Antiviral Use in Mild-to-Moderate SARS-CoV-2 Infections during the Omicron Wave in Geriatric Patients.

(1) Background: Geriatric patients are at high risk of complications of Coronavirus disease-2019 (COVID-19) and are good candidates for antiviral drugs. (2) Methods: A retrospective study of electronic health records (EHRs) aiming to describe antiviral (nirmatrelvir and ritonavir (nirmatrelvir/r) or remdesivir) use, drug-drug interactions (DDIs) and adverse drug reactions (ADRs) in elderly patients (75 and over), hospitalized with mild-to-moderate COVID-19 between July 2022 and June 2023. (3) Results: Out of 491 patients (mean age: 86.9 years), 180 (36.7%) received nirmatrelvir/r, 78 (15.9%) received remdesivir, and 233 (47.4%) received no antiviral therapy. No association was found between the choice of antiviral and the demographic or medical data. No serious ADR was observed. Nirmatrelvir/r dosage adjustment was inadequate in 65% of patients with renal impairment. In total, 128 patients (71%) on nirmatrelvir/r had potential pharmacokinetic DDIs, with 43 resulting in a possibly related ADR. In the remdesivir group, pharmacodynamic DDIs were more frequent, with QTc prolongation risk in 56 patients (72%). Only 20 patients underwent follow-up ECG, revealing QTc prolongation in 4. (4) Conclusions: There is an underutilization of antivirals despite their justified indications. Nirmatrelvir/r dosage was rarely adjusted to renal function. Dose adjustments and closer monitoring are needed due to the high risk of drug interactions.

Practice of CYP450 genotyping and phenotyping in children in a real-life setting.

Pharmacokinetics varies widely between children. Many factors play an important role in this variability, such as ontogeny, pharmacogenetics, gender, comorbidities, and drug-drug interactions. Significant work has already been done in adults to understand the impact of genetic polymorphisms on drug-metabolizing enzyme activity and drug response. Data remain poor in children due to ontogeny that impacts genotyping-phenotyping correlation and the difficulty enrolling children in prospective studies. Our study aimed to describe the use of cytochromes P450 (CYP) phenotyping and/or genotyping tests in children in a real-life setting and assess the correlation between the genotype and the phenotype. We reviewed the results of tests performed between January 2005 and December 2020. Fifty-two children were genotyped and/or phenotyped. Four patients were excluded from the present analysis as they only underwent ABCB1 genotyping, without CYP testing. Of the remainder, 18 underwent simultaneous CYP genotyping and phenotyping, while 17 underwent CYP genotyping only, and 13 underwent CYP phenotyping only. In all cases, investigations were performed after the following situations: insufficient clinical response to treatment, low plasma concentrations, and adverse drug reactions (ADR). The vast majority of cases were related to immunosuppressive or antipsychotic therapy. Genotyping and/or phenotyping explained or contributed to the aforementioned clinical events in 56% of cases. The correlation between the genotype and the phenotype showed variability depending on the assessed cytochrome. In several cases, the phenotype did not correspond to the genotype because of comedications. In conclusion, there is clearly value in guiding drug based on CYP activity in children.

Relapses of Immune Thrombocytopenia after the Second and Booster Doses of BNT162b2 Vaccine.

We present here a 65-year-old male patient known for immune thrombocytopenic purpura (ITP) and fluctuating platelet count who experienced a severe exacerbation of thrombocytopenia following BNT162b2 COVID-19 vaccination. One month after the second dose, he presented petechiae and asthenia with isolated thrombocytopenia (platelet count: 3 × 109/L). He recovered after a 4-day course of intravenous corticosteroid treatment and intravenous immunoglobulin therapy. Eight months later, his platelet count was within the normal range, and he received a booster dose of vaccine after premedication with prednisone. Eight days later, his platelet count dropped to 29 × 109/L, but he remained asymptomatic. He received a rescue treatment with prednisone followed by rituximab over 4 weeks, allowing progressive improvement. Our case suggests a strong association between COVID-19 vaccination and the exacerbation of ITP.

Opioid-related adverse drug reactions in patients visiting the emergency division of a tertiary hospital.

