Effects of Food, Gastric Acid Reduction, and Strong CYP3A Induction on the Pharmacokinetics of Tasurgratinib, a Novel Selective Fibroblast Growth Factor Receptor Inhibitor.

We conducted this three-part study in healthy subjects to investigate the pharmacokinetics of tasurgratinib (orally available selective inhibitor of fibroblast growth factor receptor 1-3) and M2 (its major metabolite) under different conditions. In Part A, subjects received tasurgratinib 35 mg either fed with a high-fat meal or fasted. In Parts B and C, subjects received tasurgratinib 35 mg alone or with either rabeprazole (acid-reducing agent) 20 mg (Part B) or rifampin (strong CYP3A inducer) 600 mg (Part C). Primary endpoints were maximum concentration (Cmax), and areas under the plasma concentration-time curve to time of last quantifiable concentration (AUC(0-t)) and extrapolated to infinite time (AUC(0-inf)). Forty-two subjects were enrolled, 14 each into Parts A, B, and C. In Part A, administration of tasurgratinib with a high-fat meal resulted in 33% reduction in Cmax and ∼23% reduction in AUC(0-t) and AUC(0-inf) of tasurgratinib, and 47% reduction in Cmax with ∼30% reduction in AUC(0-t) and AUC(0-inf) of M2. In Part B, co-administration of rabeprazole at steady state resulted in no/weak interaction with tasurgratinib (∼8% increase in AUC(0-t) and AUC(0-inf) without an effect on Cmax) and M2 (∼18% increase in AUC(0-t) and AUC(0-inf) without an effect on Cmax). In Part C, co-administration of rifampin at steady state resulted in a weak interaction with tasurgratinib (∼16% reduction in AUC(0-t) and AUC(0-inf)) and M2 (∼12% reduction in AUC(0-t) and AUC(0-inf)). Administration of tasurgratinib with a high-fat meal appeared to reduce systemic exposure of tasurgratinib, however co-administration with an acid-reducing agent or a CYP3A inducer had a minimal impact on pharmacokinetics.

First-in-Human Phase 1 Study of MORAb-202, an Antibody-Drug Conjugate Comprising Farletuzumab Linked to Eribulin Mesylate, in Patients with Folate Receptor-α-Positive Advanced Solid Tumors.

PURPOSE: MORAb-202, an antibody-drug conjugate containing farletuzumab and eribulin with a cathepsin-B cleavable linker, targets folate receptor α (FRα)-expressing tumor cells. The primary objective of this first-in-human study was to evaluate the safety and tolerability of MORAb-202 in patients with solid tumors. PATIENTS AND METHODS: Patients ≥20 years with adequate organ function and FRα-positive solid tumors who failed to respond to standard therapy were eligible. Patients received MORAb-202 intravenously at doses of 0.3 to 1.2 mg/kg once every three weeks. Endpoints included dose-limiting toxicities, safety, tumor responses, pharmacokinetics, and pharmacodynamics. TRIAL REGISTRATION NUMBER: NCT03386942 (ClinicalTrials.gov). RESULTS: Between November 28, 2017 and June 4, 2019, 22 patients (median age, 58.0 years) with advanced solid tumors were enrolled. Treatment-emergent adverse events occurred in 21 (95%) patients, with leukopenia and neutropenia in 10 (45%) patients each. One patient (0.9 mg/kg cohort) experienced two grade 3 dose-limiting toxicities: serum alanine aminotransferase and γ-glutamyl transferase increases. Following review by an independent adjudication committee, grade 1/2 interstitial lung disease thought to be related to MORAb-202 was identified in five (23%) patients. Complete response, partial response, and stable disease were observed in one, nine, and eight patients, respectively. The normalized predose serum FRα tended to be positively correlated with the maximum tumor shrinkage (R 2 = 0.2379; P = 0.0291). CONCLUSIONS: The MTD of MORAb-202 was not reached. MORAb-202 demonstrated promising antitumor activity in FRα-positive solid tumors and was generally well-tolerated at the tested doses. Further investigations are required to establish appropriate dosage and clinical utility of MORAb-202.

Pharmacokinetic disposition of topical phosphodiesterase-4 inhibitor E6005 in patients with atopic dermatitis.

Background: A novel topical phosphodiesterase-4 inhibitor E6005 shows potential as effective treatment option for atopic dermatitis (AD); however, systemic exposure may cause potentially undesirable adverse reactions. In this study, we evaluated the relationship between the systemic exposure of E6005 and clinical parameters including skin condition and the incidence of AEs in patients with AD. Methods: The association analysis used the clinical data obtained in a previously conducted clinical study with topical E6005 in adult patients with AD. To estimate associations with drug exposure, generalized estimating equation logistic regression models were used, along with clinical data and plasma concentrations of M11, the major metabolite of E6005 (as an indicator for E6005 exposure). Results: The metabolite M11 was detected in 62 of 221 plasma samples from 72 subjects. From association analysis, SCORAD-A obtained prior to E6005 treatment was identified as the clinical parameter influenced to M11 detection with statistical significance (p = .003). M11 detection was not clearly associated with the incidence of adverse events occurred. Conclusion: Exposure to topical E6005 is associated with the eczema-associated area, however, that is not distinctly associated with its adverse drug reactions occurred after drug applications possibly due to E6005's characteristics of tissue distribution.

