Background Concerns have been raised about the possibility that inhibitors of the renin-angiotensin-aldosterone system (RAAS) could predispose individuals to severe COVID-19; however, epidemiological evidence is lacking. We report the results of a case-population study done in Madrid, Spain, since the outbreak of COVID-19.Methods In this case-population study, we consecutively selected patients aged 18 years or older with a PCRconfirmed diagnosis of COVID-19 requiring admission to hospital from seven hospitals in Madrid, who had been admitted between March 1 and March 24, 2020. As a reference group, we randomly sampled ten patients per case, individually matched for age, sex, region (ie, Madrid), and date of admission to hospital (month and day; index date), from Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP), a Spanish primary health-care database, in its last available year (2018). We extracted information on comorbidities and prescriptions up to the month before index date (ie, current use) from electronic clinical records of both cases and controls. The outcome of interest was admission to hospital of patients with COVID-19. To minimise confounding by indication, the main analysis focused on assessing the association between COVID-19 requiring admission to hospital and use of RAAS inhibitors compared with use of other antihypertensive drugs. We calculated odds ratios (ORs) and 95% CIs, adjusted for age, sex, and cardiovascular comorbidities and risk factors, using conditional logistic regression. The protocol of the study was registered in the EU electronic Register of Post-Authorisation Studies, EUPAS34437.Findings We collected data for 1139 cases and 11 390 population controls. Among cases, 444 (39•0%) were female and the mean age was 69•1 years (SD 15•4), and despite being matched on sex and age, a significantly higher proportion of cases had pre-existing cardiovascular disease (OR 1•98, 95% CI 1•62-2•41) and risk factors (1•46, 1•23-1•73) than did controls. Compared with users of other antihypertensive drugs, users of RAAS inhibitors had an adjusted OR for COVID-19 requiring admission to hospital of 0•94 (95% CI 0•77-1•15). No increased risk was observed with either angiotensin-converting enzyme inhibitors (adjusted OR 0•80, 0•64-1•00) or angiotensin-receptor blockers (1•10, 0•88-1•37). Sex, age, and background cardiovascular risk did not modify the adjusted OR between use of RAAS inhibitors and COVID-19 requiring admission to hospital, whereas a decreased risk of COVID-19 requiring admission to hospital was found among patients with diabetes who were users of RAAS inhibitors (adjusted OR 0•53, 95% CI 0•34-0•80). The adjusted ORs were similar across severity degrees of COVID-19.Interpretation RAAS inhibitors do not increase the risk of COVID-19 requiring admission to hospital, including fatal cases and those admitted to intensive care units, and should not be discontinued to prevent a severe case of COVID-19.Funding Instituto de Salud Carlos III.

P-glycoprotein, encoded by ABCB1, is an ATP-dependent drug efflux pump which exports substances outside the cell. Some studies described connections between C3435T polymorphism T allele and lower P-glycoprotein expression; therefore, homozygous T/T could show higher plasma levels. Our aim was to evaluate the effect of C3435T on pharmacokinetics of 4 antipsychotics (olanzapine, quetiapine, risperidone and aripiprazole) and 4 antidepressants (trazodone, sertraline, agomelatine and citalopram). The study included 473 healthy volunteers receiving a single oral dose of one of these drugs, genotyped by real-time PCR. Multivariate analysis was performed to adjust the effect of sex and genotype of the main cytochrome P450 enzymes. C3435T polymorphism had an effect on olanzapine pharmacokinetics, as T/T individuals showed lower clearance and volume of distribution. T/T individuals showed lower T of 9-OH-risperidone, but this difference disappeared after multivariate correction. T/T homozygous individuals showed lower dehydro-aripiprazole and trazodone area under the concentration-time curve, along with lower half-life and higher clearance of trazodone. C/T genotype was associated to higher citalopram maximum concentration. C3435T had no effect on quetiapine, sertraline or agomelatine pharmacokinetics. C3435T can affect the elimination of some drugs in different ways. Regarding risperidone, trazodone and dehydro-aripiprazole, we observed enhanced elimination while it was reduced in olanzapine and citalopram. However, in quetiapine, aripiprazole, sertraline and agomelatine, no changes were detected. These results suggest that P-glycoprotein polymorphisms could affect CNS drugs disposition, but the genetic factor that alters its activity is still unknown. This fact leads to consider the analysis of ABCB1 haplotypes instead of individual variants.

Several cytochrome P450 (CYP) CYP3A polymorphisms were associated with reduced enzyme function. We aimed to evaluate the influence of these alleles on the pharmacokinetic parameters (PK) of several CYP3A substrates. We included 251 healthy volunteers who received a single dose of ambrisentan, atorvastatin, imatinib, aripiprazole, fentanyl, amlodipine, donepezil, olanzapine, fesoterodine, or quetiapine. The volunteers were genotyped for CYP3A4 and CYP3A5 polymorphisms by qPCR. To compare the PK across studies, measurements were corrected by the mean of each parameter for every drug and were logarithmically transformed. Neither CYP3A phenotype nor individual CYP3A4 or CYP3A5 polymorphisms were significantly associated with differences in PK. However, regarding the substrates that are exclusively metabolized by CYP3A, we observed a higher normalized AUC (p = 0.099) and a tendency of lower normalized Cl (p = 0.069) in CYP3A4 mutated allele carriers what was associated with diminished drug metabolism capacity. CYP3A4 polymorphisms did not show a pronounced influence on PK of the analysed drugs. If so, their impact could be detectable in a very small percentage of subjects. Although there are few subjects carrying CYP3A4 double mutations, the effect in those might be relevant, especially due to the majority of subjects lacking the CYP3A5 enzyme. In heterozygous subjects, the consequence might be less noticeable due to the high inducible potential of the CYP3A4 enzyme.

