AbstractTo establish a population pharmacokinetic (PopPK) model of posaconazole suspension in Chinese hematopoietic stem cell transplantation (HSCT) patients and to recommend an optimal dosing regimen. A single-center, retrospective, model-based study was conducted in 62 Chinese patients, including 103 with posaconazole plasma concentrations.

摘要建立泊沙康唑混悬液在中国造血干细胞移植（HSCT）患者中的群体药代动力学（PopPK）模型，并推荐最佳给药方案。对62名中国患者进行了单中心，回顾性，基于模型的研究，其中103名患有泊沙康唑血浆浓度。

PopPK analysis using NONMEM software. A one-compartment model of first-order elimination and absorption was in good agreement with the experimental data. Analysis of covariance showed that body weight (WT), creatinine clearance (CCR), and proton pump inhibitor (PPI) had a significant effect on the pharmacokinetics of posaconazole.

使用NONMEM软件进行PopPK分析。一级消除和吸收的一室模型与实验数据非常吻合。协方差分析表明，体重（WT），肌酐清除率（CCR）和质子泵抑制剂（PPI）对泊沙康唑的药代动力学有显着影响。

The dose simulation results show that patients with CCR ≥ 90 mL/min require at least 3 mg/kg TID and 7 mg/kg BID dosing regimens for prevention and treatment, respectively. However, when combined with PPI, at least 5 mg/kg BID and 5 mg/kg TID dosing regimens are required for prevention and treatment, respectively.

剂量模拟结果显示，CCR≥90 mL/min的患者分别需要至少3 mg/kg TID和7 mg/kg BID给药方案进行预防和治疗。然而，当与PPI联合使用时，预防和治疗分别需要至少5 mg/kg BID和5 mg/kg TID给药方案。

Regardless of whether it is used in combination with PPI or not, patients with a CCR of 60–90 mL/min can achieve PTA goals by using a 4 mg/kg BID and 4 mg/kg TID regimen for prevention and treatment, respectively. A dosing regimen of 3 mg/kg BID in patients with a CCR of 30–60 mL/min is sufficient to meet the PTA goal of prophylaxis, and the dose needs to be elevated to 4 mg/kg BID for the treatment of fungal infections, and there is no need to change the dose according to the coadministration of PPI.

无论是否与PPI联合使用，CCR为60-90 mL/min的患者都可以通过分别使用4 mg/kg BID和4 mg/kg TID方案进行预防和治疗来实现PTA目标。对于CCR为30-60 mL/min的患者，3 mg/kg BID的给药方案足以满足PTA的预防目标，并且需要将剂量提高至4 mg/kg BID以治疗真菌感染，并且不需要根据PPI的共同给药来改变剂量。

When the patient's CCR is less than 30 mL/min, whether or not combined with PPI, the administration regimen of 2 mg/kg BID and 3 mg/kg BID can meet the PTA goals for prevention and treatment, respectively..

当患者的CCR小于30 mL/min时，无论是否与PPI联合使用，2 mg/kg BID和3 mg/kg BID的给药方案均可分别达到PTA的预防和治疗目标。。

IntroductionPatients undergoing hematopoietic stem cell transplantation (HSCT) are at high risk for fungal infections, and invasive fungal disease (IFD) is a significant cause of morbidity and mortality in HSCT patients1. Although the epidemiology of IFD has changed dramatically with improvements in medical technology and prevention strategies, the mortality rate of infected patients remains high, mainly because of delays in treatment due to difficulties in diagnosis2.

引言接受造血干细胞移植（HSCT）的患者真菌感染的风险很高，侵袭性真菌病（IFD）是HSCT患者发病率和死亡率的重要原因1。尽管随着医疗技术和预防策略的改进，IFD的流行病学发生了巨大变化，但感染患者的死亡率仍然很高，主要是由于诊断困难导致治疗延误2。

Antifungal therapy is therefore necessary for HSCT patients. The use of antifungal drugs during patient treatment is effective in reducing morbidity and mortality3. Posaconazole is a systemic triazole broad-spectrum antifungal drug with a structure derived from itraconazole and an antifungal mechanism of action like that of other triazoles4.