Population Pharmacokinetic/Pharmacodynamic Analyses of Avatrombopag in Patients With Chronic Liver Disease and Optimal Dose Adjustment Guide With Concomitantly Administered CYP3A and CYP2C9 Inhibitors.

Avatrombopag, a c-Mpl agonist, has been developed to provide an alternative therapy to standard platelet transfusion care for the treatment of thrombocytopenia. The main objectives of this article were to describe the pharmacokinetics (PK) of avatrombopag, to characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationship between plasma avatrombopag concentrations and platelet count, and to identify potential intrinsic and extrinsic factors affecting PK or PK/PD in patients with chronic liver disease (CLD). Platelet count following avatrombopag administration with and without concomitant medication was further simulated using the final population PK/PD model to explore potential dose adjustments. Avatrombopag PK was described by a 1-compartment model with combined first- and zero-order absorption and linear elimination. The relationship between the plasma avatrombopag concentrations and platelet count was well described by a 6-compartment life-span model with a linear drug effect. The final PK and PK/PD models included statistically significant but not clinically relevant effects of body weight and CLD on apparent volume distribution and East Asian ethnicity, albumin, and thrombopoietin level on the slope parameter in the PK/PD relationship. PK/PD simulations showed comparable elevation in platelet count with and without concomitant cytochrome P450 (CYP) 3A and CYP2C9 inhibitors for the dosing regimens of 40 and 60 mg for 5 days, with predictions of <10% of CLD patients exceeding platelet count >200 × 109 /L. Dose adjustment is therefore not necessary with concomitant use of CYP3A and CYP2C9 interacting drugs considering the limited treatment duration (ie, 5 days) and lack of significant safety concerns in CLD patients.

Pharmacokinetic/pharmacodynamic drug-drug interactions of avatrombopag when coadministered with dual or selective CYP2C9 and CYP3A interacting drugs.

AIMS: Avatrombopag, a thrombopoietin receptor agonist, is a substrate of cytochrome P450 (CYP) 2C9 and CYP3A. We assessed three drug-drug interactions of avatrombopag as a victim with dual or selective CYP2C9/3A inhibitors and inducers. METHODS: This was a three-part, open-label study. Forty-eight healthy subjects received single 20 mg doses of avatrombopag alone or with one of 3 CYP2C9/3A inhibitors or inducers: fluconazole 400 mg once daily for 16 days, itraconazole 200 mg twice daily on Day 1 and 200 mg once daily on Days 2-16, or rifampicin 600 mg once daily for 16 days. Pharmacokinetics, pharmacodynamics (platelet count) and safety of avatrombopag were evaluated. RESULTS: Coadministration of a single 20-mg dose of avatrombopag with fluconazole at steady-state resulted in 2.16-fold increase of AUC of avatrombopag, prolonged terminal elimination phase half-life (from 19.7 h to 39.9 h) and led to a clinically significant increase in maximum platelet count (1.66-fold). Itraconazole had a mild increase on both avatrombopag pharmacokinetics and pharmacodynamics compared to fluconazole. Coadministration of rifampicin caused a 0.5-fold decrease in AUC and shortened terminal elimination phase half-life (from 20.3 h to 9.84 h), but has no impact on maximum platelet count. Coadministration with interacting drugs was found to be generally safe and well-tolerated. CONCLUSIONS: The results from coadministration of fluconazole or itraconazole suggest that CYP2C9 plays a more predominant role in metabolic clearance of avatrombopag than CYP3A. To achieve comparable platelet count increases when avatrombopag is coadministered with CYP3A and CYP2C9 inhibitors, an adjustment in the dose or duration of treatment is recommended, while coadministration with strong inducers is not currently recommended.

Pharmacokinetics, Pharmacodynamics, Pharmacogenomics, Safety, and Tolerability of Avatrombopag in Healthy Japanese and White Subjects.

Avatrombopag, an orally administered, small-molecule thrombopoietin receptor (c-Mpl) agonist, is currently in clinical development for the potential treatment of severe thrombocytopenia in patients with chronic liver disease undergoing an elective procedure. The objectives of this study were to characterize and compare the pharmacokinetics (including the food effect) and pharmacodynamics (platelet count) of avatrombopag following single doses in Japanese and white subjects. Following single dosing under fasted and fed conditions, mean peak concentrations occurred at 5 to 8 hours and subsequently declined with a half-life of 16 to 18 hours in Japanese and white subjects. Administration with food did not alter the rate or extent of avatrombopag absorption but substantially reduced pharmacokinetic variability relative to the fasted state. CYP2C9 polymorphism (*2, *3) was associated with higher pharmacokinetic variability but not with any clinically important effect on variability in platelet response. Plasma exposures of avatrombopag increased in a dose-proportional manner over the dose range tested. After a single dose, platelet count increased in a dose-related manner, reaching a maximum by day 11 and returning to baseline levels by day 27. No clinically important differences were found when avatrombopag pharmacokinetics and pharmacodynamics were compared between Japanese and white subjects. Administration of avatrombopag was generally well tolerated.

