Itacitinib Population Pharmacokinetics and Exposure-Response in Patients With Acute Graft-Versus-Host Disease.

This article presents the population pharmacokinetic (PopPK) analysis and exposure-response analyses for the primary efficacy end point-acute graft-versus-host disease (aGVHD) day 28 response-and select safety measures (incidence of thrombocytopenia, hypertriglyceridemia, and cytomegalovirus infection) from a phase 3 randomized, double-blind study comparing itacitinib plus corticosteroids versus placebo plus corticosteroids for the treatment of aGVHD. The PopPK data set contained sparse data from patients with aGVHD and select enriched data from healthy volunteers. The structural model was a 2-compartment model with first-order elimination and dose-dependent nonlinear absorption with dual first-order absorption pathways with lag times. Strong cytochrome P450 (CYP) 3A inhibitor coadministration, moderate renal impairment, and participant population (healthy volunteers vs patients with aGVHD) were covariates on apparent clearance. Participant population was also a covariate on apparent intercompartmental clearance and lag time of the secondary absorption compartment. Apparent clearance decreased 42% with coadministration of strong CYP3A inhibitors. Simulations supported the following dose reductions with concomitant use of a strong CYP3A inhibitor: 300 mg once daily to 200 mg once daily, 400 mg once daily to 300 mg once daily, and 600 mg once daily to 400 mg once daily. No dose adjustment is recommended for any other covariate based on the magnitude of impact when they were retained in the model. The exposure-response relationship was characterized between itacitinib exposure and probability of aGVHD day 28 response using a linear logistic regression model. Both itacitinib exposure and aGVHD risk status were significant predictors of response. There was no relationship between itacitinib exposure and thrombocytopenia, hypertriglyceridemia, or cytomegalovirus infection.

Bioanalysis of INCB000928 in human saliva: nonspecific binding and inhomogeneous concentration.

Aim: To develop a bioanalytical method for quantifying INCB000928 in human saliva. Materials & methods: Human centrifuged saliva and human whole saliva were compared for matrix selection. Protein precipitation extraction and HPLC-MS/MS was used for analysis. Results & conclusion: Nonspecific binding of INCB000928 was reduced in whole versus centrifuged saliva. Whole saliva was a preferred matrix for INCB000928 bioanalytical method validation. Incurred sample reanalysis (ISR) using a successfully validated method failed in a healthy volunteer study because of inhomogeneous INCB000928 concentration across sample tube depths. Individual mixing of sample tubes followed by immediate aliquoting corrected the ISR failure, with 97.2% of repeats passing versus 41.7% for the same ISR samples.

Fibrodysplasia ossificans progressiva (FOP) is a very rare condition where bone forms outside the skeleton (ossification), leading to restricted movement, decreased quality of life and shortened life span. Mutations in a gene called ALK2 have been identified as causing FOP. INCB000928 is a novel drug (to be taken by mouth) which inhibits ALK2 activity and prevents ossification in a laboratory mouse model of FOP. Because monitoring of the levels and efficacy of a drug often requires blood draws, which can be taxing in patients with FOP, this study aimed to develop a method to measure INCB000928 levels in saliva. The authors propose a unique procedure to process saliva samples to ensure accurate, reproducible quantitation of INCB000928 levels in saliva.

An Open-Label Study to Assess the Effect of Itraconazole and Rifampin on Parsaclisib Pharmacokinetics When Administered Orally in Healthy Participants.

Parsaclisib, a selective, potent phosphatidylinositol 3-kinase delta inhibitor being developed for the treatment of cancer and autoimmune diseases, is primarily metabolized by cytochrome P450 (CYP) 3A4. This study assessed the pharmacokinetics (PK) and safety of parsaclisib alone or combined with itraconazole (potent CYP3A inhibitor) or rifampin (potent CYP3A4 inducer) in healthy participants. In this open-label, fixed-sequence study, cohort 1 received oral parsaclisib 10 mg once daily on days 1 and 8 and oral itraconazole 200 mg once daily on days 4-11; cohort 2 received oral parsaclisib 20 mg once daily on days 1 and 11 and oral rifampin 600 mg once daily on days 4-12. Parsaclisib plasma concentration was tested and PK parameters calculated by noncompartmental analysis. Geometric mean ratios (GMRs) and 2-sided 90% confidence intervals (CIs) were estimated by 2-factor analysis of variance. Thirty-six healthy participants were enrolled (18 per cohort). Parsaclisib maximum plasma drug concentration (Cmax ) and area under the concentration-time curve extrapolated to infinity (AUC0-∞ ) were increased by 21% and 107% with concomitant itraconazole versus parsaclisib alone (GMR, 1.21; 90%CI, 1.14-1.29; and 2.07; 90%CI, 1.97-2.17, respectively). Parsaclisib Cmax and AUC were reduced by 43% and 77%, respectively, with concomitant rifampin versus parsaclisib alone (GMR, 0.57; 90%CI, 0.53-0.60; and 0.23; 90%CI, 0.21-0.24, respectively). Headache was the most common adverse event, reported by 13.9% of participants (all in cohort 2). Single-dose parsaclisib alone or combined with itraconazole or rifampin appeared safe and well tolerated in healthy participants. Parsaclisib dose adjustment may be necessary with concomitant administration of strong CYP3A4 inhibitors or inducers.

