Narrow Therapeutic Index Drugs Research Articles

Effect of patients in-use and accelerated stability conditions on quality attributes and pharmacokinetic profile of four FDA approved extended-release anti-epileptic-drug products

Divalproex (DVS) is a popular drug widely used in various neurological and psychiatric disorders. Commercially, it is a multisource-drug available in different generic equivalents. Incidents of (class II)-recalls have been repeated over the last years due to failure to consistently meet dissolution specifications. Class II recalls are known to be associated with temporary or medically reversible adverse health consequences. This study aimed to evaluate the dissolution profiles, among other quality attributes, of select FDA-approved extended-release DVS products before and after exposure to conditions usually seen as short-lived and insignificant on product stability, such as pharmacy dispensing and patients’ in-use conditions to assess their possible role in the failures observed. Products were stored for 6 weeks in pharmacy vials at 30 °C/75 % RH to simulate patient in-use conditions, for 12 weeks in unsealed HPDE bottles at 25 °C/65 % RH to simulate the pharmacy storage conditions, and for 3 days in open containers at 40 °C/75 % RH for accelerated stability studies. Physicochemical changes were detected by near infrared imaging, Fourier transformed infrared, X-ray powder diffraction and differential scanning calorimetry. All samples were analyzed for in vitro dissolution. Two products were further selected for in vivo study on Beagle dogs before and after storage. The physicochemical characterization tests revealed changes in tablets’ composition and drug crystallinity over time. An improved discriminatory dissolution test was developed and used in this study. The in vitro release testing revealed that short-lived environmental changes at 30 or 25 °C could fail some unit doses and significantly lower the drug release (average reduction among all products was 12.97 ± 11.3 % and 27.48 ± 10.26 %, respectively). Some extended-release products showed a significant increase in the amount of drug dissolved in the first 6 h (early burst) owing to changes in tablet surface morphology and enhanced drug dissolution. In vivo studies showed a decrease in the AUC0-t by overall average of 21.1 % using the non-transformed data, a decrease that mirrored the dissolution results. The study shows that significant changes can occur during routine drug dispensing and patients’ use that might variably impact the stability and quality of commercial bioequivalent unit doses. It is possible that these changes may also contribute to the adverse effects reported on DVS or upon drug switches that were previously attributed to the intersubject variability. The study findings are encouraging to further investigate the effect of such minor excursions on the drug effectiveness during products’ shelf lives especially for narrow therapeutic index drugs.

Utilization of the FTIR spectroscopic method for the quantitative determination of the narrow therapeutic index levothyroxine sodium in pharmaceutical tablets

Levothyroxine sodium is a narrow therapeutic index drug used for the treatment of hypothyroidism. The medication is marketed in tablet form with very low doses ranging from 25 to 150 µg, which requires the development of a sensitive quantitative analytical method to ensure a safe and effective pharmacological response. In the present work, a Fourier transform infrared method has been developed and validated for levothyroxine sodium determination in various pharmaceutical formulations. The proposed method involves selectively extracting levothyroxine sodium from the studied tablets using chloroform as solvent, then depositing it on a KBr pellet, followed by infrared measurements and spectra analysis. The peak band area corresponding to the C=C centered at 1409 cm-1 has been chosen for the quantification. The method has been validated according to ICH guidelines and was found to be simple, precise, accurate, and specific. The linearity, detection, and quantitation limits are 25–800, 8.121, and 24.545 µg/pellet, respectively. These values confer the method’s sensitivity and applicability for the determination of different pharmaceutical tablets with various dosages. A statistical comparison with a reference HPLC method showed no significant difference. Accordingly, the developed method can be employed for quality control testing of levothyroxine sodium due to its simplicity and the absence of sophisticated instrumentation and procedures. Graphical abstract:

COVID-19 severity gradient differentially dysregulates clinically relevant drug processing genes in nasopharyngeal swab samples.

