Potent Inhibitor Of Cytochrome P450 3A4 Research Articles

Zavegepant: a promising intranasal medication for migraine treatment

Migraine is the third most prevalent and seventh-highest specific cause of disability worldwide1. It is a neurobiological headache disorder that is caused by increased excitability of the central nervous system. This multifactorial ailment has various causes, including lack of sleep, hormonal imbalance, menstrual cycle, and emotional stress. Some individuals may even trigger migraine due to their choice of food, especially chocolate, milk, caffeine, cheese, and alcoholic beverages2. The variability seen in its clinical presentation includes the pattern of associated symptoms and pain intensity along with photophobia, osmophobia, phonophobia, vomiting, nausea, and movement sensitivity3. Considering the acute onset of this excruciating pain, patients demand rapid relief and the cure of all associated symptoms. Several medications have been introduced. However, nowadays, 5HT1B/1D receptor agonists (sumatriptan, zolmitriptan) and ergot alkaloids (dihydroergotamine mesylate) are being used as intranasal or parenteral medications for the immediate treatment of migraines. Many patients prefer intranasal medications over injectable ones because of their rapid action4. Triptans, one of the most effective treatment regimens for migraine, is unfortunately ineffective intranasally. Moreover, its contraindication for cardiovascular patients restricts its use in almost 10% of the migraine population. On the other hand, dihydroergotamine which is still less effective than triptans, the nasal spray is contraindicated in patients with uncontrolled hypertension, ischemic heart disease, and coronary artery vasospasm5. Co-administration with potent cytochrome P450 3A4 inhibitors may also result in potentially fatal peripheral and cerebral ischemia. Recent studies led to the discovery of novel modulators, like calcitonin gene-related peptide (CGRP), that are crucially implicated in the development and chronicity of migraine. This led to new medications known as gepants that can antagonize the CGRP receptor. Successive advances led to the introduction of first-generation and second-generation gepants. However, both were short-lived due to poor oral bioavailability6, associated liver injury, and less effectiveness, respectively. Zavegepant is the third generation but the first intranasally administered gepant. It is a high-affinity antagonist of the CGRP receptor, has adequate oral bioavailability, and, unlike triptans, does not induce active contraction of coronary arteries; therefore, it is safe for patients with cardiovascular comorbidities. Compared with the prior lead, the pharmacophore of zavegepant has a 2-quinolone and a 7-methylindazole, increasing oxidation stability and nasal irritancy potential while maintaining picomolar receptor binding potency7. In addition to that, it is also 10,000 times more selective for the CGRP receptor than for its counterpart, the amylin receptor8. It was FDA-approved in February 2020 for acute treatment, and results demonstrate that it is safe regarding hepatotoxicity9. Recently it cleared the phase 2 trials and now advancing to phase 3 ones. Zavegepant has a tmax of 15–20 minutes as it provides considerable efficacy over 48 hours, with ultra-rapid pain relief starting 15 minutes after a single therapeutic dose (P=0.0015), prolonged and persistent pain freedom for 2–24 hours and 2–48 hours, respectively, along with sustained pain relief for 2–24 hours10. This makes it highly potent and the safest in terms of side effects. Although the provided data gives ample proof that zavegepant is a revolutionary drug to combat migraine attacks but for definite, high-quality evidence about its efficacy and safety, results from the recent clinical trials and future research work are needed. Similarly, soft gel formulations of zavegepant also need more attention as it can be another option for the abortive treatment of migraine. Lastly, extensive trials are needed to see its effect on pregnant women and patients with severe liver and cardiovascular issues. For commercialization, it should be economically friendly so that it can compete with all the available formulas and a maximum number of patients can be benefitted from it. Rest assured. This third-generation gepant can be a promising medication in terms of timely relief from escalating pain, and further research may even help us find the ultimate cure for migraine. Ethical approval Not applicable. Sources of funding None. Author contribution The conceptualization was done by A.S. and B.S.R. The literature and drafting of the manuscript were conducted by A.S., T.N., A.W.K., S.D.E.Z.Z., A.Q. and H.S.R. The editing and supervision were performed by B.S.R. All authors have read and agreed to the final version of the manuscript. Conflicts of interest disclosure The authors declare that they have no financial conflict of interest with regard to the content of this report. Research registration unique identifying number (UIN) Not applicable. Guarantor All authors take responsibility for the work, access to data and decision to publish.