Efficacy of a novel phosphodiesterase inhibitor, E6005, in patients with atopic dermatitis: An investigator-blinded, vehicle-controlled study.

INTRODUCTION: Phosphodiesterase type 4 (PDE4) inhibition is a well-known anti-inflammatory mechanism. However, the clinical use of PDE4 inhibitors has been compromised by the occurrence of mechanism-associated adverse reactions, which often limit the maximum tolerated dose. To minimize systemic exposure, a topically active PDE4 inhibitor with low transdermal bioavailability could be clinically useful. The purpose of this study was to evaluate the efficacy of a novel topical PDE4 inhibitor, E6005, in patients with atopic dermatitis. METHODS: This randomized, investigator-blinded, vehicle-controlled, multiple ascending dose study included 40 adult male patients with atopic dermatitis, who were randomly assigned to 10 days of treatment with either E6005 ointment (0.01, 0.03, 0.1 or 0.2%) or vehicle ointment. RESULTS: Of 81 patients screened, 40 who had typical lesions on their posterior trunk were randomized into the study. One patient receiving 0.03% E6005 treatment discontinued because of acute gout and one receiving vehicle treatment discontinued because of progression of atopic dermatitis. The targeted lesion severity scores decreased in a concentration-dependent manner in patients treated with E6005. This drop was significant in the 0.2% E6005 ointment treatment group (mean percent change: -54.30%, p = 0.007). CONCLUSION: E6005 ointment showed anti-inflammatory efficacy in adult patients with atopic dermatitis.

Effect of topical phosphodiesterase 4 inhibitor E6005 on Japanese children with atopic dermatitis: Results from a randomized, vehicle-controlled exploratory trial.

This exploratory study was designed to evaluate the safety and efficacy profile of the topical phosphodiesterase 4 inhibitor E6005 in Japanese children with mild-to-moderate atopic dermatitis. The present randomized, multicenter study included 62 patients who were treated with 0.05% E6005, 0.2% E6005 or vehicle ointment twice daily for 2 weeks. Safety and pharmacokinetics were assessed with a focus on the occurrence of adverse events and the whole blood concentrations of E6005 and its metabolite. Exploratory efficacy evaluations included assessments of lesion severity and pruritus score. The 2-week application of topical E6005 was safe and well tolerated with no cutaneous adverse events. The whole blood concentration of E6005 was quantified in only one subject receiving 0.2% E6005 treatment, while its major metabolite was undetectable. The 0.2% E6005 group showed a greater decrease in the severity score than the vehicle group (-45.94% vs -32.26%), although this difference was not statistically significant. Similarly, the treatment success rate according to the investigator's global assessment of the total application sites was higher in the 0.2% E6005 group than in the vehicle group (34.4% vs 20.0%). Moreover, the 0.2% E6005 group showed a greater decrease in the pruritus score than the vehicle group (-37.5% vs -6.7%) in a predefined subpopulation. The efficacy of 0.05% E6005 treatment was comparable to that of vehicle treatment. These results suggest that topical 0.2% E6005 treatment is safe and effective in children with atopic dermatitis, although further large confirmatory clinical trials are warranted.

Safety, tolerability and pharmacokinetics of a novel phosphodiesterase inhibitor, E6005 ointment, in healthy volunteers and in patients with atopic dermatitis.

OBJECTIVES: The purpose of the present studies was to assess the safety, tolerability and pharmacokinetics of topical application of a novel phosphodiesterase inhibitor, E6005, in healthy volunteers and in patients with atopic dermatitis (AD). METHODS: In two randomized, investigator-blind, vehicle-controlled studies, we evaluated the topical application of E6005 ointment at concentrations ranging from 0.01% to 0.2% in healthy volunteers (Study 001) and in patients with AD (Study 101). RESULTS: Thirty-six subjects were enrolled in Study 001 and 40 in Study 101. Neither skin irritation nor photosensitization was observed with application of E6005 in Study 001. Four subjects receiving E6005 in Study 001 experienced a treatment-emergent adverse event (application site edema, increased alanine aminotransferase or erythema); three of these subjects discontinued the study. Two subjects receiving E6005 in Study 101 experienced an adverse event (gout or enterocolitis); one discontinued the study. Plasma concentrations of E6005 were below the limit of quantification (1 ng/ml) in both studies. CONCLUSION: E6005 ointment exhibited acceptable safety and tolerability. Topical application of E6005 ointment resulted in very low systemic exposure to E6005 in healthy volunteers and in patients with AD.