Understanding how COVID-19 impacts the expression of clinically relevant drug metabolizing enzymes and membrane transporters (DMETs) is vital for addressing potential safety and efficacy concerns related to systemic and peripheral drug concentrations. This study investigates the impact of COVID-19 severity on DMETs expression and the underlying mechanisms to inform the design of precise clinical dosing regimens for affected patients. Transcriptomics analysis of 102 DMETs, 10 inflammatory markers, and 12 xenosensing regulatory genes was conducted on nasopharyngeal swabs from 50 SARS-CoV-2 positive (17 outpatients, 16 non-ICU, and 17 ICU) and 13 SARS-CoV-2 negative individuals, clinically tested through qPCR, in the Greater Toronto area from October 2020 to October 2021. We observed a significant differential gene expression for 42 DMETs, 6 inflammatory markers, and 9 xenosensing regulatory genes. COVID-19 severity was associated with the upregulation of AKR1C1, MGST1, and SULT1E1, and downregulation of ABCC10, CYP3A43, and SLC29A4 expressions. Altogether, SARS-CoV-2-positive patients showed an upregulation in CYP2C9, CYP2C19, AKR1C1, SULT1B1, SULT2B1, and SLCO4A1 and downregulation in FMO5, MGST3, ABCC5, and SLCO4C1 compared with SARS-CoV-2 negative individuals. These dysregulations were associated with significant changes in the expression of inflammatory and xenosensing regulatory genes driven by the disease. GSTM3, PPARA, and AKR1C1 are potential biomarkers of the observed DMETs dysregulation pattern in nasopharyngeal swabs of outpatients, non-ICU, and ICU patients, respectively. The severity of COVID-19 is associated with the dysregulation of DMETs involved in processing commonly prescribed drugs, suggesting potential disease-drug interactions, especially for narrow therapeutic index drugs.

Factors Influencing Quetiapine Pharmacokinetic Variability: A Review of Population Pharmacokinetics

Abstract: Atypical antipsychotic quetiapine (QTP) exhibits high pharmacokinetic variability and population pharmacokinetic (PopPK) analysis is one of the approaches used to characterize factors influencing QTP pharmacokinetic variability. Though QTP is not regarded as a narrow therapeutic index drug, knowledge of this area is of importance. Thus, this review was conducted to summarize significant predictors for QTP pharmacokinetic variability identified using a PopPK analysis and to explore any knowledge gaps to be investigated. PubMed, Scopus, and CINAHL Complete databases were searched for eligible studies, and 75 articles were identified. Of these, only five studies were included as they were conducted using a nonlinear mixed-effects approach. This review found that only limited predictors for QTP pharmacokinetics were identified, with body weight being a predictor for the volume of distribution and age and γ-glutamyl transpeptidase being predictors for QTP clearance. None of the studies included elderly patients aged >65 years, and thus factors associated with aging were not investigated. Also, most of the participants in the PopPK analyses were from clinical trials which might not reflect real-world patients e.g., the impacts of polypharmacy may not be available. Moreover, while a population pharmacokinetic-pharmacodynamic model explaining QTP exposure and clinical response using the scores of the Brief Psychiatric Rating Scale is available, knowledge relevant to the relationship between exposure and QTP side effects has not been explored. Based on this limited information, future PopPK research encompassing a wide range of patient characteristics is required.

Development of a rapid HPLC-fluorescence method for monitoring warfarin metabolites formation: In vitro studies for evaluating the effect of piperine on warfarin metabolism and plasma coagulation