Prasugrel — gone, but not forgotten

AbstractHuman immunodeficiency virus (HIV) infection and certain retroviral therapies are associated with an increased risk of atherosclerosis with plaque rupture resulting in acute coronary syndromes. Therefore, there is often a need to co‐prescribe antiretroviral and cardiovascular therapies, including antiplatelet agents. Antiplatelet agents, such as the P2Y12 receptor antagonists clopidogrel and prasugrel, require activation by cytochrome P450 3A4 (CYP3A4). The P2Y12 receptor antagonist ticagrelor is also metabolised by CYP3A4. Pharmacokinetic enhancers, such as ritonavir and cobicistat, are utilised to increase the systemic exposure of certain agents within multidrug HIV regimens and are potent CYP3A4 inhibitors. Using these drugs together can result in unintended and undesirable drug–drug interactions. A 55‐year‐old male with a history of HIV presented to the emergency department with central chest pain. He was found to have had a non‐ST‐elevation myocardial infarction and was commenced on dual antiplatelet therapy including ticagrelor, anticoagulation and statin therapy, in addition to his usual HIV therapy, Genvoya (elvitegravir, cobicistat, emtricitabine, tenofovir alafenamide). A drug–drug interaction between Genvoya and ticagrelor was identified by the pharmacist, and the patient was switched to prasugrel on the pharmacist's recommendation. Although prasugrel was delisted from the Pharmaceutical Benefits Scheme (PBS) in July 2020, it remains accessible as a non‐PBS medicine. Prasugrel should be considered the P2Y12 antagonist of choice for patients who are on HIV regimens containing a pharmacokinetic enhancer such as ritonavir or cobicistat.

613. Novel use of Ritonavir boosting to achieve therapeutic itraconazole levels in disseminated Histoplasmosis

Abstract Background Itraconazole is a poorly soluble antifungal drug with variable pharmacokinetics. Serum levels vary between patients and over time, due to absorption issues and drug-drug interactions. Itraconazole suspension has more predictable absorption than capsules, but is poorly tolerated. Newer formulations dispersing drug in polymer aim to improve bioavailability, but are costly and not widely available. Standard therapy for histoplasmosis is induction with liposomal amphotericin B (LAmB) followed by 12+ months of itraconazole therapy with target pre-dose levels of 1-4 mg/L. Methods A 33yo M presented with weight loss, fever and dyspnoea, having returned to the UK from Nicaragua. He had been taking adalimumab for Crohn’s disease, quiescent for years following a prior small bowel resection. Empiric antifungal therapy with LAmB was commmenced, prior to confirmation of disseminated histoplasmosis by urinary antigen and blood culture. His course was complicated by significant bowel inflammation, requiring subtotal colectomy and end-ileostomy. Since surgery, he has had a high output stoma, with rapid transit time and reduced absorption. Results Despite itraconazole dose titration to 300mg TDS, levels were generally < 0.5 mg/L and maximum serum itraconazole level achieved was 0.64 mg/L. The patient was trained with a view to self-OPAT LAmB. On day 117 of antifungal therapy, ritonavir 100mg once daily was added. Four days after this, itraconazole level was 1.39 mg/L (from 0.34 mg/L) and maintained target concentration even after a switch from itraconazole suspension to capsules (Fig.1) with significant fungal marker response (Fig. 2). Figure 1.Itraconazole dosing and levels pre- and post-ritonavir Total daily itraconazole dose (suspension followed by capsules) was mapped over time. There is a period where LAmB alone was used surrounding the colorectal surgery. Serum itraconazole levels dramatically increased 2 days after the introduction of ritonavir 100mg once daily and remained above target trough even after switching to itraconazole capsules. Figure 2.Fungal marker (B-D-glucan and Histoplasma urinary Ag) response to antifungal therapy The response of serum beta-D-glucan and quantitative urinary Histoplasma antigen EIA (Miravista Labs) is represented alongside concurrent antifungal therapy. Of note, the first four urinary Histoplasma Ag levels were reporte as above the limit of detection (> 20 ng/mL) and are represented here as an arbitrary value of 25 ng/mL. Conclusion Use of ritonavir alone to boost itraconazole has not previously been described. It avoids the longer-term complications of intravenous access and adverse renal and other effects of LAmB. Itraconazole is both a substrate and inhibitor of cytochrome P450 3A4 (CYP3A4) and inhibits P-glycoprotein, resulting in considerable drug:drug interactions. Ritonavir is a more potent inhibitor of CYP3A4. Use of ritonavir-boosted itraconazole amounted to a 99% reduction in cost vs LAmB over 6 months. It may offer a reliable and cost-effective method of boosting itraconazole where other drug:drug interactions do not preclude its use. Disclosures All Authors: No reported disclosures.

