Population Pharmacokinetics of Inotuzumab Ozogamicin in Pediatric Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia: Results of Study ITCC-059.

BACKGROUND AND OBJECTIVE: Inotuzumab ozogamicin is an antibody-drug conjugate approved for treating relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in adults. Pediatric pharmacokinetic data of inotuzumab ozogamicin are lacking. This study is the first to examine the population pharmacokinetics of inotuzumab ozogamicin in pediatric patients with relapsed/refractory BCP-ALL. METHODS: From 531 adult patients with B-cell non-Hodgkin's lymphoma, 234 adult patients with BCP-ALL, and 53 pediatric patients with BCP-ALL, 8924 inotuzumab ozogamicin serum concentrations were analyzed using non-linear mixed-effects modeling. A published adult inotuzumab ozogamicin population-pharmacokinetic model, a two-compartment model with linear and time-dependent clearance, was adapted to describe the pediatric data. RESULTS: Modifications in this analysis, compared to the published adult model, included: (i) re-estimating pharmacokinetic parameters and covariate effects; (ii) modifying covariate representation; and (iii) introducing relevant pediatric covariate effects (age on the decay coefficient of time-dependent clearance and ALL effect (disease type and/or different bioanalytical analysis methods) on initial values of time-dependent clearance). For patients with relapsed/refractory BCP-ALL, increasing age was associated with a decreasing decay coefficient of time-dependent clearance, reflecting that the target-mediated drug clearance declines more rapidly in children. In pediatric BCP-ALL, the median [interquartile range] cumulative area under the concentration-time curve was significantly higher among responders (n = 42) versus non-responders (n = 10) at the end of the first cycle (26.1 [18.9-35.0] vs 10.1 [9.19-16.1], × 103 ng*h/mL, p < 0.001). From simulations performed at the recommended pediatric phase II dose, inotuzumab ozogamicin exposure reached a similar level as observed in responding pediatric trial participants. CONCLUSIONS: The pharmacokinetic profile of inotuzumab ozogamicin in pediatric patients with relapsed/refractory BCP-ALL was well described in this study. No dose adjustment is required clinically for pediatric patients with BCP-ALL based on the simulated inotuzumab ozogamicin exposure at the recommended pediatric phase II dose, promising efficacy and acceptable tolerability.

An Investigation in the Comparability of the Exposure and Recommended Dose of Selected Pfizer Drugs in East Asian Countries: Is Mutual Usage of Clinical Data Among East Asian Countries Feasible?

The current regulatory path for new drug registration in East Asian countries has led to significant delay of the new medicines in these countries. A unified regulatory path and allowance of mutual usage of clinical data in East Asian countries would lead to cost saving in drug development and expedite the new drug registration in these countries. The objectives of the present analysis are to compare the approval dates of a selection of products developed by Pfizer in the United States and East Asian countries (China, Japan, Korea) and compare the pharmacokinetics and recommended doses of these products in East Asian countries. Eighteen products (20 drugs, 2 products with 2 combination drugs) with exposure data available in at least 2 of the 3 East Asian countries across different therapeutic areas were included in the analyses. The results showed that most products had delayed approval in East Asian countries (up to 8 years) after US or EU approval. No distinct differences were observed in the drug exposure and recommended doses for the selected products in East Asian countries. These results together with literature data of genetic similarity of the East Asian populations support the mutual usage of the clinical data in the East Asian countries for expedited regulatory submission and approval.

A multi-purpose Japanese phase I study in the global development of vupanorsen: Randomized, placebo-controlled, single-ascending dose study in adults.

Vupanorsen (PF-07285557) is a second-generation tri-N-acetyl galactosamine (GalNAc3 )-antisense oligonucleotide targeted to angiopoietin-like 3 (ANGPTL3) mRNA, shown to reduce lipids and apolipoproteins in subjects with dyslipidemia. To aid bringing innovative drugs to global patients efficiently, a multi-purpose Japanese phase I study was conducted, with integrated development approaches agreed by the Pharmaceuticals and Medical Devices Agency (PMDA). This randomized, double-blind, placebo-controlled, single-ascending dose (SAD) study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of vupanorsen administered subcutaneously to Japanese adults (20-65 years) with elevated triglycerides (TG). Participants were randomized (1:1:1) to vupanorsen (80:160 mg) or placebo (N = 4 each). Vupanorsen 160 mg was a first-in-human (FIH) dose level. Vupanorsen was well-tolerated with no treatment-related adverse events reported for either dose. Absorption into the systemic circulation was rapid with median time to maximum concentration (Tmax ) of 3.5 and 2.0 h, for vupanorsen 80 and 160 mg, respectively. Following maximum concentration (Cmax ), vupanorsen underwent multiphasic decline characterized by a relatively fast initial distribution phase followed by slower terminal elimination phase, with elimination half-life (t1/2 ) of 397 and 499 h (80, 160 mg), respectively. Area under the concentration-time curve (AUC) and Cmax increased in a greater than dose-proportional manner. Pharmacodynamic markers (ANGPTL3, TG, and other key lipids) were reduced with vupanorsen versus placebo. Vupanorsen was safe and well-tolerated in healthy Japanese participants with elevated TG. This study provided FIH data for vupanorsen 160 mg. Moreover, the SAD study in Japanese participants fulfilled PMDA bridging requirements, and with the totality of global vupanorsen data, supported the PMDA waiver for a local phase II dose-finding study. ClinicalTrials.gov: NCT04459767.