Warfarin, a widely prescribed anticoagulant, is highly effective for various coagulation disorders. However, its efficacy is limited by a narrow therapeutic index and frequent drug interactions, especially those involving metabolism by Cytochrome P450 (CYP450) enzymes. Piperine, found in black and long pepper, possesses blood-thinning properties and has been observed to inhibit CYP3A and CYP2C enzymes linked to warfarin metabolism. This study investigated the effect of piperine on warfarin metabolism in liver microsomes using a rapid and sensitive HPLC-Fluorescence method. The use of PFP (pentafluorophenyl) column with core shell particles provided the selectivity and resolution to resolve warfarin and its 4-, 6-, 7-, and 10-hydroxy metabolites in addition to the internal standard naproxen in less than 3 min. This is the fastest analytical assay for warfarin and its major metabolites reported to date, making it ideal for metabolic studies. The applicability of the method was demonstrated by monitoring the metabolism of S-warfarin in human and rat liver microsomes, and evaluating the inhibitory effect of piperine on metabolite formation. The results showed that piperine inhibited the formation of the major metabolite, 7-hydroxywarfarin, with half-maximal inhibitory concentration (IC50) 14.2 μM and 3.2 μM in human and rat liver microsomes, respectively. Furthermore, coagulation studies in vitro using rat plasma showed that piperine does not affect prothrombin time (PT) and activated partial thromboplastin time (aPTT). This study suggested that piperine may present a potential drug interaction with warfarin at the metabolism level, but has no direct effect on the activation of the extrinsic or intrinsic coagulation cascades. Further clinical investigation is therefore required, as piperine may increase the bioavailability of warfarin, thus increasing risk of serious adverse events in patients.

A Two-Way Proposal for the Determination of Bioequivalence for Narrow Therapeutic Index Drugs in the European Union.

In the European Union, bioequivalence (BE) for narrow therapeutic index (NTI) drugs is currently demonstrated when the 90% confidence interval for the ratio of the population geometric means of the test and reference products for AUC, and in some cases for Cmax, falls within the acceptance range of 90.00% to 111.11%. However, meeting this requirement results in an increased difficulty of demonstrating BE and a need for clinical trials with larger subject sample sizes, especially for medium-to-high variability drugs. To address this challenge, a scaled average BE based on the reference product within-subject variability for narrowing the acceptance range of NTI drugs was recently proposed. However, this approach showed increased type I error (T1E), especially close to the cut-off point between the unscaled and scaled portions of the method. Based on simulations, this limitation can be overcome by predefining the protocol the path to be followed: either the fixed 90.00-111.11% acceptance range approach or the previously proposed scaled average BE approach with a slight adjustment of the one-sided significance level α to 0.042 for a 2 × 3 × 3 partial replicate design and without a lower cut-off point. This results in a mixed approach allowing to reduce the sample size whilst not inflating the T1E.

Quality by Design Considerations for Drop-on-Demand Point-of-Care Pharmaceutical Manufacturing of Precision Medicine.

Distributed and point-of-care (POC) manufacturing facilities enable an agile pharmaceutical production paradigm that can respond to localized needs, providing personalized and precision medicine. These capabilities are critical for narrow therapeutic index drugs and pediatric or geriatric dosing, among other specialized needs. Advanced additive manufacturing, three-dimensional (3D) printing, and drop-on-demand (DoD) dispensing technologies have begun to expand into pharmaceutical production. We employed a quality by design (QbD) approach to identify critical quality attributes (CQAs), critical material attributes (CMAs), and critical process parameters (CPPs) of a POC pharmaceutical manufacturing paradigm. This theoretical framework encompasses the production of active pharmaceutical ingredient (API) "inks" at a centralized facility, which are distributed to POC sites for DoD dispensing into/onto delivery vehicles (e.g., orodispersible films, capsules, single liquid dose vials). Focusing on the POC dispensing/dosing processes, QbD considerations and cause-and-effect analyses identified the dispensed API quantity and solid-state form (CQAs), as well as the nozzle diameter, system pressure channel, and number of drops dispensed (CPPs) for detailed investigation. Final assay quantification and content uniformity CQAs were measured from demonstrative levothyroxine sodium single-dose liquid vials of glycerin/water, meeting the standard acceptance values. Each POC facility is unlikely to maintain full quality control laboratory capabilities, requiring the development of appropriate atline or inline methods to ensure quality control. We developed control strategies, including atline ultraviolet-visible (UV-vis) verification of the API ink prior to dispensing, inline drop counting during dispensing, intermediate atline-dispensed volume checks, and offline batch confirmation by liquid chromatography-tandem mass spectrometry (LC-MS/MS) following production.