Effect of itraconazole on the safety and pharmacokinetics of antitumor SHR6390

The experimental drug SHR6390 has anti-tumor activity as a cyclin dependent kinase 4/6 inhibitor and is metabolized primarily by the cytochrome P450 3A4 enzyme. Therefore, The purpose of this trial was to evaluate the safety and pharmacokinetics of SHR6390, a potent cytochrome P450 3A4 inhibitor, in healthy Chinese subjects. In this trial study, 18 subjects received a single oral dose of SHR6390 50 mg on day 1, multiple doses of 200 mg itraconazole on days 12–24 for 13 days, and a single oral dose of SHR6390 50 mg on day 15. After coadministration with itraconazole, the maximum plasma concentration (Cmax) of SHR6390 increased by 70.7% (from 14.3 ng/ml to 24.5 ng/ml), and the area under the time curve from 0 to T (AUC0-T) increased by 110.8% from 468 h∙ng/mL to 988 h∙ng/mL. The area under the concentration-time curve extrapolated to ∞(AUC0-∞) increases from 509 H∙ng/mL to 1,040 h∙ng/mL, an increase of 105.1%. Oral gap (CL/F) decreased (47.9 L/h and 98.3 L/h) and apparent volume of distribution (Vz/F) decreased (4190 L and 5890 L). According to common terminology criteria, 15 32 adverse events were reported in 18 subjects (AEs) (27 SHR6390-related AEs and 15 Itraconazole-related AEs), AEs were all Class 1 adverse events. Overall, co-administration of Itraconazole increased the plasma exposure of SHR6390 in healthy subjects. Both SHR6390 alone and co-administration of Itraconazole showed acceptable safety profiles, which warrants further investigation. The experimental drug SHR-6390 of this clinical trial has been applied for registration, which is classified as Chemical drugs Class 1. The study drug SHR6390 registration number:ClinicalTrials.gov Identifier: NCT04423601 (https://clinicaltrials.gov/)

Interaction of CYP3A4 with Rationally Designed Ritonavir Analogues: Impact of Steric Constraints Imposed on the Heme-Ligating Group and the End-Pyridine Attachment.

Controlled inhibition of drug-metabolizing cytochrome P450 3A4 (CYP3A4) is utilized to boost bioavailability of anti-viral and immunosuppressant pharmaceuticals. We investigate structure–activity relationships (SARs) in analogues of ritonavir, a potent CYP3A4 inhibitor marketed as pharmacoenhancer, to determine structural elements required for potent inhibition and whether the inhibitory potency can be further improved via a rational structure-based design. This study investigated eight (series VI) inhibitors differing in head- and end-moieties and their respective linkers. SAR analysis revealed the multifactorial regulation of inhibitory strength, with steric constraints imposed on the tethered heme-ligating moiety being a key factor. Minimization of these constraints by changing the linkers’ length/flexibility and N-heteroatom position strengthened heme coordination and markedly improved binding and/or inhibitory strength. Impact of the end-pyridine attachment was not uniform due to influence of other determinants controlling the ligand-binding mode. This interplay between pharmacophoric determinants and the end-group enlargement can be used for further inhibitor optimization.

Discovery and Characterization of Potent Dual P-Glycoprotein and CYP3A4 Inhibitors: Design, Synthesis, Cryo-EM Analysis, and Biological Evaluations.

Targeted concurrent inhibition of intestinal drug efflux transporter P-glycoprotein (P-gp) and drug metabolizing enzyme cytochrome P450 3A4 (CYP3A4) is a promising approach to improve oral bioavailability of their common substrates such as docetaxel, while avoiding side effects arising from their pan inhibitions. Herein, we report the discovery and characterization of potent small molecule inhibitors of P-gp and CYP3A4 with encequidar (minimally absorbed P-gp inhibitor) as a starting point for optimization. To aid in the design of these dual inhibitors, we solved the high-resolution cryo-EM structure of encequidar bound to human P-gp. The structure guided us to prudently decorate the encequidar scaffold with CYP3A4 pharmacophores, leading to the identification of several analogues with dual potency against P-gp and CYP3A4. In vivo, dual P-gp and CYP3A4 inhibitor 3a improved the oral absorption of docetaxel by 3-fold as compared to vehicle, while 3a itself remained poorly absorbed.

Rational Design of CYP3A4 Inhibitors: A One-Atom Linker Elongation in Ritonavir-Like Compounds Leads to a Marked Improvement in the Binding Strength.

