Predicting Abrocitinib Efficacy at Week 12 Based on Clinical Response at Week 4: A Post Hoc Analysis of Four Randomized Studies in Moderate-to-Severe Atopic Dermatitis.

INTRODUCTION: Early prediction of abrocitinib efficacy in atopic dermatitis (AD) could help identify candidates for an early dose increase. A predictive model determined week 12 efficacy based on week 4 responses in patients receiving abrocitinib 100 mg/day and assessed the effect of an abrocitinib dose increase on platelet counts. METHODS: Analysis included the phase 3 trials JADE MONO-1 (NCT03349060), MONO-2 (NCT03575871), COMPARE (NCT03720470), and TEEN (NCT03796676). For platelet counts and simulations, a phase 2 psoriasis trial (NCT02201524) and phase 2b (NCT02780167) and phase 3 (MONO-1, MONO-2, and REGIMEN (NCT03627767)) abrocitinib trials were pooled. A training-and-validation framework assessed potential predictors of response at week 4: score and score change from baseline in the Eczema Area and Severity Index (EASI), Investigator's Global Assessment (IGA), and Peak Pruritus Numerical Rating Scale (PP-NRS), and percentage change from baseline in EASI. The dependent variables at week 12 were ≥ 75% improvement in EASI (EASI-75) and IGA score of 0 (clear) or 1 (almost clear) and ≥ 2-point improvement from baseline. The probability of each variable to predict week 12 EASI-75 and IGA responses was calculated. RESULTS: In the training cohort (n = 453), 72% of the ≥ 50% improvement in EASI (EASI-50) at week 4 responders and 16% of the nonresponders with abrocitinib 100 mg achieved EASI-75 at week 12; 48% and 6% of the week 4 EASI-50 responders and nonresponders, respectively, achieved week 12 IGA response. Similar results occurred with week 4 IGA = 2, ≥ 4-point improvement from baseline in PP-NRS, or EASI = 8 responders/nonresponders. Platelet counts after an abrocitinib dose increase from 100 to 200 mg were similar to those seen with continuous dosing with abrocitinib 100 mg or 200 mg. CONCLUSION: Achieving week 4 clinical responses with abrocitinib 100 mg may be useful in predicting week 12 responses. Week 4 nonresponders may benefit from a dose increase to abrocitinib 200 mg, and those that receive this dose increase are likely to achieve treatment success at week 12, with no significant impact on platelet count recovery. Video abstract available for this article. CLINICAL TRIAL REGISTRATION: NCT03349060, NCT03575871, NCT03720470, NCT03796676, NCT02201524, NCT02780167 and NCT03627767.

Abrocitinib is an approved treatment for people with moderate or severe atopic dermatitis. Abrocitinib tablets are available in two doses (100 and 200 mg) and are taken by mouth once daily. Some people with atopic dermatitis who are taking abrocitinib 100 mg may need to increase the dose to 200 mg to get adequate symptom relief. We studied whether people with atopic dermatitis who did or did not experience clear skin or itch relief after taking abrocitinib 100 mg for 4 weeks are likely or not likely to experience relief after 12 weeks of treatment. We also defined the level of response after 4 weeks of treatment that best differentiates people who did or did not experience symptom relief, and we identified who might benefit from increasing the abrocitinib dose from 100 to 200 mg. We found that people with atopic dermatitis who had symptom relief after 4 weeks of abrocitinib 100 mg treatment were much more likely to have greater relief after 12 weeks, and people who did not achieve symptom relief after 4 weeks may benefit from a dose increase at week 4. Some people who receive abrocitinib 200 mg may have a temporary decrease in the number of certain blood cells called platelets at week 4, but platelets return to near-normal levels by week 12. This analysis showed that increasing the abrocitinib dose from 100 to 200 mg at week 4 did not seem to affect the platelet numbers after week 4. Video abstract (MP4 174529 KB).

Tumor growth inhibition modeling to support the starting dose for dacomitinib.

