Pharmacokinetic Assessment and Treatment Effect of Lusutrombopag in Child–Pugh Class C Patients: Review of Patient Data from Two Clinical Studies and Post-Marketing Surveillance

Study Design

CP class C patient-level data were extracted from three data sets: a phase 1/2 CP class C study; a phase 3 pivotal study, despite CP class C exclusion criteria (L-PLUS 2, n = 3); and post-marketing surveillance (PMS), despite lusutrombopag being contraindicated in this population in Japan where the PMS is ongoing. Data from the L-PLUS 2 [11] and PMS were previously published [13]. The planned PMS survey period was from October 2016 to May 2021, and the enrollment period was from October 2016 to September 2020; the date of data cutoff for the PMS data set for this analysis was September 27, 2019 (Japan Pharmaceutical Information Center [JAPIC], ID: JapicCTI-163432). The phase 1/2 study (JAPIC, ID: JapicCTI-163289) was an open-label, single-arm pharmacokinetic trial conducted in Japan from July 6, 2016 to March 23, 2017 and the phase 3 pivotal study (NCT02389621) was a double-blinded, placebo-controlled trial conducted globally from June 15, 2015 to April 19, 2017. A list of study investigators for the phase 1/2 and phase 3 studies is shown in Table S1 in the supplementary material. The authors confirm that all ongoing and related trials for this drug/intervention are registered.

In the phase 1/2 and phase 3 studies, patients with baseline platelet counts below 50 × 109/L received lusutrombopag 3 mg for no more than 7 days. In the phase 3 study, invasive procedures were scheduled 9–14 days after randomization; in the phase 1/2 study, an invasive procedure was not required. The PMS was conducted under routine clinical practice; patients received 3 mg lusutrombopag and were observed for 2 months from the start of the first lusutrombopag treatment.

Compliance with Ethics Guidelines

All patients provided written informed consent in the phase 1/2 and phase 3 studies. For these studies, the study protocol was approved by the institutional review boards of each participating center, shown in Table S2 in the supplementary material. According to exemptions under the Good Post-Marketing Study Practice ordinance by the Ministry of Health, Labour, and Welfare in Japan, institutional review board approval and informed consent were not required for the PMS. In the PMS data, patients were anonymized prior to analysis. All studies conformed to the ethical principles outlined in the Declaration of Helsinki and all revisions thereof.

Assessments

In the phase 1/2 study, pharmacokinetic assessments were performed using blood sampling to determine plasma drug concentration in all patients, and parameters were calculated using non-compartmental analyses (WinNonlin, Version 6.2.1, Princeton, NJ; AutoPilotToolkit, Version 2.0, Princeton, NJ). Endpoints included maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), area under the concentration–time curve from time zero to the dosing interval time (AUC0–τ), terminal elimination rate constant (λz), terminal elimination half-life (t1/2,z), and apparent total clearance (CL/F).

In the phase 3 study, the primary endpoint was the proportion of patients who required no platelet transfusion prior to the primary invasive procedure and no rescue therapy for bleeding from randomization through 7 days after the primary invasive procedure.

Platelet counts were measured in both studies and the PMS. In the phase 1/2 study, platelet counts were assessed at screening (day -28), pre-dosing on day 1, and post-dosing on days 3–8, 10, 12, 14, 17, 21, 28, and 35. In the phase 3 study, platelet counts were assessed at screening (day -28), pre-dosing on day 1, and post-dosing on days 5–8, 10, 12, 14, 17, 21, 28, and 35. In the PMS, platelet count was assessed prior to first treatment, between initiation of first treatment and invasive procedure, and after invasive procedure.

In both the phase 1/2 and 3 studies, receipt of platelet transfusion, mean maximum increase in platelet count, and duration of platelet count ≥ 50 × 109/L were evaluated. In the phase 1/2 study, imaging for portal vein thrombosis was conducted via CT or MRI during screening and between study days 12 and 28; in the phase 3 study, imaging for portal vein thrombosis (via ultrasonography, CT, or MRI) took place during screening and following the invasive procedure.

The PMS assessed receipt of platelet transfusion and safety. When judged necessary by the physician, the presence of portal vein thrombosis was evaluated.

Statistical AnalysisPharmacokinetics

In the phase 1/2 study, the analysis of variance for class A, B, and C patients, including CP class as a fixed effect, was performed for the following pharmacokinetic parameters: the ln-transformed values for Cmax, AUC0–τ, λz, t1/2,z, and CL/F. For this analysis, Child–Pugh class A and B patients were included from the open-label, phase 3b study (1338M0633) [14]. The ratios of the geometric least squares means and the corresponding 90% confidence intervals (CIs) were estimated by exponentiating the differences in means and the corresponding 90% CIs in the logarithm.

Efficacy

The phase 1/2 and 3 studies assessed maximum platelet count, maximum change from platelet count from baseline, and the duration of platelet count greater than or equal to 50 × 109/L. In the phase 1/2 study, the number of platelet transfusions received was summarized descriptively, with no statistical testing performed because of the small number of CP class C patients. In the phase 3 study, the primary endpoint (avoidance of pre-procedure platelet transfusion and avoidance of rescue therapy for bleeding through 7 days after primary procedure) was analyzed descriptively for the subgroups by CP class (class A, B, and C), with no statistical testing performed because of the small number of CP class C patients. Additionally, a pooled analysis of CP class A/B and C patients from the phase 1/2 and phase 3 trials was conducted.

In the PMS, the proportion of patients who did not require platelet transfusion was calculated, as well as the factors potentially affecting effectiveness.

Safety

In the phase 1/2 and phase 3 study, adverse events were reported according to Medical Dictionary for Regulatory Activities (MedDRA) system organ class and preferred term. Safety analysis for the two studies and the PMS included serious adverse events and thrombosis- and embolism-related adverse events.

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