因此，HSCT患者需要抗真菌治疗。在患者治疗期间使用抗真菌药物可有效降低发病率和死亡率3。泊沙康唑是一种全身性三唑广谱抗真菌药物，其结构来源于伊曲康唑，具有与其他三唑类似的抗真菌作用机制4。

Compared to echinocandins and other triazoles, posaconazole offers a wider antibacterial range, higher antibacterial activity, and superior economic advantages. Posaconazole has a wide variety of uses in the prevention and treatment of IFD and is advised as a first-line medication in several guidelines and studies5.The U.S.

与棘白菌素和其他三唑类药物相比，泊沙康唑具有更广泛的抗菌范围，更高的抗菌活性和优越的经济优势。泊沙康唑在预防和治疗IFD方面有多种用途，在一些指南和研究中被建议作为一线药物5。

Food and Drug Administration (FDA) initially authorized posaconazole as an oral suspension in 2006, and its delayed-release tablet and intravenous injection were additionally authorized there in 2013 and 2014, correspondingly6. The pharmacokinetic profile of posaconazole is highly variable, and for posaconazole oral suspension, higher gastric pH and gastric motility may reduce the bioavailability of posaconazole by decreasing its solubility and shortening its gastric emptying time, whereas concomitant administration with food may increase its bioavailability by increasing its gastric emptying time.

美国食品和药物管理局（FDA）最初于2006年批准泊沙康唑作为口服混悬剂，其延迟释放片剂和静脉注射在2013年和2014年获得了相应的授权6。泊沙康唑的药代动力学特征变化很大，对于泊沙康唑口服混悬液，较高的胃pH和胃动力可能通过降低其溶解度和缩短其胃排空时间来降低泊沙康唑的生物利用度，而与食物同时给药可能通过增加其胃排空时间来增加其生物利用度。

Posaconazole is highly lipid-soluble and tissue-pe.

泊沙康唑具有高度脂溶性和组织pe。

(1)

(1)

In Eqs. (a), θi denotes the value of the PK parameter for the i-th subject, θpop denotes the population-typical value of this PK parameter, and ηi denotes the inter-individual variability among subjects obeying a normal distribution with a mean of 0 and variance of ω2. Four residual models, summation, proportional, power exponential, and mixed, were run on the one- and two-compartment models, respectively, and the OFV from the runs, as well as the model diagnostic plots, were compared to find a residual model that is more suitable for describing the variability of the residuals.

在等式（a）中，θi表示第i个受试者的PK参数值，θpop表示该PK参数的总体典型值，ηi表示服从正态分布的受试者之间的个体间变异性，平均值为0，方差为ω2。四个残差模型，总和，比例，幂指数和混合，分别在一室和二室模型上运行，并比较运行中的OFV以及模型诊断图，以找到更适合描述残差变异性的残差模型。

The residual model is formulated as Eq. (2), Eq. (3), Eq. (4) and Eq. (5). Where ERR denotes the residual error, which follows a normal distribution with mean 0 and variance σ2.$$ {\text{Summation error model}}:{\text{Y }} = {\text{ F}}\left( {\text{x}} \right) \, + {\text{ ERR}}\left( {1} \right) $$.

