Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.
Department of Pharmacy, Great Ormond Street Hospital, London, United Kingdom.
Antimicrob Agents Chemother. 2023 Jul 18;67(7):e0007723. doi: 10.1128/aac.00077-23. Epub 2023 Jun 1.
Invasive fungal infections are a major cause of morbidity and mortality for immunocompromised patients. Posaconazole is approved for treatment and prophylaxis of invasive fungal infection in adult patients, with intravenous, oral suspension, and gastroresistant/delayed-released tablet formulations available. In Europe, until very recently, posaconazole was used off-label in children, although a new delayed-release suspension approved for pediatric use is expected to become available soon. A population pharmacokinetic model was developed which uses posaconazole therapeutic drug monitoring data following intravenous and oral dosing in hospitalized children, thus enabling estimation of pediatric suspension and tablet oral bioavailability. In total, 297 therapeutic drug monitoring plasma levels from 104 children were included in this analysis. The final model was a one-compartment model with first-order absorption and nonlinear elimination. Allometric scaling on clearance and volume of distribution was included . Tablet bioavailability was estimated to be 66%. Suspension bioavailability was estimated to decrease with increasing doses, ranging from 3.8% to 32.2% in this study population. Additionally, concomitant use of proton pump-inhibitors was detected as a significant covariate, reducing suspension bioavailability by 41.0%. This is the first population pharmacokinetic study to model posaconazole data from hospitalized children following intravenous, tablet, and suspension dosing simultaneously. The incorporation of saturable posaconazole clearance into the model has been key to the credible joint estimation of tablet and suspension bioavailability. To aid rational posaconazole dosing in children, this model was used alongside published pharmacodynamic targets to predict the probability of target attainment using typical pediatric dosing regimen.
侵袭性真菌感染是免疫功能低下患者发病率和死亡率的主要原因。泊沙康唑已被批准用于治疗和预防成人侵袭性真菌感染，有静脉注射、口服混悬剂和胃耐/延迟释放片剂制剂。在欧洲，直到最近，泊沙康唑仍被超适应证用于儿童，尽管一种新的用于儿科的延迟释放混悬剂预计很快将获准使用。建立了一个群体药代动力学模型，该模型使用了泊沙康唑在住院儿童中静脉内和口服给药后的治疗药物监测数据，从而能够估计儿科混悬剂和片剂的口服生物利用度。总共纳入了 104 名儿童的 297 个治疗药物监测血浆水平进行分析。最终模型为一室模型，具有一级吸收和非线性消除。包括了清除率和分布容积的比例缩放。估计片剂生物利用度为 66%。混悬剂生物利用度随剂量增加而降低，在本研究人群中范围为 3.8%至 32.2%。此外，同时使用质子泵抑制剂被检测为显著的协变量，使混悬剂生物利用度降低 41.0%。这是第一项同时对泊沙康唑静脉注射、片剂和混悬剂给药后住院儿童数据进行建模的群体药代动力学研究。将泊沙康唑清除率的饱和纳入模型是对片剂和混悬剂生物利用度进行可信联合估计的关键。为了帮助儿童合理使用泊沙康唑，该模型与已发表的药效学目标一起使用，以使用典型的儿科给药方案预测目标达标概率。