The Effect of Inflammatory Bowel Disease and Irritable Bowel Syndrome on Pravastatin Oral Bioavailability: In vivo and in silico evaluation using bottom-up wbPBPK modeling.

The common disorders irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) can modify the drugs' pharmacokinetics via their induced pathophysiological changes. This work aimed to investigate the impact of these two diseases on pravastatin oral bioavailability. Rat models for IBS and IBD were used to experimentally test the effects of IBS and IBD on pravastatin pharmacokinetics. Then, the observations made in rats were extrapolated to humans using a mechanistic whole-body physiologically-based pharmacokinetic (wbPBPK) model. The rat in vivo studies done herein showed that IBS and IBD decreased serum albumin (> 11% for both), decreased PRV binding in plasma, and increased pravastatin absolute oral bioavailability (0.17 and 0.53 compared to 0.01) which increased plasma, muscle, and liver exposure. However, the wbPBPK model predicted muscle concentration was much lower than the pravastatin toxicity thresholds for myotoxicity and rhabdomyolysis. Overall, IBS and IBD can significantly increase pravastatin oral bioavailability which can be due to a combination of increased pravastatin intestinal permeability and decreased pravastatin gastric degradation resulting in higher exposure. This is the first study in the literature investigating the effects of IBS and IBD on pravastatin pharmacokinetics. The high interpatient variability in pravastatin concentrations as induced by IBD and IBS can be reduced by oral administration of pravastatin using enteric-coated tablets. Such disease (IBS and IBD)-drug interaction can have more drastic consequences for narrow therapeutic index drugs prone to gastric degradation, especially for drugs with low intestinal permeability.

The bioequivalence study design recommendations for immediate-release solid oral dosage forms in the international pharmaceutical regulators programme participating regulators and organisations: differences and commonalities.

Bioequivalence (BE) studies are considered the standard for demonstrating that the performance of a generic drug product in the human body is sufficiently similar to that of its comparator product. The objective of this article is to describe the recommendations from participating Bioequivalence Working Group for Generics (BEWGG) members of the International Pharmaceutical Regulators Programme (IPRP) regarding the conduct and acceptance criteria for BE studies of immediate release solid oral dosage forms. A survey was conducted among BEWGG members regarding their BE recommendations and requirements related to study subjects, study design, sample size, single or multiple dose administration, study conditions (fasting or fed), analyte to be measured, selection of product strength, drug content, handling of endogenous substances, BE acceptance criteria, and additional design aspects. All members prefer conducting single dose cross-over designed studies in healthy subjects with a minimum of 12 subjects and utilizing the parent drug data to assess BE. However, differences emerged among the members when the drug's pharmacokinetics and pharmacodynamics become more complex, such that the study design (e.g., fasting versus fed conditions) and BE acceptance criteria (e.g., highly variable drugs, narrow therapeutic index drugs) may be affected. The survey results and discussions were shared with the ICH M13 Expert Working Group (EWG) and played an important role in identifying and analyzing gaps during the harmonization process. The draft ICH M13A guideline developed by the M13 EWG was endorsed by ICH on 20 December 2022, under Step 2.

Delivery Strategies for Colchicine as a Critical Dose Drug: Reducing Toxicity and Enhancing Efficacy.

Colchicine (COL), a widely used natural drug, has potent anti-inflammatory effects; however, as a narrow therapeutic index drug, its clinical application is limited by its serious gastrointestinal adverse effects, and only oral formulations are currently marketed worldwide. Recent studies have shown that transdermal, injection, and oral drug delivery are the three main delivery strategies for COL. This article elaborates on the research progress of different delivery strategies in terms of toxicity reduction and efficacy enhancement, depicting that the transdermal drug delivery route can avoid the first-pass effect and the traumatic pain associated with the oral and injection routes, respectively. Therefore, such a dosage form holds a significant promise that requires the development of further research to investigate effective COL delivery formulations. In addition, the permeation-promoting technologies utilized for transdermal drug delivery systems are briefly discussed. This article is expected to provide scientific ideas and theoretical guidance for future research and the exploration of COL delivery strategies.