Opioid use and associated morbidity and mortality have increased in several countries during the past 20 years. We performed a study whose objective was to assess the frequency and causes of opioid-related emergency division (ED) visits in an adult tertiary Swiss University Hospital over 9 weeks in 2018. We primarily assessed opioid-related adverse drug reactions (ADR), secondary overdose, misuse, abuse, and insufficient pain relief. Current opioid use was identified in 1037 (8.3%) of the 12 470 included ED visits. In 64 opioid users, an ADR was identified as a contributing cause of the ED visit, representing 6.2% of opioid users, and 0.5% of the total ED visits. Moreover, we identified an overdose in 16 opioid users, misuse or abuse in 19 opioid users, and compatible withdrawal symptoms in 7 opioid users. After pooling all these events, we conclude that the ED visits could be related to opioid use in 10.2% of opioid users. Finally, in 201 opioid users, insufficient pain relief (pain not responding to the current pharmacological treatment) was identified as a contributing cause of ED visits. In these cases, other factors than simply pharmacological nonresponse may have been involved. In the context of an ever-increasing opioid use to better control chronic pain situations, these results should reinforce emergency network epidemiological surveillance studies at a national level.

Case Report: Opioid Use Disorder Associated With Low/Moderate Dose of Loperamide in an Intellectual Disability Patient With CYP3A and P-Glycoprotein Reduced Activity.

Loperamide is an over-the-counter antidiarrheal for which increasing cases of abuse or misuse are described. We report the onset of opioid use disorder associated with low to moderate doses of loperamide in an intellectual disability patient without previous history of substance use disorder (SUD). Our patient presented strongly reduced activities of CYP3A and P-glycoprotein, which are mainly involved in loperamide metabolism and transport. We suggest that this led to an increase in bioavailability, systemic exposure, and brain penetration thus allowing loperamide to act on the central nervous system and contributing to the development of SUD. Slow release oral morphine (SROM) was chosen as opioid agonist treatment, which successfully contained loperamide use and globally improved her clinical condition. This situation highlights the need for caution and awareness when prescribing loperamide, particularly in vulnerable patients with few cognitive resources to understand the risks of self-medication and little insight into its effects.

Dexamethasone exposure in normal-weight and obese hospitalized COVID-19 patients: An observational exploratory trial.

During the latest pandemic, the RECOVERY study showed the benefits of dexamethasone (DEX) use in COVID-19 patients. Obesity has been proven to be an independent risk factor for severe forms of infection, but little information is available in the literature regarding DEX dose adjustment according to body weight. We conducted a prospective, observational, exploratory study at Geneva University Hospitals to assess the impact of weight on DEX pharmacokinetics (PK) in normal-weight versus obese COVID-19 hospitalized patients. Two groups of patients were enrolled: normal-weight and obese (body mass index [BMI] 18.5-25 and >30 kg/m2 , respectively). All patients received the standard of care therapy of 6 mg DEX orally. Blood samples were collected, and DEX concentrations were measured. The mean DEX AUC0-8 and Cmax were lower in the obese compared to the normal-weight group (572.02 ± 258.96 vs. 926.92 ± 552.12 ng h/ml and 138.67 ± 68.03 vs. 203.44 ± 126.30 ng/ml, respectively). A decrease in DEX AUC0-8 of 4% per additional BMI unit was observed, defining a significant relationship between weight and DEX AUC0-8 (p = 0.004, 95% CI 2-7%). In women, irrespective of the BMI, DEX AUC0-8 increased by 214% in comparison to men (p < 0.001, 95% CI 154-298%). Similarly, the mean Cmax increased by 205% in women (p < 0.001, 95% CI 141-297%). Conversely, no significant difference between the obese and normal-weight groups was observed for exploratory treatment outcomes, such as the length of hospitalization. BMI, weight, and gender significantly affected DEX AUC. We conclude that dose adjustment would be needed if the aim is to achieve the same exposures in normal-weight and obese patients.

Fracture Risk Following an Atypical Femoral Fracture.