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Aims Pupillography is a noninvasive and cost‐effective method to determine autonomic nerve activity. Genetic variants in cytochrome P450 (CYP), dopamine receptor (DRD2, DRD3), serotonin receptor (HTR2A, HTR2C) and ATP‐binding cassette subfamily B (ABCB1) genes, among others, were previously associated with the pharmacokinetics and pharmacodynamics of antipsychotic drugs. Our aim was to evaluate the effects of aripiprazole and olanzapine on pupillary light reflex related to pharmacogenetics. Methods Twenty‐four healthy volunteers receiving 5 oral doses of 10 mg aripiprazole and 5 mg olanzapine tablets were genotyped for 46 polymorphisms by quantitative polymerase chain reaction. Pupil examination was performed by automated pupillometry. Aripiprazole, dehydro‐aripiprazole and olanzapine plasma concentrations were measured by high‐performance liquid chromatography–tandem mass spectrometry. Results Aripiprazole affected pupil contraction: it caused dilatation after the administration of the first dose, then caused constriction after each dosing. It induced changes in all pupillometric parameters (P < .05). Olanzapine only altered minimum pupil size (P = .046). Polymorphisms in CYP3A, HTR2A, UGT1A1, DRD2 and ABCB1 affected pupil size, the time of onset of constriction, pupil recovery and constriction velocity. Aripiprazole, dehydro‐aripiprazole and olanzapine pharmacokinetics were significantly affected by polymorphisms in CYP2D6, CYP3A, CYP1A2, ABCB1 and UGT1A1 genes. Conclusions In conclusion, aripiprazole and its main metabolite, dehydro‐aripiprazole altered pupil contraction, but olanzapine did not have such an effect. Many polymorphisms may influence pupillometric parameters and several polymorphisms had an effect on aripiprazole, dehydro‐aripiprazole and olanzapine pharmacokinetics. Pupillography could be a useful tool for the determination of autonomic nerve activity during antipsychotic treatment.

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Introduction Aripiprazole and olanzapine are atypical antipsychotics. Both drugs can induce metabolic changes; however, the metabolic side effects produced by aripiprazole are more benign. The aim of the study was to evaluate if aripiprazole and olanzapine alter prolactin levels, lipid and glucose metabolism and hepatic, haematological, thyroid and renal function. Methods Twenty-four healthy volunteers received a daily oral dose of 10 mg aripiprazole and 5 mg olanzapine tablets for 5 days in a crossover randomised clinical trial and were genotyped for 51 polymorphisms in 18 genes by qPCR. Drug plasma concentrations were measured by LC–MS. The biochemical and haematological analyses were performed by enzymatic methods. Results Olanzapine induced hyperprolactinaemia but aripiprazole did not. Dopamine D3 receptor ( DRD3 ) Ser/Gly and ATP binding cassette subfamily B member 1 ( ABCB1 ) rs10280101, rs12720067 and rs11983225 polymorphisms and cytochrome P450 3A (CYP3A) phenotype had an impact on plasma prolactin levels. C-peptide concentrations were higher after aripiprazole administration and were influenced by catechol- O -methyltransferase ( COMT ) rs4680 and rs13306278 polymorphisms. Olanzapine and the UDP glucuronosyltransferase family 1 member A1 ( UGT1A1 ) rs887829 polymorphism were associated with elevated glucose levels. CYP3A poor metabolizers had increased insulin levels. Volunteers’ weight decreased significantly during aripiprazole treatment and a tendency for weight gain was observed during olanzapine treatment. Triglyceride concentrations decreased as a result of olanzapine and aripiprazole treatment, and varied on the basis of CYP3A phenotypes and the apolipoprotein C-III ( APOC3 ) rs4520 genotype. Cholesterol levels were also decreased and depended on 5-hydroxytryptamine receptor 2A ( HTR2A ) rs6314 polymorphism. All hepatic enzymes, platelet and albumin levels, and prothrombin time were altered during both treatments. Additionally, olanzapine reduced the leucocyte count, aripiprazole increased free T4 and both decreased uric acid concentrations. Conclusions Short-term treatment with aripiprazole and olanzapine had a significant influence on the metabolic parameters. However, it seems that aripiprazole provokes less severe metabolic changes. Trial Registration Clinical trial registration number (EUDRA-CT): 2018-000744-26 Graphical Abstract Electronic Supplementary Material The online version of this article (10.1007/s12325-020-01566-w) contains supplementary material, which is available to authorized users.