Inhibition of the major human drug-metabolizing cytochrome P450 3A4 (CYP3A4) by pharmaceuticals and other xenobiotics could lead to toxicity, drug–drug interactions and other adverse effects, as well as pharmacoenhancement. Despite serious clinical implications, the structural basis and attributes required for the potent inhibition of CYP3A4 remain to be established. We utilized a rational inhibitor design to investigate the structure–activity relationships in the analogues of ritonavir, the most potent CYP3A4 inhibitor in clinical use. This study elucidated the optimal length of the head-group spacer using eleven (series V) analogues with the R1/R2 side-groups as phenyls or R1–phenyl/R2–indole/naphthalene in various stereo configurations. Spectral, functional and structural characterization of the inhibitory complexes showed that a one-atom head-group linker elongation, from pyridyl–ethyl to pyridyl–propyl, was beneficial and markedly improved Ks, IC50 and thermostability of CYP3A4. In contrast, a two-atom linker extension led to a multi-fold decrease in the binding and inhibitory strength, possibly due to spatial and/or conformational constraints. The lead compound, 3h, was among the best inhibitors designed so far and overall, the strongest binder (Ks and IC50 of 0.007 and 0.090 µM, respectively). 3h was the fourth structurally simpler inhibitor superior to ritonavir, which further demonstrates the power of our approach.

An increase in side-group hydrophobicity largely improves the potency of ritonavir-like inhibitors of CYP3A4

Identification of structural determinants required for potent inhibition of drug-metabolizing cytochrome P450 3A4 (CYP3A4) could help develop safer drugs and more effective pharmacoenhancers. We utilize a rational inhibitor design to decipher structure-activity relationships in analogues of ritonavir, a highly potent CYP3A4 inhibitor marketed as pharmacoenhancer. Analysis of compounds with the R1 side-group as phenyl or naphthalene and R2 as indole or naphthalene in different stereo configuration showed that (i) analogues with the R2-naphthalene tend to bind tighter and inhibit CYP3A4 more potently than the R2-phenyl/indole containing counterparts; (ii) stereochemistry becomes a more important contributing factor, as the bulky side-groups limit the ability to optimize protein-ligand interactions; (iii) the relationship between the R1/R2 configuration and preferential binding to CYP3A4 is complex and depends on the side-group functionality/interplay and backbone spacing; and (iv) three inhibitors, 5a-b and 7d, were superior to ritonavir (IC50 of 0.055–0.085 μM vs. 0.130 μM, respectively).

Midazolam Hydroxylation Assay as a Marker for Endogenous CYP3A4‐mediated Metabolism: Metabolic Interaction with Natural Health Supplements

BackgroundEndogenous substances (endobiotics) such as vitamin D3 and estrogen are metabolized by cytochrome P450 3A4 (CYP3A4). However, measurement of endobiotic metabolites is often technology‐limited and expensive. Because of structural similarity of midazolam with vitamin D3, midazolam metabolic profile could present valuable information in identifying potential interaction of drugs or natural health supplements (NHS) with endogenous substances. Polyphenols (quercetin, raspberry ketone, gallic acid, rutin), furanocoumarin (imperatorin) and terpenoids (ursolic acid) are the biologically active human dietary constituents from grapes, berry fruits, pomegranate, and olive oil, but are also widely ingested as over‐the‐counter natural health supplements (NHS) in United States. NHS have the ability to inhibit CYP3A4‐mediated metabolism, possibly causing the plasma concentrations of the midazolam as well as vitamin D3 to increase. The objective of the present study was to develop a simple and effective metabolism assay to measure CYP3A4‐mediated midazolam hydroxylation and to screen certain NHS (polyphenols, furanocoumarin, terpenoids) for their potential to cause CYP3A4 related herb‐endobiotic interactions in humans.MethodsThe hydroxylation of midazolam to 1′‐hydroxymidazolam assay was developed and optimized. Reaction mixtures containing potassium phosphate buffer (pH 7.4), recombinant CYP3A4 protein (30 pmol/ml), NADPH‐regenerating system, and midazolam (5 uM or 2 uM) were incubated for 15 min. Substrate, metabolites and internal standard were analyzed with a reverse phase assay by a Shimadzu Prominence high‐performance liquid chromatography (HPLC) coupled to a photodiode array detector set at 220 nm using a C18 column. SigmaPlot enzyme kinetics module (version 13; Systat Software, Inc., San Jose, CA) and GraphPad Prism software (GraphPad Software Inc., San Diego, CA) were used to determine the kinetics parameters and inhibitory constants, respectively.ResultsThe Km and Vmax values for rCYP3A4‐mediated 1′‐hydroxymidazolam formation were 1.9±0.3 uM and 75.4±3.7 pmol/min/mg, respectively. Imperatorin inhibited 1′‐hydroxymidazolam formation to undetectable levels at both 2 uM and 5 uM concentrations of midazolam, whereas quercetin inhibited the formation by 31–44%. The IC50 values of imperatorin for 1′‐hydroxymidazolam and 4‐hydroxymidazolam were 7.7 uM and 2.6 uM, respectively. Ketoconazole, a known potent inhibitor of CYP3A4, yielded IC50 concentrations of 0.16–0.20 uM for midazolam hydroxylation.ConclusionsA midazolam hydroxylation assay was developed to screen potential metabolic interactions. Imperatorin was identified as an inhibitor of rCYP3A4. Quercetin showed low rCYP3A4 inhibition potential. This research further shows that NHS studied here can potentially inhibit one of the most ubiquitous enzymes responsible for inactivation of endobiotics and may provide additional health benefits. Vitamin D3 is metabolized by CYP3A4 and midazolam could potentially be used as a marker for interaction of commonly used NHS with vitamin D3. The cost‐effective HPLC method developed in this study provides a useful tool in predicting NHS‐endobiotic interactions.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Retrospective Analysis of Severe Neutropenia in Patients Receiving Concomitant Administration of Docetaxel and Clarithromycin