残差模型表示为方程（2），方程（3），方程（4）和方程（5）。其中ERR表示残差，它遵循均值为0和方差σ2的正态分布。$${\ text{求和误差模型}}：{\ text{Y}={\ text{F}\ left（{\ text{x}\ right）\，+{\ text{ERR}\ left（{1}\ right）$$。

(2)

(2)

$$ {\text{Proportional error model}}:{\text{Y }} = {\text{ F}}\left( {\text{x}} \right) \times \left( {{1 } + {\text{ ERR}}\left( {1} \right)} \right) $$

$${\text{比例误差模型}}：{\text{Y}}={\text{F}}\左（{\text{x}}\右）\times \左（{{{1}+{\text{ERR}}\左（{1}\右）}\右）$$

(3)

(3)

$$ {\text{Power exponential error model}}:{\text{Y }} = {\text{ F}}\left( {\text{x}} \right) \times {\text{e}}^{{{\text{ERR}}({1})}} $$

$${\text{幂指数误差模型}}：{\text{Y}}={\text{F}}\左（{\text{x}}\右）\times{\text{e}}^{{{\text{ERR}}（{1}}}$$

(4)

(4)

$$ {\text{Mixederror model}}:{\text{Y }} = {\text{ F}}\left( {\text{x}} \right) \times \left( {{1 } + {\text{ ERR }}\left( {1} \right) \, + {\text{ ERR }}\left( {2} \right)} \right) $$

$${\text{Mixederror model}}：{\text{Y}}={\text{F}}\left（{\text{x}}\right）\times\left（{{1}+{\text{ERR}}\left（{1}\right）\，+{\text{ERR}}\left（{2}\right）}\right）$$

(5)

(5)

Each covariate will be substituted into the population model in turn, and a covariate will be considered significant (P < 0.05) if its OFV decreases by more than 3.84 after it is substituted into the model. Covariates were included using a round-by-round screening approach, where the covariates with the largest declines in OFV were selected in each round to remain in the model and continued to be screened using this model as the baseline until all covariates had declines in OFV of less than 3.84 to stop screening.

每个协变量将依次替换到人口模型中，如果协变量被替换到模型中后其OFV降低超过3.84，则协变量将被认为是显着的（P<0.05）。使用逐轮筛选方法包括协变量，其中在每轮中选择OFV下降最大的协变量保留在模型中，并继续使用该模型作为基线进行筛选，直到所有协变量的OFV下降小于3.84以停止筛选。

All significant covariates were substituted together into the model and then eliminated sequentially using backward elimination, at which point a more stringent p-value test (P < 0.001) was used, i.e., if the OFV increased by more than 10.83 after the elimination of a covariate, the factor was significant.

将所有显着的协变量一起替换到模型中，然后使用反向消除依次消除，此时使用更严格的p值检验（p<0.001），即如果消除协变量后OFV增加超过10.83，则该因素是显着的。

The backward elimination process also uses the round-by-round screening method, eliminating the covariates with the smallest elevated OFV in each round until all covariates have elevated OFV greater than 10.83, and finally obtaining the final model.Pharmacokinetic model evaluationThe accuracy of the parameters and their respective standard errors were used to gauge the model's goodness-of-fit (GOF).

反向消除过程还使用逐轮筛选方法，消除每轮中OFV升高最小的协变量，直到所有协变量的OFV升高大于10.83，最后获得最终模型。药代动力学模型评估参数的准确性及其各自的标准误差用于衡量模型的拟合优度（GOF）。

The stability of the final model is assessed by the nonparametric bootstrapping method. The percentage of successful model bootstrap and the median and 5th and 95th quartiles of the bootstrap parameters were calculated by sampling the original data with put-back 1000 times to get 1000 new datasets. Evaluate the predictability of the final model using the normalized prediction distribution errors (NPDE) test in terms of data and graphs.

通过非参数自举方法评估最终模型的稳定性。通过对原始数据进行1000次采样以获得1000个新数据集，计算成功模型引导的百分比以及引导参数的中位数和第5和第95个四分位数。使用数据和图形方面的归一化预测分布误差（NPDE）测试来评估最终模型的可预测性。

The NPDE is expected to follow a (0, 1) normal distribution based on 1000 simulations of the dataset with the fin.

基于使用fin对数据集进行的1000次模拟，预计NPDE将遵循（0,1）正态分布。

Data availability

数据可用性

The data that support the findings of this study are available from the corresponding author upon reasonable request.

