Guldbæk Johan Mikkel, Mariager Theis, Nielsen Mikkel Dreyer, Terkelsen Jacob Holmen, Nau Roland, Bjarkam Carsten Reidies, Nielsen Henrik, Bodilsen Jacob
Department of Clinical Medicine, Aalborg University, Aalborg, North Denmark, Denmark.
Department of Infectious Diseases, Aalborg University Hospital, Aalborg, North Denmark, Denmark.
Antimicrob Agents Chemother. 2025 May 7;69(5):e0181524. doi: 10.1128/aac.01815-24. Epub 2025 Mar 21.
Ganciclovir is often used compassionately for encephalitis due to cytomegalovirus (CMV) and human herpes virus 6b (HHV-6b). Ganciclovir pharmacokinetic studies in the central nervous system (CNS) generally rely on single measurements in the cerebrospinal fluid (CSF) or homogenized brain tissue. Therefore the objective was to compare brain extracellular fluid (ECF) concentrations of ganciclovir with plasma and CSF concentrations in a porcine model, using microdialysis during a 24 h period. Six Danish landrace pigs (female, age 4 months, 31-37 kg) received two weight-adjusted intravenous doses of ganciclovir. Unbound ganciclovir concentrations were determined by microdialysis over 24 h in five compartments: CSF (lateral ventricle, cisterna magna, and lumbar) and brain ECF (cortical and subcortical). Data were compared with paired plasma samples. Ganciclovir concentrations >IC for CMV (1.6 µg/mL) were achieved in all compartments. Concentrations >IC for CMV (8.3 µg/mL) were only achieved in plasma and the lumbar CSF compartment. The concentration time curves indicated higher lumbar and cisternal CSF concentrations than ECF concentrations. The ECF compartments achieved greater maximum concentration (C), area under the concentration time curve (AUC), and time >IC after the second dose, and an accumulation ratio (R) >1. The greater C, AUC, time >IC, and R >1 in the ECF compartments with repeated dosages suggest that therapeutic concentrations may be achieved during long-term treatment. A higher loading dose might be warranted to improve early viral inhibition.
更昔洛韦常被用于因巨细胞病毒（CMV）和人疱疹病毒6b型（HHV - 6b）引起的脑炎的同情用药。更昔洛韦在中枢神经系统（CNS）的药代动力学研究通常依赖于脑脊液（CSF）或匀浆脑组织中的单次测量。因此，本研究的目的是在猪模型中，使用微透析技术在24小时内比较更昔洛韦在脑细胞外液（ECF）中的浓度与血浆和脑脊液中的浓度。六只丹麦长白猪（雌性，4月龄，31 - 37千克）接受了两次根据体重调整的静脉注射更昔洛韦剂量。通过微透析在五个隔室中测定24小时内未结合的更昔洛韦浓度：脑脊液（侧脑室、枕大池和腰椎）和脑ECF（皮质和皮质下）。将数据与配对的血浆样本进行比较。所有隔室中更昔洛韦的浓度均达到了针对CMV的抑制浓度（IC）（1.6μg/mL）。仅在血浆和腰椎脑脊液隔室中达到了针对CMV的更高抑制浓度（IC）（8.3μg/mL）。浓度 - 时间曲线表明，腰椎和枕大池脑脊液浓度高于ECF浓度。ECF隔室在第二次给药后达到了更高的最大浓度（C）、浓度 - 时间曲线下面积（AUC）以及高于IC的时间，并且蓄积比（R）>1。重复给药后ECF隔室中更大的C、AUC、高于IC的时间以及R>1表明，在长期治疗期间可能达到治疗浓度。可能需要更高的负荷剂量以改善早期病毒抑制。