Background: Neutropenia is one of the most important dose-limiting toxicities of docetaxel. Docetaxel is metabolized by cytochrome P450 3A4 (CYP3A4). Clarithromycin, a potent inhibitor of CYP3A4, is occasionally used in combination with docetaxel. The aim of this study was to evaluate whether the risk of severe neutropenia induced by docetaxel was increased by concomitant administration of clarithromycin. Methods: Patients with advanced lung cancer receiving docetaxel were identified from an electronic medical record system and divided into 2 groups: concomitant administration of clarithromycin and no concomitant administration of clarithromycin. The proportion of patients experiencing grade 4 neutropenia between the 2 groups was compared. Potential risk factors associated with grade 4 neutropenia were also examined using univariate and multivariate logistic regression analyses. Results: One hundred and fifty-eight patients were analysed. Grade 4 neutropenia was more frequently detected in the patients receiving clarithromycin than in those not receiving the drug (63.2 vs. 35.3%; p = 0.025). Multivariate analysis showed that co-administration of clarithromycin [odds ratio (OR) 4.98; p = 0.004], pre-treatment absolute neutrophil count (OR 2.62; p = 0.011) and female gender (OR 2.75; p = 0.029) resulted in an increase in the incidence of grade 4 neutropenia. Conclusions: This study shows that concomitant administration of clarithromycin potentiated docetaxel-induced myelosuppression.

Ascending Single-Dose Study of the Safety Profile, Tolerability, and Pharmacokinetics of Bosutinib Coadministered With Ketoconazole to Healthy Adult Subjects

BackgroundBosutinib (SKI-606) is an orally bioavailable, competitive tyrosine kinase inhibitor that selectively targets both Src and Abl tyrosine kinases. Bosutinib is metabolized primarily through the cytochrome P450 3A4 pathway. Inhibition of bosutinib metabolism by coadministration with the potent cytochrome P450 3A4 inhibitor ketoconazole could potentially increase plasma concentrations of bosutinib, allowing for the study of bosutinib tolerability at supratherapeutic concentrations in a healthy subject population. ObjectiveThis study assessed the safety profile, tolerability, and pharmacokinetics of different dose combinations of bosutinib coadministered with ketoconazole in healthy adults, and determined whether supratherapeutic concentrations of bosutinib can be achieved with ketoconazole. MethodsThis was a randomized, Phase I, double-blind, placebo-controlled, sequential-group study conducted in healthy adults. Single oral doses of bosutinib 100, 200, 300, 400, 500, and 600 mg or placebo were administered with ketoconazole and food on day 1; daily single oral doses of ketoconazole 400 mg were administered on days –1 and 1 through 4. ResultsForty-eight subjects were enrolled. Their mean (SD) age was 32.0 (10.7) years (range, 18–50 years). The majority of the subjects (n = 44 [92%]) were white, 2 (4%) were black or African American, and 2 (4%) were of other races. Bosutinib was associated with acceptable tolerability at doses from 100 to 600 mg, with adverse events either mild (n = 30 [63%]) or moderate (n = 12 [25%]) in severity; no subject discontinued treatment due to adverse events, and no serious events were reported. Mean (SD) values for bosutinib 100 to 600 mg ranged from 58.4 (13.3) to 426 (100) ng/mL for Cmax and 2980 (802) to 23,000 (4020) ng·h/mL for AUC0–∞; mean AUC0–24 and AUC0–last ranged from 876 (234) to 7080 (1640) ng· h/mL and from 2740 (854) to 22,200 (3630) ng · h/mL, respectively. Cmax and AUC were linear and dose proportional. Mean Cmax at 600 mg was 2.1-fold higher than the steady-state Cmax previously observed for patients with chronic myelogenous leukemia who received bosutinib 500 mg once daily with food. ConclusionsSingle doses of bosutinib up to 600 mg coadministered with multiple doses of ketoconazole were acceptably well tolerated in this small, selected group of healthy male volunteers. In addition, supratherapeutic exposure was achieved within this range for bosutinib when coadministered with ketoconazole. ClinicalTrials.gov identifier: NCT00777530.

