Population Pharmacokinetic Modeling for Twice-Daily Intravenous Busulfan in a Large Cohort of Pediatric Patients Undergoing Hematopoietic Stem Cell Transplantation—A 10-Year Single-Center Experience

Reaching target exposure of busulfan-based conditioning prior to hematopoietic stem cell transplantation is vital for favorable therapy outcomes. Yet, a wide inter-patient and inter-occasion variability in busulfan exposure has been reported, especially in children. We aimed to identify factors associated with the variability of busulfan pharmacokinetics in 124 consecutive patients transplanted at the University Children’s Hospital Zurich between October 2010 and February 2020. Clinical data and busulfan plasma levels after twice-daily intravenous administration were analyzed retrospectively by population pharmacokinetic modeling. The volume of distribution correlated with total body water. The elimination rate constant followed an age-dependent maturation function, as previously suggested, and correlated with the levels of serum albumin. Acute lymphoblastic leukemia reduced busulfan clearance by 20%. Clearance significantly decreased by 17% on average from the start to the third day of busulfan administration, in agreement with other studies. An average reduction of 31% was found in patients with hemophagocytic lymphohistiocytosis and X-linked lymphoproliferative disease. In conclusion, we demonstrate that in addition to known factors, underlying disease and serum albumin significantly impact busulfan pharmacokinetics in pediatric patients; yet, substantial unexplained variability in some patients remained. Thus, we consider repeated pharmacokinetic assessment essential to achieve the desired target exposure in twice-daily busulfan administration

Intracerebral endotheliitis and microbleeds are neuropathological features of COVID‐19

Coronavirus disease 19 (COVID-19), caused by infection with the severe acute respiratory syndrome coronavirus 2 (Sars-CoV-2), has become a worldwide pandemic (1). Symptoms of COVID-19 vary widely and range from asymptomatic disease to severe pneumonia and multiorgan failure (2). A severe disease course is more likely in older patients and patients with pre-existing respiratory and cardiovascular conditions (2). Patients with severe Sars-CoV-2 infection may present with ischaemic stroke (3, 4) or even fatal intracerebral haemorrhage (5). To date, little is known about the neuropathological sequelae of COVID-19. The largest published autopsy series of COVID-19 neuropathology reported microthrombi and acute haemorrhagic infarction in a significant number of patients (6), while another more recent study found evidence of lymphocytic encephalitis and meningitis (7). Endotheliitis of the brain and extraneural organs has been shown in Sars-CoV infected patients (8). Similarly, it is a recurrent feature in the lungs and other peripheral organs of Sars-CoV-2 infected patients (9) but has not yet been reported in the central nervous system. We speculated that cerebrovascular pathology in COVID-19 patients could be a direct consequence of hitherto unidentified cerebral endotheliitis caused by Sars-CoV-2