Pregled lista i preporuka za zamenljivost lekova u izabranim evropskim zemljama

Generic substitution has been introduced in the healthcare systems of many countries to reduce the costs and ensure the continuity of drug market supply. Common and country-specific strategies on this topic have been presented for several European countries, as well as for the Republic of Serbia. The factors that need to be considered when assessing the interchangeability of medicines may be related to the medicine or the individual patient. Particular caution is required with narrow therapeutic index drugs, drugs with non-linear pharmacokinetics, antiepileptic drugs, medicines with prolonged release formulations, medicines administered in a specific way or with a medical device. Factors such as the different appearance of the medicines, excipients, packaging, indications, but also the patient's condition, age, concomitant diseases, pregnancy, hand function, vision, ability to swallow, and the patient's attitude towards the alternative medicines should also be taken into account. When substituting two generic medicines, it should be noted that those medicines may not be bioequivalent, since bioequivalence is confirmed between a generic medicine and a reference (usually original) medicine, and thus pose an additional risk to the patient's safety. Some countries have opted to form lists of interchangeable medicines and/or detailed guidelines regarding interchangeability to assist healthcare professionals in making decisions on drug substitution.

Retrospective analysis of lithium treatment: examination of blood levels.

Lithium is a key medication for treating various neuropsychiatric disorders, with a narrow therapeutic index and significant drug interactions. Monitoring lithium blood levels is crucial. This study aims to investigate the relationship between lithium blood levels and demographic characteristics such as age and gender, as well as possible drug interactions, in patients with a history of lithium use who applied to various services and outpatient clinics. The files of 438 patients who were admitted to various services and outpatient clinics of Kırklareli Training and Research Hospital between January 1 and December 31, 2023, were retrospectively reviewed. Patients' blood lithium levels, gender, age, service/outpatient clinic they admitted to, other medications used, urea, creatinine, and eGFR values were recorded. When the demographic characteristics of 438 patients were examined, 62% were female (270), 38% were male (168), and the average age was 46.3 ± 14.8 years, showing a normal distribution. It was found that 192 patients (71 males, 121 females) had therapeutic lithium blood levels, while 244 patients (97 males, 147 females) had levels below 0.6 mmol/L. Two female patients had blood levels above the therapeutic range (1.23 and 1.43 mmol/L). Among the clinics and services, the four most frequented were the psychiatry clinic (314 patients), internal medicine clinic (36 patients), emergency service (27 patients), and medical oncology clinic (17 patients). Of the 314 patients admitted to the psychiatry clinic, 168 had therapeutic drug levels; only 7 of the 36 admitted to internal medicine had therapeutic levels; 12 of the 27 patients in the emergency service had therapeutic levels; and all 17 patients in medical oncology had levels below therapeutic limits. The data emphasize the importance of regular blood level monitoring to ensure lithium treatment's efficacy and patient safety. It is noteworthy that most patients in the psychiatry clinic had therapeutic drug levels, while those in other clinics had lower levels. In conclusion, this study highlights the importance of regular blood level monitoring to ensure the efficacy and safety of lithium treatment.

Generic orphan drug substitution: a critical analysis of global practices and Saudi Arabia's perspective.

In an era of cost pressure, substituting generic drugs represents one of the main cost-containment strategies of healthcare systems. Despite the obvious financial benefits, in a minority of cases, substitution may require caution or even be contraindicated. In most jurisdictions, to obtain approval, the bioequivalence of generic products with the brand-name equivalent needs to be shown via bioavailability studies in healthy subjects. Rare diseases, defined as medical conditions with a low prevalence, are a group of heterogenous diseases that are typically severe, disabling, progressive, degenerative, and life-threatening or chronically debilitating, and disproportionally affect the very young and elderly. Despite these unique features of rare diseases, generic bioequivalence studies are typically carried out with single doses and exclude children or the elderly. Furthermore, the excipients and manufacturing processes for generic/biosimilar products can differ from the brand products which may affect the shelf-life of the product, its appearance, smell, taste, bioavailability, safety and potency. This may result in approval of generics/biosimilars which are not bioequivalent/comparable in their target population or that meet bioequivalence but not therapeutic equivalence criteria. Another concern relates to the interchangeability of generics and biosimilars which cannot be guaranteed due to the phenomenon of biocreep. This review summarizes potential concerns with generic substitution of orphan drugs and discusses potentially problematic cases including narrow therapeutic index drugs or critical conditions where therapeutic failure could lead to serious complications or even death. Finally, we put forward the need for refining regulatory frameworks, with emphasis on Saudi Arabia, for generic substitution and recent efforts toward this direction.

