Pilot Study of Oral Realgar-Indigo Naturalis Formula in Pediatric Acute Promyelocyticleukemia: Effectiveness and Population Pharmacokinetics
Authors: Zhang Li , Yang Xin-mei , Chen Jing , Hu Lei , Yang Fan , Zhou Yue , Zhao Bei-bei , Zhao Wei , Zhu Xiao-fan 
Published: November 2019

# The first two authors contributed equally
* The last two authors contributed equally
Background: Realgar-Indigo Naturalis Formula (RIF), the only commercially oral arsenic agent, was launched in China from 2009. It has been recommended as consolidation or maintenance therapy in adults with acute promyelocytic leukemia (APL). Recently, RIF had been off-label used in pediatric APL in China. However, the knowledge of efficacy and dosage of RIF in pediatric was limited until now.
Objective: The purpose of this pilot study was to evaluate effectiveness and pharmacokinetics of RIF as consolidation or maintenance therapy for newly diagnosed and relapsed APL in pediatric after induction therapy with intravenous arsenic trioxide. Meanwhile, modeling and simulation techniques were used to evaluate and optimize RIF dosing regimen in pediatric population.
Patients and Methods: A total of 11 newly diagnosed APL and 1 relapsed patient (4-14years of age) were included from July 2016 to August 2017.The one relapsed and six newly diagnosed patients were treated with RIF (60 mg/kg/day TID) as maintenance therapy. Five newly diagnosed patients were treated with RIF (60 mg/kg/day TID) as consolidation and maintenance therapy. The treatment protocol and MRD results are shown in Figure 1. Event-free survival and overall survival were used to evaluate the efficacy. The plasma concentration of arsenic was quantified by inductively coupled plasma mass spectrometry (ICP-MS). Population pharmacokinetic analysis was carried out using the nonlinear mixed effects modeling program NONMEM V 7.2 (Icon Development Solutions, USA).
Results: All newly diagnosed APL patients were alive as of July 1, 2019 and were in MCR with a median follow-up of 28 months (range, 23 to 37 months). Both the estimated 3-year EFS and OS rates were 100%. Of note, all the patients completed the postremission therapy containing RIF on an outpatient basis. A total of 107 arsenic concentrations were used for population pharmacokinetic model building. The arsenic concentrations of the blood samples ranged from 0.1 to 75.0 µg/L. The steady-state trough plasma arsenic concentration during the RIF treatment was 47.43μg/L (range, 25.74 to 62.97μg/L).A one-compartment model with first-order elimination fitted the data. Body weight was the only significant covariate of CL for the final model development. The developmental pharmacokinetic model was evaluated by goodness-of-fit plots and bootstrap analysis. The mean and variance of NPDE were -0.118 and 0.93, respectively.
Conclusions: The effectiveness and pharmacokinetics were evaluated for the first time in pediatricAPL.The developmental population pharmacokinetic model for RIF in children revealed that one-compartment model with first-order elimination fitted the data.The current dosing regimen of 60 mg/kg/day TID resulted higher steady-state through concentration than that in adults (24.4μg/L, range:11.5 to 64μg/L).
Disclosures:No relevant conflicts of interest to declare.
This trial was conducted in accordance with the Declaration of Helsinki.

OffLabel Disclosure:
The combination of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) has become the front-line treatment for patients with acute promyelocytic leukemia (APL). Realgar-Indigo Naturalis Formula (RIF), the only commercially oral arsenic agent, was launched in China from 2009. Since then, RIF had been used for over 5000 adults with acute promyelocytic leukemia (APL). One pill of RIF is 270 mg which contains 30 mg of Realgar, 125 mg of Indigo naturalis, 50 mg of Radix salviae miltiorrhizae, 45 mg of Radix pseudostellariae, and 20mg of garment film. However, the pharmacokinetics of RIF in children has not been studied.