Atypical femoral fractures (AFFs) occurring during the course of osteoporosis treatment usually lead to discontinuation of anti-resorptive (AR) drugs. However, the risk of fracture after an AFF is unknown. We conducted a follow-up study of patients with AFF matched 1:3 for age and gender with patients with a peripheral major osteoporotic fracture (pMOF), in the setting of a fracture liaison service, to investigate the incidence of subsequent low-trauma fractures. Fifty-five patients with AFF (95% women, age [mean ± standard deviation] 75 ± 10 years, 89% exposed to AR drugs), followed for 6.2 ± 3.7 years, were compared to 165 matched controls with a pMOF (hip 85%) followed for 4.3 ± 2.6 years. During the follow-up, 38% of patients in the AFF group and 16% in the pMOF group received AR therapies. Continuation of AR drugs after an AFF was associated with contralateral AFF in 27% of subjects. The risks of new low-trauma, major osteoporotic and imminent (within 2 years) fractures, were similar between the two groups: incidence rate ratio (95% confidence interval [CI]) of subsequent fracture following AFF relative to pMOF, 1.30 (95% CI, 0.82-2.04), 1.28 (95% CI, 0.74-2.15), and 1.11 (95% CI, 0.54-2.15), respectively. Moreover, the risk of sustaining multiple fractures per participant was significantly increased among patients with AFF compared to pMOF (hazard ratio 1.48 [95% CI, 1.00-2.19]; p = 0.049). When taking mortality into account, the risk of subsequent fractures tended to be higher in the AFF group (sub-hazard ratio 1.42 [95% CI, 0.95-2.12]). In conclusion, patients who sustained an AFF are at high risk of subsequent fragility fractures, at least equal or even greater to the risk observed after a pMOF. However, continuation of AR drugs increases the risk of contralateral AFF. Therefore, optimal modalities for secondary fracture prevention after AFF require further evaluation. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

CYP450 Genotype-Phenotype Concordance Using the Geneva Micrococktail in a Clinical Setting.

Pharmacokinetic variability is a major source of differences in drug response and can be due to genetic variants and/or drug-drug interactions. Cytochromes P450 are among the most studied enzymes from a pharmacokinetic point of view. Their activity can be measured by phenotyping, and/or predicted by genotyping. Depending on the presence of drugs and/or diseases that can affect their in vivo activity, both approaches can be complementary. In 2014, the Geneva cocktail using dried blood spots was validated in healthy volunteers for CYP450 phenotyping. Since its clinical implementation, it has been used in approximately 500 patients in various clinical situations. Our study aims to report the concordance between CYP450 genotype and phenotype in real-life patients. The prospectively collected data from patients who were genotyped and/or phenotyped between January 2014 and December 2020 were reviewed. A total of 537 patients were genotyped and/or phenotyped for CYP450 during this period, and 241 underwent simultaneous genotyping and phenotyping allowing for genotype/phenotype concordance assessment. Genotyping correctly predicted poor metabolizer phenotypes for most CYPs isoenzymes studied, whereas agreement was more variable for intermediate, normal, and ultrarapid metabolizers. Discrepancies between the phenotype predicted on the basis of genotyping and the measured phenotype were not always explained by concurrent medication (phenotypic switch). Therefore genotyping and phenotyping tests are complementary approaches when aiming to individualize drug therapy. In the 537 patients, the majority of clinical situations were observed with analgesic/anesthetic drugs (n = 187), followed by antidepressants (n = 153), antineoplastics (n = 97), and immunosuppressants (n = 93). Inefficacy (or low drug levels) and adverse drug reaction (or high drug levels) were the main reasons for testing. Genotype and/or phenotype results explained or at least contributed to the clinical event in 44% of cases.

Automatic Classification of Discharge Letters to Detect Adverse Drug Reactions.

Adverse drug reactions (ADRs) are frequent and associated to significant morbidity, mortality and costs. Therefore, their early detection in the hospital context is vital. Automatic tools could be developed taking into account structured and textual data. In this paper, we present the methodology followed for the manual annotation and automatic classification of discharge letters from a tertiary hospital. The results show that ADRs and causal drugs are explicitly mentioned in the discharge letters and that machine learning algorithms are efficient for the automatic detection of documents containing mentions of ADRs.

Outcomes of drug exposition during pregnancy: Analysis from a teratology information service.

OBJECTIVE: We aimed to characterize drug exposures during pregnancy where the outcome was known that had benefited from counselling through our Teratology Information Service (TIS) between 1994-2016. STUDY DESIGN: This observational study analysed data collected through the drug exposures during pregnancy counselling. Data was analysed descriptively. RESULTS: Data from a total of 1'374 pregnant women were collected. Mean age was of 32 years. These women were exposed to more than ten drugs in 1.4 % (N = 19) of cases, with a mean drug intake of two. Analysis of the drugs altogether (N = 3'129) showed that FDA Pregnancy Category C drugs represented 42.9 % (N = 1'342) of drugs and ATC code N (nervous system) represented 36.4 % (N = 1'138). The onset of drug exposure was during the first trimester of pregnancy in 95.1 % (N = 2'982) of patients. Regarding outcomes, the rate of induced abortion was 10.8 % (N = 151), of pregnancy complications was 11.2 % (N = 157) and of malformations was 4.5 % (N = 49). CONCLUSION: Pregnant women counselled by our TIS take a mean of two drugs, ranging from one to 17. Drugs are from FDA Pregnancy Category C and ATC N drugs in most cases, 42.9 % and 36.4 % respectively. The rate of malformation of our cohort was of 4.5 %, close to the estimated spontaneous rate of malformation. This data gives a reassuring aspect of drug exposure in pregnancy but takes into account the outcome at birth only.