Silodosin for the Treatment of Benign Prostatic Hyperplasia: Pharmacology and Cardiovascular Tolerability

Relief of benign prostatic hyperplasia (BPH)-related lower urinary tract symptoms by α-blockers (α₁-adrenoceptor antagonists) is mediated primarily through the blockade of α(1A)-receptors, leading to relaxation of smooth muscle in the prostate and bladder neck. Early α-blockers that were nonselective for adrenoceptor subtypes have been associated with blood pressure-related adverse effects, such as orthostatic hypotension, that may be attributed at least in part to the blockade of α(1B)-adrenoceptors in arterial vessels. Silodosin, a novel α-blocker with exceptionally high selectivity for α(1A-) versus α(1B)-adrenoceptors, was recently approved in the United States for the treatment of urinary symptoms related to BPH. The unique receptor selectivity profile likely accounts for some of the desirable clinical features of the drug. Silodosin possesses an excellent cardiac- and blood pressure-related safety profile, and data have demonstrated that it does not promote QT-interval prolongation. Therapeutic doses of silodosin are safe for men with mild-to-moderate liver dysfunction; dosage adjustment is recommended in those with moderate renal impairment. The drug should not be taken with potent cytochrome P450 3A4 inhibitors. Silodosin may be especially beneficial in patients who need to maximize cardiovascular tolerability.

Drug-Induced Arrhythmia

Prolongation of the QTc interval has been associated with proarrhythmia resulting from a potentially fatal form of polymorphic ventricular tachycardia called torsades de pointes (TdP). Genetic forms of the long-QT syndrome (LQTS) associated with high arrhythmic risk have been causally related to mutations in ion channels responsible for the cardiac action potential; genetic factors associated with milder degrees of QTc prolongation and arrhythmic risk have also been described. Acquired forms of QTc prolongation and proarrhythmia, particularly related to drug therapy, are frequently related to drug effects on the same ion channels involved in genetic forms of LQTS. As is true for genetic forms of LQTS, there is a wide spectrum of potential drug effects on the QTc interval ranging from trivial to potentially lethal. Drug-induced QTc prolongation is a complicated phenomenon related not just to the properties or dose of a particular drug but also to drug-drug interactions and a variety of patient factors, including age, gender, the presence and severity of underlying heart disease, and genetic predisposition. Additionally, drug effects on other ion channels, including blockade of sodium channels (causing prolongation of the QRS interval rather than the QTc interval), are an important cause of drug-induced proarrhythmia. The purpose of this review is to summarize the available data related to acquired forms of LQTS, with particular focus on drug-related LQTS and proarrhythmia. A brief summary is presented here of genetic LQTS because the relevant genes and proteins form the basis for an understanding of the causes of acquired LQTS, and in any given patient, the QTc is determined by genetic, substrate, and environmental factors. Emphasis is placed on practical strategies for clinicians, with the goal of minimizing the risk of dangerous proarrhythmia related to the use of both cardiac and noncardiac drugs with the potential for QTc prolongation. Genetic …

Fatal Hydrocodone Overdose in a Child: Pharmacogenetics and Drug Interactions

Fatal opioid toxicity occurred in a developmentally delayed child aged 5 years 9 months who was inadvertently administered high doses of hydrocodone for a respiratory tract infection. The concentration of hydrocodone in postmortem blood was in the range associated with fatality; however, hydromorphone, a major metabolite catalyzed by cytochrome P450 2D6 (CYP2D6), was not detected when using mass spectrometry. Genetic analysis revealed that the child had a reduced capability to metabolize the drug via the CYP2D6 pathway (CYP2D6*2A/*41). Coadministration of clarithromycin (a potent cytochrome P450 3A4 inhibitor) for an ear infection and valproic acid for seizures since birth further prevented drug elimination from the body. This case highlights the interplay between pharmacogenetic factors, drug-drug interactions, and dose-related toxicity in a child.