Lorlatinib in previously treated anaplastic lymphoma kinase-rearranged non-small cell lung cancer: Japanese subgroup analysis of a global study.

Lorlatinib is a potent, brain-penetrant, third-generation anaplastic lymphoma kinase (ALK)/ROS proto-oncogene 1 (ROS1) tyrosine kinase inhibitor (TKI) that is active against most known resistance mutations. This is an ongoing phase 1/2, multinational study (NCT01970865) investigating the efficacy, safety and pharmacokinetics of lorlatinib in ALK-rearranged/ROS1-rearranged advanced non-small cell lung cancer (NSCLC) with or without intracranial (IC) metastases. Because patterns of ALK TKI use in Japan differ from other regions, we present a subgroup analysis of Japanese patients. Patients were enrolled into six expansion (EXP) cohorts based on ALK/ROS1 mutation status and treatment history. The primary endpoint was the objective response rate (ORR) and the IC-ORR based on independent central review. Secondary endpoints included pharmacokinetic evaluations. At data cutoff, 39 ALK-rearranged/ROS1-rearranged Japanese patients were enrolled across the six expansion cohorts; all received lorlatinib 100 mg once daily. Thirty-one ALK-rearranged patients previously treated with ≥1 ALK TKI (EXP2 to EXP5) were evaluable for ORR and 15 were evaluable for IC-ORR. The ORR and the IC-ORR for Japanese patients in EXP2-5 were 54.8% (95% confidence interval [CI]: 36.0-72.7) and 46.7% (95% CI: 21.3-73.4), respectively. Among patients who had received prior alectinib only (EXP3B), the ORR was 42.9%; 95% CI: 9.9-81.6). The most common treatment-related adverse event (TRAE) was hypercholesterolemia (79.5%). Hypertriglyceridemia was the most common grade 3/4 TRAE (25.6%). Single-dose and multiple-dose pharmacokinetic profiles among Japanese patients were similar to those in non-Japanese patients. Lorlatinib showed clinically meaningful responses and IC responses among ALK-rearranged Japanese patients with NSCLC who received ≥1 prior ALK TKI, including meaningful responses among those receiving prior alectinib only. Lorlatinib was generally well tolerated.

Phase 2 study of bosutinib in Japanese patients with newly diagnosed chronic phase chronic myeloid leukemia.

This open-label, single-arm, phase 2 study (ClinicalTrials.gov, NCT03128411) evaluated the efficacy, safety, and pharmacokinetics of bosutinib at a starting dose of 400 mg once daily (QD) in Japanese patients with newly diagnosed chronic phase chronic myeloid leukemia (CP CML). The primary endpoint was major molecular response (MMR) at Month 12 in the modified as-treated population (Philadelphia chromosome-positive [Ph+] patients with e13a2/e14a2 transcripts). Sixty Japanese patients with CP CML were treated with bosutinib; median age was 55 years (range 20-83), 60.0% were males, and all were Ph+ and had e13a2/e14a2 transcripts. After median follow-up of 16.6 months (range 11.1-21.9), 41 (68.3%) patients remained on bosutinib. The MMR rate at Month 12 was 55.0% (2-sided 90% confidence interval: 44.4-65.6). There were no on-treatment transformations to accelerated/blast phase, and no patient died on treatment or within 28 days of the last bosutinib dose. The most common treatment-emergent adverse events were diarrhea (86.7%), increased alanine aminotransferase (55.0%), and increased aspartate aminotransferase (46.7%). The primary objective of this phase 2 study was met, and there were no new safety signals for bosutinib. These data suggest bosutinib is an effective first-line treatment option for Japanese patients with newly diagnosed CP CML.

Free-surface molecular command systems for photoalignment of liquid crystalline materials.

The orientation of liquid crystal molecules is very sensitive towards contacting surfaces, and this phenomenon is critical during the fabrication of liquid crystal display panels, as well as optical and memory devices. To date, research has focused on designing and modifying solid surfaces. Here we report an approach to control the orientation of liquid crystals from the free (air) surface side: a skin layer at the free surface was prepared using a non-photoresponsive liquid crystalline polymer film by surface segregation or inkjet printing an azobenzene-containing liquid crystalline block copolymer. Both planar-planar and homoeotropic-planar mode patterns were readily generated. This strategy is applicable to various substrate systems, including inorganic substrates and flexible polymer films. These versatile processes require no modification of the substrate surface and are therefore expected to provide new opportunities for the fabrication of optical and mechanical devices based on liquid crystal alignment.

Liquid-crystalline polymer and block copolymer domain alignment controlled by free-surface segregation.

An orientational change from homeotropic to planar of liquid crystal (LC) mesogens and the microphase separation (MPS) domains is attained by the segregated skin layer at the free surface. This allows for an efficient in-plane photoalignment of the cylindrical domains. The surface segregation strategy is very simple and is therefore expected to open up new possibilities for the orientation control of various types of LC materials.