Direct-acting antiviral interactions with opioids, alcohol or illicit drugs of abuse in HCV-infected patients.

The hepatitis C virus (HCV) prevalence is extremely high in patients who consume and inject illicit drugs. Concerns about poor adherence and fear of interaction with drugs of abuse could constitute further disincentive for treatment initiation in these patients. We discussed the pharmacokinetics (PKs) and pharmacodynamics (PD) of currently prescribed direct antiviral agents (NSA5 inhibitors: daclatasvir, elbasvir, ledipasvir, pibrentasvir, velpatasvir; NS5B inhibitor: sofosbuvir; NS3/4A protease inhibitors: glecaprevir, grazoprevir, voxilaprevir) and most common substances of abuse (opioids: buprenorphine, fentanyl, heroin, methadone, morphine, oxycodone; stimulants: amphetamines, cathinones, cocaine; cannabinoids; ethanol). Overall, most direct-acting antivirals (DAAs) are substrates and inhibitors of the transmembrane transporter P-glycoprotein (P-gp), and several of them are metabolized by cytochrome P450 enzymes. Clinically relevant interactions are associated with P-gp and CYP3A modulators. Most substances of abuse are eliminated by Phase I and Phase II metabolizing enzymes, but none of them are either major inhibitors or inducers. PK studies did not show any relevant interactions between DAA and methadone or buprenorphine. Based on pharmacological considerations, neither efficacy loss nor adverse drug event associated with detrimental interaction are expected with opioids, stimulants, cannabinoids and ethanol. In summary, our literature review shows that the interaction potential of DAA with most opioids and illicit drugs is limited and should not be a hurdle to the initiate DAA.

[Importance and specificity of pharmacovigilance in the pediatric population]. / Importance et particularités de la pharmacovigilance en pédiatrie.

Clinical trials are usually conducted in a limited time and on a selected population, most often excluding children. These clinical trials provide a first safety profile of the drugs, undeniably essential but often partial, highlighting only the most common adverse drug reactions. In addition in pediatrics, due to growth and physiologic maturation, adverse drug reactions may differ between children and adults and extrapolation of data obtained in adults to children, including safety data, may be inaccurate. Pharmacovigilance, which is based on spontaneous notifications of adverse drug reactions, helps to refine the risk/benefit ratio of drugs and to increase their safety after market launch. This article aims to highlight the importance of pharmacovigilance in general and in particular in the pediatric population and to remind the modalities of reporting in Switzerland.

Les essais cliniques sont le plus souvent effectués sur une durée limitée et une population sélectionnée, excluant les enfants. Ils fournissent un premier profil de sécurité des médicaments, souvent partiel, ne mettant en évidence que les effets indésirables les plus fréquents. En pédiatrie, les phénomènes de croissance et de maturation peuvent être à l'origine de réactions aux médicaments différentes que chez l'adulte et empêchent la simple extrapolation à l'enfant des données, notamment de sécurité, obtenues chez l'adulte. La pharmacovigilance repose sur la notification spontanée des effets indésirables. Elle permet d'affiner le rapport risques/bénéfices et d'augmenter la sécurité des médicaments une fois commercialisés. Cet article a pour but de souligner l'importance de la pharmacovigilance, en particulier dans la population pédiatrique, et de rappeler les modalités d'annonces.

"Late" Withdrawal Syndrome after Carbamazepine In Utero Exposure in a CYP2C9 Slow Metabolizer Newborn.

We report a case of carbamazepine withdrawal syndrome following in utero exposure to carbamazepine related to a pharmacogenetic predisposition factor. The infant was born at 37 1/7 weeks' gestation by cesarean section to a mother treated for epilepsy with carbamazepine. One hour and thirty minutes after birth, the infant presented a respiratory distress with severe oxygen desaturation requiring intubation 5 h after birth. On the third day of life the infant developed clinical signs of a withdrawal syndrome which resolved progressively after 16 days and symptomatic treatment. The infant genotype analysis showed two low activity CYP2C9 allelic variants (∗2/∗3 heterozygote) predicting a CYP2C9 slow metabolizer phenotype which could explain reduced carbamazepine elimination and a late and long-lasting withdrawal symptoms observed 3 days after birth. The association of a withdrawal syndrome with carbamazepine exposure has not been previously reported and pharmacogenetic tests might therefore be useful in identifying patients at risk.

