  =  0.270 vs. placebo), 29.4% for 200 mg once daily (p  =  0.118), 35.2% for 200 mg twice daily (p  =  0.053), 42.4% for 600 mg once daily (p  =  0.003) and 12.5% for placebo. Across groups, 11.1% to 45.5% achieved an sPGA score of 1 versus 0% for placebo. INCB039110 was generally well tolerated; the most common treatment-emergent adverse event was nasopharyngitis (18.4%). Conclusion: INCB039110 produced significant improvements in sPGA, demonstrating proof of concept in chronic plaque psoriasis.

Population pharmacokinetic analysis of orally-administered ruxolitinib (INCB018424 Phosphate) in patients with primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF) or post-essential thrombocythemia myelofibrosis (PET MF).

Ruxolitinib is a selective inhibitor of Janus kinase 1 and 2, which is approved to treat intermediate or high‐risk myelofibrosis. The population pharmacokinetics for ruxolitinib were characterized by a modeling dataset of 272 subjects from a Phase 2 and a Phase 3 study and validated by an external validation dataset of 142 subjects from a second Phase 3 study. The PK of ruxolitinib was adequately described by a two‐compartment disposition model with first‐order absorption and linear elimination. All model parameters were estimated with good precision. Gender and body weight were identified as covariates for oral clearance (CL/F) and volume of distribution for central compartment (Vc/F), respectively. Apparent oral clearance was 22.1 and 17.7 L/h for a typical male and female subject, respectively, with 39.1% unexplained inter‐individual variability (IIV). The typical Vc/F for a subject with a median weight of 72.9 kg was estimated to be 58.6 L, with 28% unexplained IIV. The model predictive performance was validated by visual predictive check (VPC) and the external validation dataset. This analysis suggests that effects of gender and body weight on ruxolitinib PK are not clinically significant and hence no dose adjustment is needed based on gender and weight.

Pharmacokinetics and pharmacodynamics of orally administered ruxolitinib (INCB018424 phosphate) in renal and hepatic impairment patients

Hepatic and renal impairment studies were conducted with ruxolitinib, a JAK1&2 inhibitor that is cleared predominantly by metabolism. Both studies were open label, single‐dose studies. Ruxolitinib area under the curve (AUC) was increased by 87%, 28%, and 65%, respectively, in subjects with mild, moderate, and severe hepatic impairment compared to healthy subjects with no correlation between exposure of ruxolitinib and the degree of hepatic impairment. The pharmacodynamics (PD) data were consistent with ruxolitinib pharmacokinetics (PK). The renal impairment study showed a surprising finding. While there was no change in ruxolitinib PK with varying degrees of renal impairment, the PD showed increasing pharmacological activity with increased severity of renal impairment. Analysis of the metabolite exposures revealed that active metabolites contributed to the observed incremental increase in PD activity. The recovery of ruxolitinib in dialysate was negligible. The starting dose of ruxolitinib in subjects with any hepatic impairment or moderate or severe renal impairment should be decreased to 10 mg twice daily (BID) if their platelet counts are between 100 × 109/L and 150 × 109/L. Subjects on dialysis should initiate dosing with a single dose of 15 or 20 mg, based on platelet counts, with dosing only on the days of dialysis.

Potential Underprediction of Warfarin Drug Interaction From Conventional Interaction Studies and Risk Mitigation: A Case Study With Epacadostat, an IDO1 Inhibitor

Drug–drug interaction (DDI) studies involving warfarin are typically conducted with subtherapeutic doses of warfarin to ensure the safety of volunteers. However, this approach may potentially have a systemic bias of underestimating pharmacodynamic (PD) DDI effect on warfarin at therapeutic levels of anticoagulation. We demonstrate here the utility of model‐based DDI prediction for a clinically relevant warfarin regimen, using the example of epacadostat (INCB024360), the first‐in‐class indoleamine 2,3‐dioxygenase 1 inhibitor in clinical development as a novel orally active immuno‐oncological therapy. Observed data from a dedicated clinical DDI study using subtherapeutic warfarin suggested warfarin pharmacokinetics (PK), but not PD (anticoagulation), was significantly affected by concomitant epacadostat. However, subsequent PK/PD modeling and simulations indicated a clinically important DDI effect on warfarin PD at a higher baseline of the international normalization ratio (INR) and enabled recommendation of warfarin dose adjustment that is dependent on epacadostat dosing regimen and target INR.