Iatrogenic Cushing's Syndrome due to Coadministration of Ritonavir and Inhaled Budesonide in an Asthmatic Human Immunodeficiency Virus Infected Patient

Introduction. Iatrogenic Cushing's syndrome (CS) is caused by exposure to glucocorticoids and may be promoted by interaction with additional drugs. It is well known in asthmatic human immunodeficiency virus (HIV)-infected patients treated with inhaled fluticasone with ritonavir-containing antiretroviral regimen (cART). Case Report. The authors present an asthmatic HIV-infected Ethiopian woman, treated with fluticasone/salmeterol, commencing cART with tenofovir, emtricitabine, and lopinavir/ritonavir. During 7 months she gained 9 kg and hyperpigmentation, mild edema, marked abdominal striae, and increase in blood pressure were noted. Plasma am and urine free cortisol levels confirmed CS diagnosis and fluticasone was discontinued. Complete resolution of CS occurred within 2 months. However, frequent asthma symptoms required resumption of inhaled corticosteroid (ICS) treatment, and budesonide/formeterol was prescribed. Soon reemergence of symptomatic CS was noted. Ritonavir dose was halved, but CS symptoms continued to develop. Budesonide was stopped and montelukast initiated. Resolution of cushingoid symptoms was observed within weeks. Discussion. Corticosteroids are metabolized by cytochrome P450 3A4 (CYP3A4). Fluticasone has the longest glucocorticoid receptor–binding half-life and is 300 times more lipophilic than budesonide. Inhaled fluticasone possesses a high suppression rate of hypothalamic-pituitary-adrenal axis. Ritonavir, a potent CYP3A4 inhibitor, may inhibit corticosteroid degradation and increase its accumulation. Inhaled budesonide is less likely to cause adrenal suppression. Diagnosing Cushing's syndrome presents a clinical challenge due to similarities with clinical manifestations and side effects related to cART. In patients treated with inhaled or intranasal corticosteroids together with cART there may be a higher incidence of iatrogenic CS. CS should be looked for, and management considered carefully.

Phase 1 pharmacokinetic and drug‐interaction study of dasatinib in patients with advanced solid tumors

The recently developed the Src and Abelson (Abl) kinase inhibitor dasatinib has antitumor effects in epithelial and mesenchymal tumors. Preclinical data have indicated that dasatinib is metabolized primarily through cytochrome P450 3A4 (CYP3A4) and may cause QT prolongation. In light of its improved tolerability, the authors were interested in the safety of a once-daily dasatinib regimen. The authors conducted a phase 1 trial of dasatinib in 29 patients with advanced solid tumors. Segment 1 of the trial was short term and sequential and was designed to determine whether the coadministration of the potent CYP3A4 inhibitor ketoconazole had an effect on the pharmacokinetics of dasatinib. Segment 2 was designed to evaluate the safety of dasatinib as dosing was increased. QT intervals were monitored closely in both segments. Efficacy was assessed in Segment 2 using both positron emission tomography and computed tomography. Hematologic toxicities were markedly less than those observed in patients with leukemia, whereas nonhematologic toxicities were similar. The authors determined that the maximum recommended dose was 180 mg once daily based on the incidence of pleural effusion. Coadministration of ketoconazole led to a marked increase in dasatinib exposure, which was correlated with an increase in corrected QT (QTc) values of approximately 6 msec. No adverse cardiac events were observed. The dose-limiting toxic effect for dasatinib was pleural effusion. The pharmacokinetic and cardiac studies indicated that coadministration of dasatinib with potent CYP3A4 inhibitors or agents that prolong the QTc interval should be avoided if possible. Close monitoring for toxicity and dose reduction should be considered if the coadministration of such agents cannot be avoided.

The direct factor Xa inhibitor rivaroxaban

Warfarin and heparin are the traditional mainstay anticoagulant therapies for treating thromboembolic disease. These drugs, with a documented history of utility, also have inherent difficulties in usage; in particular, the complicated monitoring and numerous drug-drug interactions of warfarin, and the need for parenteral administration of heparins. New agents have recently emerged that target specific elements of the clotting pathway. Rivaroxaban, which inhibits activated factor X (Xa), is currently in clinical trials and is the most advanced factor Xa inhibitor. The drug offers once-daily oral dosing, with no need for injections, dose titration, or frequent blood tests to monitor the international normalised ratio. It has a rapid onset of action and, although there is no specific antidote, it has a short plasma elimination half-life (about 5-9 hours). Evidence from recently published large-scale phase III clinical trials shows rivaroxaban to be superior to enoxaparin for prophylaxis of venous thromboembolism after major orthopaedic surgery. Studies have shown rivaroxaban to have a sound safety profile, with an incidence of bleeding similar to enoxaparin in phase III clinical trials. Few side effects and drug-drug interactions between rivaroxaban and common medications have been found thus far, although some interactions with potent cytochrome P450 3A4 inhibitors have been observed. It is hoped that rivaroxaban may be used as a first-line anticoagulant for prophylaxis of venous thromboembolic disease in postsurgical patients.

