Showing papers by "Henrik B. Rasmussen published in 2020"

Effect of Routine Cytochrome P450 2D6 and 2C19 Genotyping on Antipsychotic Drug Persistence in Patients With Schizophrenia: A Randomized Clinical Trial.

Abstract: Importance Genetic polymorphism of genes encoding the drug metabolizing enzymes, cytochrome P450 2D6 and 2C19 (CYP2D6andCYP2C19), is associated with treatment failure of and adverse reactions to psychotropic drugs. The clinical utility of routineCYP2D6andCYP2C19genotyping (CYP testing) is unclear. Objective To estimate whether routine CYP testing effects the persistence of antipsychotic drug treatment. Design, Setting, and Participants This single-masked, 3-group randomized clinical trial included patients aged 18 years or older who had been diagnosed within the schizophrenic spectrum (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes, F20-F29) and not previously genotyped. A total of 669 of 1406 potentially eligible patients from 12 psychiatric outpatient clinics in Denmark were approached between July 2008 and December 2009. Overall, 528 patients were genotyped and randomly allocated to 1 of 3 study groups or exclusion in a sequence of 1:1:1:3 using a predictive enrichment design, aiming to double the proportion of poor or ultrarapid metabolizers for CYP2D6 or CYP2C19. Outcome measurements were recorded at baseline and 1-year follow-up. Data analysis was performed in December 2012 and updated March 2019. Interventions The trial included 2 intervention groups, where antipsychotic drug treatment was guided by either CYP test (CYP test–guided [CTG]) or structured clinical monitoring (SCM), in which adverse effects and factors influencing compliance were systematically recorded at least once quarterly, and 1 control group. Main Outcomes and Measures Primary outcome was antipsychotic drug persistence, ie, days to first modification of the initial treatment. Secondary outcomes were number of drug and dose changes, adverse effects, and psychotic symptoms, ie, hallucinations and delusions. Results A total of 528 participants were genotyped, and 311 (median [interquartile range {IQR} age, 41 [30-50] years; 139 [45%] women; median [IQR] duration of illness, 6 [3-13] years) were randomly allocated to 1 of 3 study groups. Overall, 61 participants (20%) were extreme metabolizers. There was no difference in antipsychotic drug persistence between the CTG group and the control group (hazard ratio [HR], 1.02; 95% CI, 0.71-1.45) or SCM and the control group (HR, 0.88; 95% CI, 0.61-1.26). Subanalyses among extreme metabolizers showed similar results (CTG: HR, 0.99; 95% CI, 0.48-2.03; SCM: HR, 0.93; 95% CI, 0.44-1.96). Conclusions and Relevance The results of this randomized clinical trial do not support routine CYP testing in patients with schizophrenia. Trial Registration ClinicalTrials.gov Identifier:NCT00707382

Pulmonary administration of remdesivir in the treatment of COVID-19.

Abstract: We read, with great interest, the commentary “Remdesivir for Treatment of COVID-19: Combination of Pulmonary and IV Administration May Offer Additional Benefit” by Sun [1]. In this commentary, Sun [1] suggests that intravenous administration of remdesivir is unlikely to produce sufficiently high concentrations of its active antiviral agent, the nucleoside triphosphate (Nuc-TP), in human lungs to effectively eliminate SARS-CoV-2. This led Sun [1] to propose investigations into pulmonary delivery of remdesivir, modifications of its prodrugmoiety, and use of nanoformulations of this agent to improve treatment of COVID-19 pneumonia. We consider that these issues are highly relevant but are uncertain about the conclusion that intravenous administration of remdesivir in the treatment of COVID-19 is unlikely to produce therapeutically effective concentrations of this prodrug and its active antiviral agent in human lungs. First, results from in vitro assays for assessment of the activity of antiviral agents vary substantially being highly dependent on viral quantificationmethod, viral isolate, and cell type used for viral propagation [2, 3]. Sun [1] retrieved 50% and 90% maximal inhibitory concentrations (IC50 and IC90) of 0.77 and 1.76 μM, respectively, for the anti-SARS-CoV-2 activity of remdesivir in Vero E6African greenmonkey kidney cells from a study byWang et al. [4]. Assuming a 10-fold intracellular accumulation of Nuc-TP relative to extracellular remdesivir, these inhibitory values were used to derive the intracellular Nuc-TP IC50 and IC90 values of 7.7 and 17.6 μM, which were compared with an estimated intracellular Nuc-TP concentration in the range of 4 to 10 μM in human lungs [1]. However, other studies have reported IC50 and IC90 values for the anti-SARS-CoV-2 activity of remdesivir that differed from those adopted by Sun. This includes the study by Pruijssers et al. [5] that reported IC50 values of 0.001 and 0.009 μM in primary human airway epithelial (HAE) cells in two independent experiments, whereas a higher IC50 value of 0.28 μM and an IC90 value of 2.48 μMwere observed with Calu-3 2B4 respiratory epithelial cells. Pruijssers et al. [5] also found that remdesivir inhibited SARS-CoV2 with IC50 and IC90 values of 1.65 and 2.40 μM, respectively, in Vero E6 cells, which are highly permissive to SARS-CoV-2 and therefore commonly used to study this virus [6, 7]. Moreover, an IC50 value of 0.38 μMhas been reported for the anti-SARS-CoV-2 activity of remdesivir in Caco-2 colorectal adenocarcinoma cells [8]. The differences in in vitro antiviral activity of remdesivir between different cell types may partially reflect differences in the ability to convert this prodrug to its antiviral active agent with the Vero E6 cell line apparently activating remdesivir less efficiently than other types of cells [5]. Hence, this cell line, and probably other Vero cell lines as well, may be less suitable for studies of the intracellular pharmacology of remdesivir. Assuming that Nuc-TP in general accumulates 10-fold intracellularly relative to extracellular remdesivir, the estimated intracellular IC50 values of Nuc-TP in the above cells would all fall below the intracellular Nuc-TP concentration range of 4 to 10 μM in human lungs except for those found using Vero E6 cells. Importantly, the primary HAE cells, in which markedly low IC50 values were produced, may represent a biologically more appropriate in vitro model than established cell lines such as Vero E6. Taken together, the intracellular IC50 and IC90 values of the Nuc-TP in human lungs estimated by Sun [1] appear excessively high as they were based on findings done using the Vero E6 cell line. Second, the achievable maximum plasma concentration (Cmax) of remdesivir administered intravenously at an approved dose has been reported to exceed two out of four IC50 values and two out of three IC90 values determined for this prodrug [3]. These IC50 and IC90 values had all been estimated using Vero cell lines for propagation of SARS-CoV-2. Accordingly, comparison of Cmax of remdesivir with the IC50 values for its antiSARS-CoV-2 activity in primary HAE cell cultures would have produced markedly higher Cmax/IC50 ratios and suggested that this prodrug effectively eliminates SARS-CoV-2 in human lungs at approved intravenous doses. 1 Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Roskilde, Denmark. 2 Cardiology Department, Herlev and Gentofte Hospital, Hellerup, Denmark. 3 Université de Paris, INSERM U1133, CNRS UMR 8251, 75006, Paris, France. 4 Section of Forensic Chemistry, Department of Forensic Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. 5 Clinical Pharmacology Unit, Roskilde Hospital, Roskilde, Denmark. 6 To whom correspondence should be addressed. (e–mail: henrik.berg.rasmussen@regionh.dk) The AAPS Journal (2020) 22:121 DOI: 10.1208/s12248-020-00506-4