Dacomitinib is a second-generation, irreversible EGFR tyrosine kinase inhibitor for first-line treatment of patients with metastatic non-small cell lung cancer and EGFR-activating mutations. A high rate of dose reductions in the pivotal trial led to an observed inverse exposure-response (ER) relationship with the primary end points. Three ER models were developed to determine if the starting dose from the pivotal trial, 45 mg once daily (q.d.) dose, is appropriate: a longitudinal logistic regression model for adverse event-related dose changes, a Claret tumor growth inhibition (TGI) model, and a Cox model for progression-free survival (PFS) based on the TGI model predictions. This analysis included 266 patients taking dacomitinib with a starting dose of 45 mg (N = 250) or 30 mg (N = 16) q.d. The ER relationships with the time-varying exposure metrics, most recent maximum plasma concentration (Cmax ) and average concentration (Cavg ) from the first dose, were established for the dose reduction and TGI models, respectively. The TGI model characterized the tumor inhibition over time with constant growth rate (kL  = 0.0012 years-1 ) and highly variable kill rate (kD  = 1.002 years-1 /[µg/L]θcavg , coefficient of variation [CV] = 89%) and drug resistance (λ = 14.47 years-1 , CV = 96%) leading to prolonged tumor shrinkage. The ER relationship was characterized using an exposure parameter with a power parameterization (θcavg = 0.454, p < 0.0001). The Cox model found that baseline tumor size (p = 0.0166) and week 8 tumor shrinkage rate (p = 0.0726) were the best predictors of PFS. Simulations of dose reductions and drug interruptions on tumor shrinkage over time showed greater and more prolonged tumor shrinkage with a starting dose of 45 mg q.d.

Population pharmacokinetic-pharmacodynamic modelling of platelet time-courses following administration of abrocitinib.

AIMS: Abrocitinib is a selective Janus kinase 1 inhibitor for the treatment of moderate-to-severe atopic dermatitis. Herein we describe the time-course of drug-induced platelet reduction following abrocitinib administration, identify covariates affecting platelet counts, and determine the probability of patients experiencing thrombocytopaenia while receiving abrocitinib. METHODS: This analysis included data from two Phase 2 and three Phase 3 studies in psoriasis and atopic dermatitis patient populations administered abrocitinib 10-400 mg QD orally for up to 12 weeks, with platelet counts determined up to week 16. A semi-mechanistic model was developed to assess the impact of baseline platelet counts (170, 220 and 270 × 1000/µL), age and race on the platelet nadir and week 12 counts with once-daily abrocitinib 200 mg or 100 mg. RESULTS: Decreases in platelet counts were transient with the nadir occurring on average 24 days (95% prediction interval, 23-24) after continuous administration of abrocitinib 200 mg QD. Following administration of once-daily abrocitinib 200 mg, the probabilities of thrombocytopaenia (<150 × 1000/µL) at the nadir were 8.6% and 95.5% for the typical patient with baseline platelet count of 270 × 1000/µL or 170 × 1000/µL, respectively. Adolescents had a lower probability of thrombocytopaenia compared with adults; platelet count distribution was similar in Asian and Western patients at the nadir and at week 12. CONCLUSION: This analysis supports the safety of once-daily abrocitinib 200 mg and 100 mg dosing regimens, with low probability of thrombocytopaenia during treatment, except for higher risk of low-grade thrombocytopaenia that diminished after 4 weeks in patients with low baseline platelet counts.

Population Pharmacokinetics of Abrocitinib in Healthy Individuals and Patients with Psoriasis or Atopic Dermatitis.

BACKGROUND AND OBJECTIVE: Abrocitinib is a Janus kinase 1 inhibitor in development for the treatment of atopic dermatitis (AD). This work characterized orally administered abrocitinib population pharmacokinetics in healthy individuals, patients with psoriasis, and patients with AD and the effects of covariates on abrocitinib exposure. METHODS: Abrocitinib concentration measurements (n = 6206) from 995 individuals from 11 clinical trials (seven phase I, two phase II, and two phase III) were analyzed, and a non-linear mixed-effects model was developed. Simulations of abrocitinib dose proportionality and steady-state accumulation of maximal plasma drug concentration (Cmax) and area under the curve (AUC) were conducted using the final model. RESULTS: A two-compartment model with parallel zero- and first-order absorption, time-dependent bioavailability, and time- and dose-dependent clearance best described abrocitinib pharmacokinetics. Abrocitinib coadministration with rifampin resulted in lower exposure, whereas Asian/other race coadministration with fluconazole and fluvoxamine, inflammatory skin conditions (psoriasis/AD), and hepatic impairment resulted in higher exposure. After differences in body weight are accounted for, Asian participants demonstrated a 1.43- and 1.48-fold increase in Cmax and AUC, respectively. The overall distribution of exposures (Cmax and AUC) was similar in adolescents and adults after accounting for differences in total body weight. CONCLUSIONS: A population pharmacokinetics model was developed for abrocitinib that can be used to predict abrocitinib steady-state exposure in the presence of drug-drug interaction effects or intrinsic patient factors. Key covariates in the study population accounting for variability in abrocitinib exposures are Asian race and adolescent age, although these factors are not clinically meaningful. CLINICAL TRIAL NUMBERS: NCT01835197, NCT02163161, NCT02201524, NCT02780167, NCT03349060, NCT03575871, NCT03634345, NCT03637790, NCT03626415, NCT03386279, NCT03937258.