The Effect of Renal Impairment on the Pharmacokinetics and Safety of Itacitinib.

Itacitinib is a novel, selective, Janus kinase 1 inhibitor in development for treatment of graft-versus-host disease. The objective of this study was to assess pharmacokinetics and safety of 300-mg itacitinib dosed in participants with normal renal function (n = 10), severe renal impairment (n = 8), and end-stage renal disease (ESRD) on hemodialysis (n = 8). Serial plasma and urine samples (urine from normal and severe groups only) were collected before dosing until 72 hours after dosing. In the ESRD group, itacitinib was evaluated in 2 periods, when dosed before (period 1) and after (period 2) a hemodialysis session. Geometric mean ratios (90% confidence interval) in participants with severe renal impairment, ESRD period 1 and ESRD period 2 relative to participants with normal renal function were 1.65 (1.13-2.39), 0.71 (0.49-1.03), and 0.83 (0.57-1.20) for maximum plasma drug concentration and 2.23 (1.56-3.18), 0.81 (0.57-1.16), and 0.95 (0.66-1.35) for area under the plasma concentration-time curve from time zero to infinity. Itacitinib was well tolerated, and 3 grade 1 treatment-emergent adverse events were reported over the course of the study. Given the magnitude of exposure changes in participants with severe renal impairment or ESRD and the historic risk-benefit profile, no dose adjustment is recommended for itacitinib in patients with impaired renal function, although the final dosage recommendation will be based on cumulative pharmacokinetics and safety from this study and from the pivotal graft-versus-host disease trial. Additionally, itacitinib may be administered to patients undergoing dialysis regardless of the time of dialysis.

Effect of Itraconazole or Rifampin on Itacitinib Pharmacokinetics When Administered Orally in Healthy Subjects.

Itacitinib is a potent, selective JAK-1 inhibitor currently in phase 3 development for the treatment of acute and chronic graft-versus-host disease (GVHD) in combination with corticosteroids. Itacitinib is primarily eliminated via metabolism by cytochrome P-450 (CYP)3A4 with minimal renal elimination. A drug-drug interaction study was conducted to evaluate the impact of the strong CYP3A inhibitor itraconazole or the strong CYP3A4 inducer rifampin on the pharmacokinetics of itacitinib in healthy volunteers. In cohort 1, subjects received 200 mg sustained release (SR) tablets of itacitinib on days 1 and 6 and 200 mg itraconazole on days 2-7. In cohort 2, subjects received 200 mg SR itacitinib on days 1 and 9 and 600 mg rifampin on days 2-9. Thirty-six subjects were enrolled, 18 in each cohort with 17 completing itacitinib dosing in cohort 1 and 15 completing itacitinib dosing in cohort 2. Coadministration of itraconazole with itacitinib resulted in a nearly 5-fold increase in area under the concentration-time curve (AUC0-∞ ) (geometric mean ratio [GMR] 4.88, 90%Cl 4.17-5.72) and an ∼3-fold increase in peak concentration (Cmax ) (GMR 3.15, 90%Cl 2.58-3.54). Coadministration of rifampin with itacitinib resulted in a nearly 80% decrease in AUC0-∞ (GMR 0.208, 90%Cl 0.173, 0.249) and Cmax (GMR 0.231, 90%Cl 0.195, 0.274). Results of this study informed the study design of the phase 3 GVHD protocols with regard to coadministration of strong CYP3A inhibitors and CYP3A4 inducers. These data combined with phase 3 data will inform final dosing recommendations.