Co‐medication of statins and CYP3A4 inhibitors before and after introduction of new reimbursement policy

HMG-CoA reductase inhibitors (statins) are frequently used drugs in the treatment of dyslipidaemia. Co-medication with interacting drugs increases the risk of statin-induced muscular side-effects. Simvastatin exhibits particularly high interaction potential due to substantial metabolism via cytochrome P450 3A4 (CYP3A4). In June 2005, a new reimbursement policy was introduced by the Norwegian Medicines Agency stating that simvastatin should be prescribed as first-line lipid-lowering therapy. Following introduction of the new policy, the number of patients co-medicated with simvastatin and CYP3A4 inhibitors almost doubled. A potential consequence is increased incidence of muscular side-effects in the statin-treated population. To assess the prevalence of co-medication of statins and CYP3A4 inhibitors before and after introduction of a new Norwegian reimbursement policy, which states that all patients should be prescribed simvastatin as first-line lipid-lowering therapy. Data from patients receiving simvastatin, lovastatin, pravastatin, fluvastatin or atorvastatin in 2004 and 2006, including co-medication of potent CYP3A4 inhibitors, were retrieved from the Norwegian Prescription Database covering the total population of Norway. Key measurements were prevalence of continuous statin use (two or more prescriptions on one statin) and proportions of different statin types among all patients and those co-medicated with CYP3A4 inhibitors. In 2004, 5.9% (n= 272 342) of the Norwegian population received two or more prescriptions on one statin compared with 7.0% (n= 324 267) in 2006. The relative number of simvastatin users increased from 39.7% (n= 112 122) in 2004 to 63.1% (n= 226 672) in 2006. A parallel increase was observed within the subpopulation co-medicated with statins and CYP3A4 inhibitors, i.e. from 42.9% (n= 7706) in 2004 to 63.6% (n= 13 367) in 2006. For all other statins the number of overall users decreased to a similar extent to those co-medicated with CYP3A4 inhibitors. In both 2004 and 2006, the choice of statin type did not depend on whether the patient used a CYP3A4 inhibitor or not. Considering the pronounced interaction potential of simvastatin with CYP3A4 inhibitors, a negative influence of the new policy on overall statin safety seems likely.

Pharmacological enhancement of protease inhibitors with ritonavir: an update

Advances in HIV treatment since the approval of the first antiretroviral (ARV) medication have occurred at a rapid pace. However, resistance to these medications can occur quickly owing to inadequate plasma concentrations resulting from poor adherence related to intolerable drug toxicities and complex dosing schedules. Drug–drug and drug–food interactions can also result in inadequate ARV drug exposure. Ritonavir is a potent cytochrome P450 3A4 inhibitor and low doses can be used in combination with almost all protease inhibitors to overcome most drug–drug and drug–food interactions. Little toxicity can be attributed to the addition of low-dose ritonavir to an ARV regimen, and most patients find that the added pills do not adversely affect adherence. This article reviews the pharmacological use of ritonavir for pharmacokinetic enhancement (or boosting) and updates the clinical use of boosted protease inhibitors.

Potent Inhibition of Human Cytochrome P450 3A4, 2D6, and 2C9 Isoenzymes by Grapefruit Juice and Its Furocoumarins

The cytochrome P450 enzyme family is the most abundant and responsible for the metabolism of more than 60% of currently marketed drugs and is considered central in many clinically important drug interactions. Seven different grapefruit and pummelo juices as well as 5 furocoumarins isolated from grapefruit juice were evaluated at different concentration on cytochrome P450 3A4 (CYP3A4), cytochrome P450 2C9 (CYP2C9), and cytochrome P450 2D6 (CYP2D6) isoenzyme activity. Grapefruit and pummelo juices were found to be potent inhibitors of cytochrome CYP3A4 and CYP2C9 isoenzymes at 25% concentration, while CYP2D6 is inhibited significantly low at all the tested concentration of juices (P < 0.05). Among the 5 furocoumarins tested, the inhibitory potency was in the order of paradisin A > dihydroxybergamottin > bergamottin > bergaptol > geranylcoumarin at 0.1 microM to 0.1 mM concentrations. The IC(50) value was lowest for paradisin A for CYP3A4 with 0.11 microM followed by DHB for CYP2C9 with 1.58 microM.