Novel application of PBBM to justify impact of faster dissolution on safety and pharmacokinetics – a case study and utility in regulatory justifications

Physiologically based biopharmaceutics modelling (PBBM) was recognised as potential approach for biopharmaceutics applications. However, PBBM to justify safety is an unexplored area. In this manuscript, we elucidated PBBM application for safety justification. Product DRL is a generic extended release tablet containing an anti-epileptic narrow therapeutic index (NTI) drug. During dossier review, regulatory agency requested to evaluate the impact of faster dissolution profiles observed during stability on safety aspects. In order to justify, PBBMbased strategy was adapted. Model was validated and population simulations were performed for reference and test formulations and the predictions matched with clinical outcome. The model was found to be sensitive to dissolution changes and hence applied for the prediction of stability batches exhibiting faster dissolution profiles, virtually generated profiles at lower and upper specifications. The maximum predicted plasma levels were well below the reported safety levels, thereby demonstrating safety of the product. Overall, a novel application of PBBM to justify safety was demonstrated. Similar justifications using PBBM and linking with safety can be adopted where safety can be impacted due to aggravated dissolution profiles. Such justifications have potential to avoid clinical safety studies and helps in faster approval of drug product.

Herb-drug interaction: Effect of sinapic acid on the pharmacokinetics of dasatinib in rats

Dasatinib (DAS) is a narrow therapeutic index drug and novel oral multitarget inhibitor of tyrosine kinase and approved for the first-line therapy for chronic myelogenous leukemia (CML) and Philadelphia chromosome (Ph + ) acute lymphoblastic leukemia (ALL). DAS, a known potent substrate of cytochrome (CYP) 3A, P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) and is subject to auto-induction. The dietary supplementation of sinapic acid (SA) or concomitant use of SA containing herbs/foods may alter the pharmacokinetics as well as pharmacodynamics of DAS, that may probably lead to potential interactions. Protein expression in rat hepatic and intestinal tissues, as well as the in vivo pharmacokinetics of DAS and the roles of CYP3 A2 and drug transporters Pgp-MDR1 and BCPR/ABCG2, suggested a likely interaction mechanism. The single dose of DAS (25 mg/kg) was given orally to rats with or without SA pretreatment (20 mg/kg p.o. per day for 7 days, n = 6). The plasma concentration of DAS was estimated by using Ultra-High-Performance Liquid Chromatography Mass spectrometry (UHPLC-MS/MS). The in vivo pharmacokinetics and protein expression study demonstrate that SA pretreatment has potential to alter the DAS pharmacokinetics. The increase in Cmax, AUC and AUMC proposes increase in bioavailability and rate of absorption via modulation of CYP3 A2, PgP-MDR1 and BCPR/ABCG2 protein expression. Thus, the concomitant use of SA alone or with DAS may cause serious life-threatening drug interactions.