根据合理的要求，通讯作者可以提供支持本研究结果的数据。

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Download referencesFundingZhong Nanshan Medical Foundation of Guangdong Province (No. ZNSXS-20240086); Shandong Provincial Natural Science Foundation (No. ZR2021QH296); Clinical pharmaceutical research special fund project of ShanDong Provincial Medical Association (YXH2021ZX009); The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital Cultivation Fund Project (No.

下载参考文献广东省南山医学基金会（编号ZNSXS-20240086）；山东省自然科学基金（编号：ZR2021QH296）；山东省医学会临床药学研究专项基金项目（YXH2021ZX009）；山东第一医科大学第一附属医院和山东省前佛山医院培养基金项目（No。

QYPY2023NSFC0605).Author informationAuthor notesThese authors contributed equally: Yi-Shuo Shu and Zhong-Hua Dong.Authors and AffiliationsDepartment of Clinical Pharmacy, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Pediatric Drug Clinical Evaluation and R&D Research Center of Engineering Technology, Jinan, 250014, ChinaYi-Shuo Shu, Zhong-Hua Dong, Yi-Lei Yang, Si-Wen Li, Qiao-Yan Yi, Peng Wang, Yin-Ping Shi, Ying-Ying Zhang & Hai-Yan ShiAuthorsYi-Shuo ShuView author publicationsYou can also search for this author in.

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PubMed Google ScholarPeng WangView author publicationsYou can also search for this author in

PubMed Google ScholarPeng WangView作者出版物您也可以在

PubMed Google ScholarYin-Ping ShiView author publicationsYou can also search for this author in

PubMed Google ScholarYing-Ying ZhangView author publicationsYou can also search for this author in

PubMed Google ScholarYing Ying ZhangView作者出版物您也可以在

PubMed Google ScholarHai-Yan ShiView author publicationsYou can also search for this author in

PubMed Google ScholarHai Yan ShiView作者出版物您也可以在

PubMed Google ScholarContributionsS.H.Y conceived and designed the study. Z.H.D and Y.S.S conducted the experiment. Y.L.Y, S.W.L and Q.Y.Y collected clinical data and contributed to manuscript preparation. P.W, Y.P.S and Y.Y.Z analysed the data. Y.S.S.Corresponding authorCorrespondence to.

PubMed谷歌学术贡献。H、 Y构思并设计了这项研究。Z、 H.D和Y.S.S进行了实验。Y、 L.Y，S.W.L和Q.Y.Y收集了临床数据，并为稿件准备做出了贡献。P、 W，Y.P.S和Y.Y.Z分析了数据。Y、 S.S.对应作者对应。

Hai-Yan Shi.Ethics declarations

海燕市。道德宣言

Competing interests

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The authors declare no competing interests.

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Reprints and permissionsAbout this articleCite this articleShu, YS., Dong, ZH., Yang, YL. et al. Individualized regimen of Posaconazole oral suspension in Chinese HSCT patients based on population pharmacokinetic model.

转载和许可本文引用本文Shu，YS。，Dong，ZH。，杨，YL。等。基于群体药代动力学模型的泊沙康唑口服混悬液在中国HSCT患者中的个体化方案。

Sci Rep 14, 20288 (2024). https://doi.org/10.1038/s41598-024-70955-wDownload citationReceived: 22 March 2024Accepted: 22 August 2024Published: 31 August 2024DOI: https://doi.org/10.1038/s41598-024-70955-wShare this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

Sci Rep 1420288（2024）。https://doi.org/10.1038/s41598-024-70955-wDownload引文接收日期：2024年3月22日接受日期：2024年8月22日发布日期：2024年8月31日OI：https://doi.org/10.1038/s41598-024-70955-wShare本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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KeywordsPosaconazolePharmacokineticsHematopoietic stem cell transplantationDosageInvasive fungal infections

关键词Sposaconazolepharmacokineticshematopoietic stem cell transplantation剂量侵袭性真菌感染

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