Phase 1 study of the PI3Kδ inhibitor INCB040093 ± JAK1 inhibitor itacitinib in relapsed/refractory B-cell lymphoma

Because both phosphatidylinositol 3-kinase δ (PI3Kδ) and Janus kinase (JAK)-signal transducer and activator of transcription pathways contribute to tumor cell proliferation and survival in B-cell malignancies, their simultaneous inhibition may provide synergistic treatment efficacy. This phase 1 dose-escalation/expansion study assessed the safety, efficacy, pharmacokinetics, and pharmacodynamics of INCB040093, a selective PI3Kδ inhibitor, as monotherapy or combined with itacitinib (formerly INCB039110), a selective JAK1 inhibitor, in adult patients with relapsed or refractory (R/R) B-cell lymphomas. Final results are reported. Overall, 114 patients were treated (monotherapy, n = 49; combination therapy, n = 72 [7 patients crossed over from monotherapy to combination]). INCB040093 100 mg twice daily (monotherapy) and INCB040093 100 mg twice daily + itacitinib 300 mg once daily (combination) were the recommended phase 2 doses. One dose-limiting toxicity (gastrointestinal bleed secondary to gastric diffuse large B-cell lymphoma [DLBCL] regression) occurred with monotherapy. The most common serious adverse events with monotherapy were pneumonia (n = 5) and pyrexia (n = 4), and with combination Pneumocystis jiroveci pneumonia (n = 5), pneumonia (unrelated to P jiroveci; n = 5), and pyrexia (n = 4). Grade 3 or higher transaminase elevations were less common with combination. INCB040093 was active across the B-cell lymphomas; 63% of patients (5/8) with follicular lymphoma responded to monotherapy. Adding itacitinib provided promising activity in select subtypes, with responses of 67% (14/21) in classic Hodgkin lymphoma (vs 29% [5/17] with monotherapy) and 31% (4/13) in nongerminal center B-cell-like DLBCL. INCB040093 with/without itacitinib was tolerated and active in this study, and is a promising treatment strategy for patients with select R/R B-cell lymphomas. This trial was registered at www.clinicaltrials.gov as #NCT01905813.

Population Pharmacokinetic and Pharmacodynamic Modeling of Epacadostat in Patients With Advanced Solid Malignancies

Epacadostat (EPA, INCB024360) is a selective inhibitor of the enzyme indoleamine 2,3‐dioxygenase 1 (IDO1) and is being developed as an orally active immunotherapy to treat advanced malignancies. In the first clinical study investigating the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of EPA in oncology patients, increasing doses of EPA ranging from 50 mg once daily to 700 mg twice daily were administered as a monotherapy to 52 subjects with advanced solid tumors. The EPA plasma concentration‐time profiles were adequately described by a population PK model comprised of the first‐order kinetics of oral absorption with 2‐compartment distribution and constant clearance from the central compartment. Body weight was the only significant covariant to influence EPA PK. Determination of EPAs on‐target potency, ie, its half‐maximal inhibitory concentration (IC50) against IDO1, is important for dose selection but complicated by the bioconversion of tryptophan (TRP) to kynurenine (KYN) catalyzed by both IDO1 and TRP 2,3‐dioxygenase (TDO). In vitro and ex vivo, the IC50 was estimated following the selective induction of IDO1, rendering the TDO activity relatively insignificant; however, it was desirable to determine the in vivo IC50 without inducing an IDO1 abundance. A mechanistic population PD model was developed based on time‐matched EPA, TRP, and KYN plasma concentrations in 44 oncology patients, and EPA in vivo IC50 was estimated to be ∼70 nM, consistent with the ex vivo value independently determined. The model suggests that ∼60% and 40% of TRP→KYN bioconversion was mediated by IDO1 and TDO, respectively, in the cancer patients at baseline. For this study population of limited numbers of subjects, neither age nor sex was a significant covariate for EPA PK or PD.

Evaluation of the effect of ruxolitinib on cardiac repolarization: A thorough QT study

This was a randomized, four‐way crossover study that evaluated the effects of placebo, single doses of ruxolitinib 25 and 200 mg, and a single dose of moxifloxacin 400 mg on heart rate‐corrected QT interval in healthy subjects. Electrocardiograms (ECGs) and pharmacokinetic samples were obtained on each dosing day; baseline ECGs were taken pre‐dose. The primary endpoint was placebo‐subtracted change from baseline heart rate‐corrected QT (Fridericia formula [ΔΔQTcF]). The ΔΔQTcF for either dose of ruxolitinib ranged from −3.09 to 3.28 milliseconds (1‐sided 95% confidence interval of 0.06–6.62 milliseconds). The ΔΔQTcF for moxifloxacin (lower confidence interval) was significantly >5 milliseconds at 1, 2, and 3 hours post‐dose. Individual QTcF >450 milliseconds and QTcF from baseline >30 milliseconds following ruxolitinib were similar to placebo. Based on the International Conference on Harmonization E14 guidance, the study results were considered negative for QTc prolongation. In conclusion, ruxolitinib did not have a clinically significant effect on QT interval.