B-301 In-vivo Continuous Therapeutic Drug Monitoring With Electrochemical Aptamer-based Sensors

Abstract Therapeutic drug monitoring (TDM) is a clinical practice involving quantification of plasma drug concentrations to adjust treatment efficacy and minimize toxicity in patient care. TDM is relevant for drugs with a narrow therapeutic index, defined as the plasma concentration range over which a molecule is therapeutically effective without causing significant adverse effects. For narrow therapeutic index drugs, indirect predictors of a patient’s metabolism, such as age, body mass, or genotype, are insufficient to ensure effective dosing, and metabolic variability across different individuals needs to be considered. The importance of TDM is illustrated by the difficulty in treating a patient with vancomycin, an essential antibiotic used to combat gram-positive bacterial infections. The practice typically involves determining trough concentration, peak concentration, or exposure to the vancomycin area under the curve, necessitating blood sampling. After sampling, the current practices require patient blood to be sent to a laboratory, which can only provide an answer from hours after sample collection. Electrochemical aptamer-based (E-AB) sensors provide significant opportunities to make TDM a practice as frequent and convenient as the measurement of blood sugar has become for people with diabetes. This is because E-AB sensing is a molecular approach to continuously measuring concentrations of specific molecules. We present the selection of an aptamer against vancomycin and its adaptation into an E-AB sensor. Using this sensor, we then demonstrate the opportunities for rapid (seconds) measurement of plasma vancomycin and the real-time measurement of subject-specific vancomycin pharmacokinetics on rats (Fig. 1) [3]. Such capability provides a route toward improving TDM and the personalized delivery of pharmacological interventions.Fig. 1.Real-time continuous monitoring of subject-specific vancomycin pharmacokinetics with electrochemical aptamer-based sensors. Reprinted with permission from the American Chemical Society.

Predicting bioequivalence and developing dissolution bioequivalence safe space in vitro for warfarin using a Physiologically-Based pharmacokinetic absorption model

ObjectiveBioequivalence (BE) studies support the approval and clinical use of both new and generic drug products. Narrow therapeutic index (NTI) drugs have relatively high costs and low success rates of BE evaluation clinical trials as high-risk drugs. A physiologically-based pharmacokinetic (PBPK) model can be used to evaluate the BE of two preparations. MethodsThis study inputs the basic physical and chemical property parameters of warfarin sodium available at the present stage into GastroPlus™ software, and combined it with the Advanced Compartmental Absorption and Transit (ACAT™) model built into the software. The PBPK model of Chinese individuals taking 2.5 mg of warfarin sodium orally while fasted condition was developed using the disposal parameters calculated from the clinically measured PK data of the reference preparations. The model was tested using the PK data of other reference preparations and tested preparations from different domestic manufacturers. ResultsThe results revealed that at least 30% of drugs are released in 30 min under a pH of 4.5 condition, and at least 80% are released in 30 min under a pH of 6.8 condition, which can be used as bioequivalent dissolution limits under fasted conditions. The risk of BE failure in the fed condition will be significantly reduced for the clinical study on the BE of warfarin sodium, which is a NTI drug if the fasted condition is bioequivalent. ConclusionThe results revealed that the PBPK models were successfully developed for 2.5 mg of warfarin sodium tablets in Chinese individuals. Developing a PBPK model for NTI drugs based on in vitro dissolution data in software is a promising method for BE evaluation, which can provide great help for developing new drugs and the clinical trial research of BE of generic drugs.

Assessment of drug-related problems associated with narrow therapeutic index drugs: A prospective cohort study

Background A narrow therapeutic index drug (NTID) has a narrow window between its effective doses and doses that can cause adverse toxic effects, necessitating strict monitoring for drug safety. This study aimed to identify and classify the drug-related problems (DRPs) associated with the use of NTI drugs. Method A prospective cohort study was carried out in the in-patient departments of General Medicine, Paediatrics, Cardiology, and Neurology at a tertiary care hospital over a nine-month period. Patients of either gender receiving at least one NTID included after obtaining their consent. The patients were followed until their discharge for any DRP occurrence. The list of the NTIDs was compiled through a review of literature review and the hospital's formulary. Hepler & Strand's classification was adopted to classify the identified DRPs. The odds ratio with a 95% confidence interval was used to determine the predictors for DRP occurrence. Results A total of 241 DRPs associated with NTIDs were identified among 120 patients. Drug–drug interactions accounted for 61% of the DRPs, followed by subtherapeutic dosing (18.26%) and adverse drug reactions (9.96%). On average, each patient experienced 2.74 DRPs. The predictors for DRP occurrence included gender (odds ratio [OR] 2.65, p = .012), comorbid conditions (OR 2.947, p < .001), polypharmacy involving more than 11 drugs (OR 3.987, p < .033), and a hospital stay exceeding 7 days (OR 1.087, p = .022). Conclusion Despite providing the best therapeutic care, DRPs associated with NTIDs persist and can compromise patient safety. Therefore, involving clinical pharmacists in the early detection of DRPs can enhance overall patient safety.