Rivaroxaban-Induced Hemorrhage Associated with ABCB1 Genetic Defect.

We report a patient who presented a non-ST segment elevation myocardial infarction in the context of severe normocytic hypochromic anemia related to gastrointestinal bleeding, 3 months after switching anticoagulant from the vitamin K antagonist acenocoumarol to the direct oral anticoagulant rivaroxaban. High levels of both anti-Xa activity and rivaroxaban plasma concentrations were measured despite rivaroxaban withdrawal, suggesting reduced elimination/drug clearance. Estimated half-life was 2-3 times longer than usually reported. The patient is a homozygous carrier of ABCB1 variant alleles, which could have participated to reduced elimination of rivaroxaban. Furthermore, CYP3A4/5 phenotyping showed moderately reduced enzyme activity. Drug-drug interaction with simvastatin may have contributed to decreased rivaroxaban elimination. Although in the present case moderate acute renal failure probably played a role, more clinical data are required to elucidate the impact of ABCB1 polymorphism on rivaroxaban pharmacokinetics and bleeding complications.

Severe Vincristine-induced Neuropathic Pain in a CYP3A5 Nonexpressor With Reduced CYP3A4/5 Activity: Case Study.

PURPOSE: Peripheral neuropathy is a frequent vincristine-induced adverse effect. Vincristine is a substrate of P-glycoprotein and is metabolized by the cytochrome P-450 (CYP) 3A5 and 3A4 isoforms, with CYP3A5 contributing to 75% of the intrinsic clearance of vincristine. Alterations in the function of these proteins may lead to an increase in vincristine toxicity. CYP3A5 nonexpressor status has been associated with vincristine-induced peripheral neuropathy. The severity of neuropathy has been reported to be inversely correlated to vincristine metabolite concentrations. Recently, the presence of a mutation in the CEP72 gene, which encodes for a protein involved in microtubule formation, has also been associated with vincristine-induced peripheral neuropathy. However, a clear correlation between genetic polymorphisms and vincristine toxicity has not been established. METHODS: Here we report the case of a 21-year old patient in whom severe neuropathic pain developed after vincristine treatment. FINDINGS: The patient was a CYP3A5 nonexpressor and presented with reduced CYP3A4/5 functional activity, a likely reason for the occurrence of the adverse event, as genotyping showed that his status was wild type for the ABCB1 and CEP72 genes. IMPLICATIONS: CYP phenotype and genotype may explain the occurrence of severe neuropathy in some patients treated with vincristine.

[Clinical pharmacology of medical cannabinoids in chronic pain]. / Cannabinoïdes médicaux dans les douleurs chroniques: aspects pharmacologiques.

In Switzerland, medical cannabinoids can be prescribed under compassionate use after special authorization in justified indications such as refractory pain. Evidence of efficacy in pain is limited and the clinical benefit seems to be modest. Their drug-drug interactions (DDI) profile is poorly documented. Cytochromes P450 (CYP) 2C9 and 3A4 are involved in the metabolism of tetrahydrocannabinol and cannabidiol, which implies possible DDI with CYP450 inhibitor and inducer, such as anticonvulsivants and HIV protease inhibitors, which may be prescribed in patients with neuropathic pain.

Therapeutic drug monitoring of voriconazole: a case report of multiple drug interactions in a patient with an increased CYP2C19 activity.

BACKGROUND: Voriconazole is metabolized by cytochrome P450 (CYP) 2C19 and CYP 3A4. Drug-drug interactions and genetic polymorphisms modulate their activities. CASE PRESENTATION: A 35-year old African female patient with resistant HIV and a cerebral mass of unknown origin was treated with voriconazole for a suspicion of disseminated Aspergillosis infection. Voriconazole trough concentrations (C0) were within target range while the patient was under esomeprazole, a CYP2C19 inhibitor. Phenotyping showed decreased CYP2C19 activity, whereas genotyping showed a variant allele associated with increased enzyme activity. The patient was switched to ranitidine because of the introduction of atazanavir. CYP3A4 inhibition by atazanavir combined with uninhibited CYP2C19 activity resulted in subtherapeutic voriconazole C0. The reintroduction of esomeprazole allowed restoring voriconazole C0 back to target range. CONCLUSION: The integration of drug-drug interactions and pharmacogenetics data is crucial to interpret drug concentrations correctly, thus preventing suboptimal exposure to voriconazole.