Abrocitinib is a drug approved in the UK and Japan for the treatment of atopic dermatitis. A population pharmacokinetic model for abrocitinib was developed based on data from 11 clinical trials that included 995 healthy individuals or patients with atopic dermatitis or psoriasis. Simulations of different patient factors, such as age, race, sex, body weight, liver function, and drug­drug interactions, were tested to examine differences in abrocitinib drug levels achieved in the body. The results of these simulations indicate that although there are some differences in abrocitinib exposure, no dose adjustments of abrocitinib are necessary based on these factors.

Exposure-response modeling of the effect of glasdegib on cardiac repolarization in patients with cancer.

PURPOSE: To characterize the effect of glasdegib on cardiac repolarization (QTc) in patients with advanced cancer. METHODS: A concentration-QTc model was developed using data from two glasdegib single-agent, dose-escalation trials. Triplicate electrocardiogram was performed at pre-specified timepoints paired with pharmacokinetic blood collections after a single dose and at steady-state. Changes in QTc from baseline were predicted by model-based simulations at the clinical dose (100 mg QD) and in a supratherapeutic setting. RESULTS: Glasdegib did not affect the heart rate, but had a positive effect on the corrected QT interval, described by a linear mixed-effects model with ΔQTcF (QTc using Fridericia's formula) as the dependent variable with glasdegib plasma concentrations from doses of 5-640 mg QD. The predicted mean QTcF change (upper bound of the 95% CI) was 5.30 (6.24) msec for the therapeutic 100-mg QD dose; at supratherapeutic concentrations (40% and 100% increase over the therapeutic Cmax), it was 7.42 (8.74) and 12.09 (14.25) msec, respectively. CONCLUSIONS: The relationship of glasdegib exposure and QTc was well characterized by the model. The effect of glasdegib on the QTc interval did not cross the threshold of clinical concern for an oncology drug. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT01286467 and NCT00953758.

Metabolism, Excretion, and Pharmacokinetics of Lorlatinib (PF-06463922) and Evaluation of the Impact of Radiolabel Position and Other Factors on Comparability of Data Across 2 ADME Studies.

While an initial clinical absorption, distribution, metabolism, and excretion (ADME) study (Study 1; N = 6) with 100 mg/100 µCi [14 C]lorlatinib, radiolabeled on the carbonyl carbon, confirmed that the primary metabolic pathways for lorlatinib are oxidation (N-demethylation, N-oxidation) and N-glucuronidation, it also revealed an unanticipated, intramolecular cleavage metabolic pathway of lorlatinib, yielding a major circulating benzoic acid metabolite (M8), and an unlabeled pyrido-pyrazole substructure. Concerns regarding the fate of unknown metabolites associated with this intramolecular cleavage pathway led to conduct of a second ADME study (Study 2; N = 6) of identical design but with the radiolabel positioned on the pyrazole ring. Results were similar with respect to the overall mass balance, lorlatinib plasma exposures, and metabolic profiles in excreta for the metabolites that retained the radiolabel in both studies. Differences were observed in plasma total radioactivity exposures (2-fold area under the plasma concentration-time curve from time 0 to infinity difference) and relative ratios of the percentage of dose recovered in urine vs feces (48% vs 41% in Study 1; 28% vs 64% in Study 2). In addition, an approximately 3-fold difference in the mean molar exposure ratio of M8 to lorlatinib was observed for values derived from metabolic profiling data relative to those derived from specific bioanalytical methods (0.5 vs 1.4 for Studies 1 and 2, respectively). These interstudy differences were attributed to a combination of factors, including alteration of radiolabel position, orthogonal analytical methodologies, and intersubject variability, and illustrate that results from clinical ADME studies are not unambiguous and should be interpreted within the context of the specific study design considerations.

