2566. Effect of CYP2C19 on Voriconazole Pharmacokinetics in Children with Malignancy or Inborn Errors in Immunity
Authors: Shoji Kensuke , Hikino Keiko , Saito Jumpei , Matsui Toshihiro , Utano Tomoyuki , Takebayashi Akira , Tomizawa Daisuke , Kato Motohiro , Matsumoto Kimikazu , Ishikawa Takashi , Kawai Toshinao , Nakamura Hidefumi , Miyairi Isao , Terao Chikashi , Mushiroda Taisei 
Published: November 2023

Abstract

Background
Voriconazole pharmacokinetics (PK) are known to be affected by genetic polymorphisms of drug-metabolizing enzymes such as CYP2C19; however, such information is limited for the pediatric population.

Methods
This was a single-center population PK study. Information regarding patient background, laboratory test data, voriconazole serum concentration, voriconazole dosing status, and concurrent medications were extracted from electronic medical records. CYP2C19 genotypes was assessed by whole genome genotyping and defined as follows: *1/*1, *1/*17: normal metabolizer [NM], *1/*2, *1/*3: intermediate metabolizer [IM], and *2/*2, *2/*3, *3/*3: poor metabolizer [PM]. Population PK analysis was performed using Phoenix NLME (v8.3.0). The voriconazole serum concentration profile was described by a two-compartment model with first-order absorption, mixed linear and nonlinear (Michaelis-Menten) elimination, and allometric scaling, as described in previous reports. Covariates were examined using a stepwise method and included to the model when the objective function [-2LL (log-likelihood)] by the maximum likelihood method decreased significantly (Δ-2LL &gt; 6.63, p &lt; 0.01 by likelihood ratio test).

Results
Voriconazole concentration data were available from 60 patients with a median age of 5.3 years. In total, 526 measurements were available for population PK analysis. The phenotypes predicted from CYP2C19 genotypes were NM in 22 patients, IM in 27 patients, and PM in 11 patients. Underlying diseases included 40 patients with malignancy (66.7%), 18 patients with inborn errors of immunity (30.0%), and 2 patients with other comorbidities. Among the CYP2C19 phenotypes, PM was predicted to show complete inhibition (the degree of Vmax inhibition (Vmax,inh) = 100%; Vmax= 0). The estimated parameters of Vmax,inh were +0.8 higher in patients with γ-GTP Grade 2 or higher compared with those with Grade 1 or lower. The increase in Vmax,inh was shown to be caused by an increase in C-reactive protein (CRP); the estimated parameters of Vmax,inh were +2.7 higher when CRP was 2.0 mg/dL or higher.

Conclusion
CYP2C19 genetic polymorphisms (PM), γ-GTP, and CRP affect Vmax,inh of voriconazole in Japanese children with malignancy or inborn errors in immunity

Disclosures
Kensuke Shoji, MD, PhD, AstraZeneca K.K.: Honoraria|Gilead Sciences, Inc.: Honoraria|KYORIN Pharmaceutical Co.,Ltd.: Honoraria|Meiji Seika Pharma Co., Ltd.: Honoraria|Nippon Becton Dickinson Company, Ltd.: Honoraria|Novartis Pharma Co., Ltd.: Honoraria|Viatrs, Inc: Honoraria Motohiro Kato, MD, PhD, Amgen: Honoraria|Bayer: Honoraria|Chugai Pharm: Honoraria|CSL Behring: Honoraria|Daiichi Sankyo: Grant/Research Support|Konica Minolta REALM: Honoraria|Kyowa KIRIN: Honoraria|Maruho: Honoraria|Nippon Shinyaku: Honoraria|Novartis: Honoraria|Ohara Pharma: Honoraria|Riken Genesis: Honoraria|Sanofi: Honoraria|Sumitomo Pharma: Honoraria|Takeda Pharma: Honoraria Toshinao Kawai, MD, PhD, Novartis Pharmaceuticals: Honoraria|Takeda Pharmaceutical Company: Advisor/Consultant|Takeda Pharmaceutical Company: Honoraria Hidefumi Nakamura, MD, PhD, Asahi Kasei Corporation: Stocks/Bonds|Bristol Myers Squibb Company: Honoraria|Chugai Pharmaceutical Co., Ltd.: Honoraria|Daiichi Sankyo Company, Ltd.: Advisor/Consultant|Pfizer Global Supply Japan Inc.: Advisor/Consultant|Pfizer R&D Japan G.K.: Advisor/Consultant|Sato Pharmaceutical Co., Ltd.: Advisor/Consultant|Shionogi & Co., Ltd.: Honoraria|Taisho Pharmaceutical Holdings Co., Ltd: Advisor/Consultant Isao Miyairi, MD, PhD, Astrazeneca: Honoraria|Mitsubishi-Tanabe: Honoraria|Pfeizer: Honoraria|Sanofi: Advisor/Consultant|Shionogi: Honoraria Taisei Mushiroda, PhD, Zenyaku Kogyo Company, Limited: Grant/Research Support