Review: Failure of current digoxin monitoring for toxicity: new monitoring recommendations to maintain therapeutic levels for efficacy.

The current recommendations for monitoring digoxin, a narrow therapeutic index drug, are limited to confirming medication use or investigating suspicion of toxicity and fail our oath to do no harm. Numerous meta-analyses evaluating digoxin use consistently recommend frequent monitoring to maintain the level of 0.5 to ≤1.0 ng/ml because higher levels lead to increased morbidity and mortality without benefit. Data from the United States National Poison Control Center (2012-2020) show annual deaths due to digoxin of 18-36 compared to lithium's 1-7, and warfarin's 0-2 respectively. The latter drugs also have narrow therapeutic indexes like digoxin yet are more carefully monitored. Recognition of digoxin toxicity is impaired as levels are not being routinely checked after medications are added to a patient's regimen. In addition, providers may be using ranges to guide treatment that are no longer appropriate. It is imperative that monitoring guidelines and laboratory therapeutic levels are revised to reduce morbidity and mortality due to digoxin. In this review, we provide a comprehensive literature review of digoxin monitoring guidelines, digoxin toxicity, and evidence to support revising the ranges for serum digoxin monitoring.

Rational Therapeutic Approaches for the Management of Congestive Cardiac Failure

Background: Heart failure is a serious and progressive condition where the heart's ventricle fails to pump sufficient blood to the body's tissues. Flaws in the rationality of medication use, particularly with narrow therapeutic index drugs like digoxin, have been observed. These include multiple drug-drug interactions, polypharmacy, and therapeutic duplication. Pharmacists play a crucial role in minimizing medication errors through dose adjustments, patient counseling, and ensuring proper administration. Aims and Objectives: The objective of this project was to assess the appropriateness of recommended pharmacotherapies and their implementation in a clinical setting, focusing on drug-drug interactions, polypharmacy, contraindications, and untreated conditions. Study Design: For this study, a specialized questionnaire-based approach was used to gather data on congestive heart failure (CHF) patients. The collected information included patient demographics (name, gender, and age), chief complaints, co-morbidities, past medical and medication history, biochemical tests, diagnosis, social history, allergies, family history, and past surgeries. Materials and Methods: From a collection of 20 patient histories, it was observed that the majority of cases involved congestive heart failure (43.57%), followed by left ventricular dysfunction (30.35%), myocardial infarction (17.23%), and atrial fibrillation (8.71%) as the primary causes of hospitalization. Among the patients, co-morbidities such as diabetes mellitus (31.71%) and hypertension (25.23%) were prevalent. The collected data was regularly examined and analyzed. Results were evaluated based on ±SD (Standard). Results and Conclusion: In this study, 60 drugs were identified as contraindicated for patients, and some drugs required monitoring due to their profiles. Among the identified drug-related errors, 56.66% were attributed to drug interactions, often resulting from the simultaneous prescription of two interacting drugs. The incidence of polypharmacy was found to be 8.88%. Narrow therapeutic index drugs accounted for 5.55% of the medications, which were not adequately monitored. The analysis revealed that 33.35% and 25.80% of patients had diabetes and hypertension, respectively, in addition to heart failure. Heart failure was most commonly observed in individuals aged 51-60 years. The study highlighted several irrationalities in prescription practices, including inadequate dose adjustment for patients with chronic renal failure, polypharmacy, drug duplication, adverse drug reactions, cost-related issues, unavailability of therapeutic alternatives, and lack of monitoring for narrow therapeutic index medications.