Pharmacokinetic/Pharmacodynamic Modeling to Support the Re-approval of Gemtuzumab Ozogamicin.

Gemtuzumab ozogamicin (Mylotarg; Pfizer, New York, NY) was the first antibody-drug conjugate to be approved for CD33-positive acute myeloid leukemia (AML). However, it was voluntarily withdrawn from the US market due to lack of clinical benefit in the confirmatory phase III trial. In 2012, several investigator cooperative studies using a different dosing regimen showed efficacy, but pharmacokinetic (PK) data were not collected in these trials. Through simulation of expected concentrations for new dosing regimens, PK/pharmacodynamic modeling was able to support the safety and efficacy of these regimens. Significant exposure-response relationships were found for the attainment of complete remission with and without platelet recovery, attainment of blast-free status, the time course of myelosuppression, several grade ≥ 3 hepatic adverse events, and veno-occlusive disease. Gemtuzumab ozogamicin received full approval by the US Food and Drug Administration (FDA) in September 2017 for newly diagnosed and relapsed AML in adult patients and relapsed AML in pediatric patients aged 2-17 years.

PharmTeX: a LaTeX-Based Open-Source Platform for Automated Reporting Workflow.

Every year, the pharmaceutical industry generates a large number of scientific reports related to drug research, development, and regulatory submissions. Many of these reports are created using text processing tools such as Microsoft Word. Given the large number of figures, tables, references, and other elements, this is often a tedious task involving hours of copying and pasting and substantial efforts in quality control (QC). In the present article, we present the LaTeX-based open-source reporting platform, PharmTeX, a community-based effort to make reporting simple, reproducible, and user-friendly. The PharmTeX creators put a substantial effort into simplifying the sometimes complex elements of LaTeX into user-friendly functions that rely on advanced LaTeX and Perl code running in the background. Using this setup makes LaTeX much more accessible for users with no prior LaTeX experience. A software collection was compiled for users not wanting to manually install the required software components. The PharmTeX templates allow for inclusion of tables directly from mathematical software output as well and figures from several formats. Code listings can be included directly from source. No previous experience and only a few hours of training are required to start writing reports using PharmTeX. PharmTeX significantly reduces the time required for creating a scientific report fully compliant with regulatory and industry expectations. QC is made much simpler, since there is a direct link between analysis output and report input. PharmTeX makes available to report authors the strengths of LaTeX document processing without the need for extensive training. Graphical Abstract ᅟ.

Inotuzumab ozogamicin in adults with relapsed or refractory CD22-positive acute lymphoblastic leukemia: a phase 1/2 study.

This study evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of inotuzumab ozogamicin (InO) for CD22-positive relapsed/refractory acute lymphoblastic leukemia. In phase 1, patients received InO 1.2 (n = 3), 1.6 (n = 12), or 1.8 (n = 9) mg/m2 per cycle on days 1, 8, and 15 over a 28-day cycle (≤6 cycles). The recommended phase 2 dose (RP2D) was confirmed (expansion cohort; n = 13); safety and activity of InO were assessed in patients receiving the RP2D in phase 2 (n = 35) and in all treated patients (n = 72). The RP2D was 1.8 mg/m2 per cycle (0.8 mg/m2 on day 1; 0.5 mg/m2 on days 8 and 15), with reduction to 1.6 mg/m2 per cycle after complete remission (CR) or CR with incomplete marrow recovery (CRi). Treatment-related toxicities were primarily cytopenias. Four patients experienced treatment-related venoocclusive disease/sinusoidal obstruction syndrome (VOD/SOS; 1 fatal). Two VOD/SOS events occurred during treatment without intervening transplant; of 24 patients proceeding to poststudy transplant, 2 experienced VOD/SOS after transplant. Forty-nine (68%) patients had CR/CRi, with 41 (84%) achieving minimal residual disease (MRD) negativity. Median progression-free survival was 3.9 (95% confidence interval, 2.9-5.4) months; median overall survival was 7.4 (5.7-9.2) months for all treated patients, with median 23.7 (range, 6.8-29.8) months of follow-up for all treated patients alive at data cutoff. Achievement of MRD negativity was associated with higher InO exposure. InO was well tolerated and demonstrated high single-agent activity and MRD-negativity rates. This trial was registered at www.clinicaltrials.gov as #NCT01363297.