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Drug Repurposing and Novel Antiviral Drugs for COVID-19 Management
Published in Debmalya Barh, Kenneth Lundstrom, COVID-19, 2022
Shailendra Dwivedi, Aakanksha Rawat, Amit Ranjan, Ruchika Agrawal, Radhieka Misra, Sunil Kumar Gupta, Surekha Kishore, Sanjeev Misra
In an attempt to solve the puzzle, the WHO embarked on an ambitious global “mega-trial” called SOLIDARITY in January 2020. In the trial, confirmed cases of COVD-19 were randomized to standard care or one of four active treatment arms (remdesivir, CQ or HCQ, lopinavir/ritonavir, or lopinavir/ritonavir plus interferon beta-1a). In early July 2020, the treatment arms in hospitalized patients that included HCQ, CQ, or lopinavir/ritonavir were discontinued. Interim results released in mid-October 2020 stated that the four aforementioned repurposed antiviral agents appeared to have little or no effect on hospitalized patients with COVID-19 in comparison to standard care, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay [10]. With weak evidence and theoretically unfavorable pharmacodynamics the NIH Panel for COVID-19 Treatment Guidelines and Infectious Diseases Society of America (IDSA) did not recommend use of lopinavir/ritonavir or any other HIV protease inhibitors for the treatment of COVID-19 patients. IDSA also mentioned that CYP3A inhibition can result in increased risk of severe cutaneous reactions, QT prolongation, and potential drug interactions. Various combinations of methylprednisolone with umifenovir or lopinavir/ritonavir are still being studied to improve the treatment outcomes [11].
Paediatric clinical pharmacology
Published in Evelyne Jacqz-Aigrain, Imti Choonara, Paediatric Clinical Pharmacology, 2021
Evelyne Jacqz-Aigrain, Imti Choonara
Interestingly, CYP3A is not only localised in the liver, but also in the intestine. Therefore, intestinal drug metabolism also contributes to presystemic clearance of CYP3A substrates. A recent study showed in vitro that the ontogeny of intestinal CYP3A activity mirrors that of hepatic CYP3A activity [24]. Therefore, the oral bioavailability of CYP3A substrates may be increased consequent to reduced presystemic clearance in newborn infants. This assumption is supported by the finding that midazolam oral bioavailability is higher in preterm infants when compared to adults [25].
Role of Genetic Variability in Breast Cancer Treatment Outcomes
Published in Brian Leyland-Jones, Pharmacogenetics of Breast Cancer, 2020
Kandace L. Amend, Ji-Yeob Choi, Christine B. Ambrosone
CYP3A4 also plays a large role in the metabolism of CP, and the CYP3A4 gene has a number of known variant alleles, including some having functional significance (19). A single base substitution in the 5’ promoter region of the gene (20), present in 9% of European-Americans and 53% of African-Americans (21), with the CYP3A4*1B allele associated with expression levels is 1.4-fold higher than that in common alleles (22). Using enzyme kinetic analyses to evaluate intersample variation in activation of CP by CYP3A and 2B in human liver, both Chang et al. (1993) and Roy et al. (1999) found considerable interindividual differences in CYP3A and CYP2B levels and variation over a wide range in CP hydroxylation (10,23). Variation in CYP3A enzyme levels and expression may be related, in part, to genetic differences or to other chemotherapeutic and natural agents that have been shown to increase CYP3A4 expression (24).
Pemigatinib for the treatment of myeloid/lymphoid neoplasms with FGFR1 rearrangement
Published in Expert Review of Anticancer Therapy, 2023
Craig W. Freyer, Mitchell E. Hughes, Alison Carulli, Adam Bagg, Elizabeth Hexner
Pemigatinib has a long half-life of 15.4 hours and reaches steady state within 4 days with repeated daily dosing. This coupled with a high volume of distribution allow for once daily dosing. High-calorie meals do not significantly impact absorption so it may be taken with or without food [17]. Pemigatinib is primarily metabolized by hepatic CYP3A. Strong CYP3A inducers decreased Cmax by 62% and AUC by 85%. A 50% exposure reduction is expected when pemigatinib is combined with a moderate CYP3A inducer. Based on the potential for reduced concentrations and efficacy, it is recommended to avoid moderate and strong CYP3A inducers when possible. Combining pemigatinib with a strong CYP3A inhibitor increased Cmax by 17% and AUC by 88%. Moderate CYP3A inhibitors are anticipated to increase exposure by at least 50%. Higher concentrations may increase the risk of adverse reactions and dose reductions are recommended when the combination cannot be avoided [15,17].
Managing cystic fibrosis in children aged 6-11yrs: a critical review of elexacaftor/tezacaftor/ivacaftor combination therapy
Published in Expert Review of Respiratory Medicine, 2023
Kamyron D. Jordan, Edith T. Zemanick, Jennifer L. Taylor-Cousar, Jordana E. Hoppe
Elexacaftor, tezacaftor and ivacaftor are all metabolized by CYP3A. If administered with other medications that are inhibitors or inducers of CYP3A, levels of these medications may be increased or decreased, respectively. Therefore, strong inducers of CYP3A should not be used concurrently with ETI and a dose adjustment is required with co-administration with moderate or strong inhibitors of CYP3A4 [41]. Importantly, dose adjustments are required when treating with Paxlovid (nirmatrelvir-ritonavir; a CYP3A4 inhibitor) for coronavirus 19 disease caused by SARS-CoV2 infection [43]. Concurrent use with antimicrobials including rifampin (CYP3A4 inducer) and azole medications (CYP34A inducers) is not recommended due to changes in drug exposure [44]. Critically, unlike the dual combination LUM/IVA, ETI does not interact with hormonal contraception [44,45]. It is primarily excreted through the stool with renal elimination as a secondary path [40].
The effect of co-administration of berberine, resveratrol, and glibenclamide on xenobiotic metabolizing enzyme activities in diabetic rat liver
Published in Drug and Chemical Toxicology, 2022
Azra Bozcaarmutlu, Canan Sapmaz, Ömer Bozdoğan, Aysel Kükner, Leyla Kılınç, Salih Tunç Kaya, Oğulcan Talat Özarslan, Didem Ekşioğlu
Co-administration of R+B in the diabetic rats decreased CYP2B-associated PROD activity to the non-diabetic control activity level. Co-administration of R+G and R+B in diabetic rats significantly decreased CYP3A-associated ERND activities compared to the non-diabetic control group. CYP3A is responsible for the metabolism of both endogenous and exogenous molecules such as drugs. Similarly, GST activities of D+R+G and D+R+B groups were less than the non-diabetic control group. Glutathione S-transferases are also responsible for the elimination of many exogenous molecules and they generally catalyze detoxification reactions. Co-administration of these chemicals may inhibit the metabolism of endogenous and exogenous molecules and may cause a toxic reaction by inhibiting the metabolism of drugs metabolized by CYP3A and GST.