Narrow Therapeutic Index Drugs Research Articles

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.

Validated ion exchange HPLC method for the quantification of levothyroxine – a narrow therapeutic index drug – used for the treatment of hypothyroidism

Drugs with narrow therapeutic index (NTI-drugs) have been defined by the FDA as drugs with small differences between therapeutic and toxic doses that might lead to serious therapeutic failures or life-threatening adverse drug reactions. Levothyroxine sodium pentahydrate (LT4), a synthetic T4 hormone used for the treatment of hypothyroidism (a condition where there is a hormonal imbalance in the thyroid gland that is responsible for the regulation of several physiological, metabolic, cardiovascular, and neurological processes). LT4 is designated by the FDA as a narrow therapeutic index drug and is available in the market in the form of very low dose pharmaceutical formulations ranging from 25 mcg to 150 mcg. This requires that the pharmaceutical dosage form should contain the exact labeled amount of the active ingredient, LT4, such that safety and efficacy are maintained. Therefore, it is necessary to develop an a precise, accurate and sensitive analytical method for LT4 quantification considering the treatment doses being in micrograms. In the present work, an ion exchange HPLC method has been developed and validated for the determination of LT4 as per ICH guidelines. The developed method was found to be simple, sepcific, precise and accurate. The low LOD and LOQ values allowed the quantitfication of the active ingredient in different pharmaceutical products qualifying the method to be applied in quality control assays.

Physiologically based pharmacokinetic modeling of tacrolimus for food-drug and CYP3A drug-drug-gene interaction predictions.

The immunosuppressant and narrow therapeutic index drug tacrolimus is metabolized mainly via cytochrome P450 (CYP) 3A4 and CYP3A5. For its pharmacokinetics (PK), high inter- and intra-individual variability can be observed. Underlying causes include the effect of food intake on tacrolimus absorption as well as genetic polymorphism in the CYP3A5 gene. Furthermore, tacrolimus is highly susceptible to drug-drug interactions, acting as a victim drug when coadministered with CYP3A perpetrators. This work describes the development of a whole-body physiologically based pharmacokinetic model for tacrolimus as well as its application for investigation and prediction of (i) the impact of food intake on tacrolimus PK (food-drug interactions [FDIs]) and (ii) drug-drug(-gene) interactions (DD[G]Is) involving the CYP3A perpetrator drugs voriconazole, itraconazole, and rifampicin. The model was built in PK-Sim® Version 10 using a total of 37 whole blood concentration-time profiles of tacrolimus (training and test) compiled from 911 healthy individuals covering the administration of tacrolimus as intravenous infusions as well as immediate-release and extended-release capsules. Metabolism was incorporated via CYP3A4 and CYP3A5, with varying activities implemented for different CYP3A5 genotypes and study populations. The good predictive model performance is demonstrated for the examined food effect studies with 6/6 predicted FDI area under the curve determined between first and last concentration measurements (AUClast ) and 6/6 predicted FDI maximum whole blood concentration (Cmax ) ratios within twofold of the respective observed ratios. In addition, 7/7 predicted DD(G)I AUClast and 6/7 predicted DD(G)I Cmax ratios were within twofold of their observed values. Potential applications of the final model include model-informed drug discovery and development or the support of model-informed precision dosing.

Effects of Apigenin on Pharmacokinetics of Dasatinib and Probable Interaction Mechanism.

Dasatinib (DAS), a narrow-therapeutic index drug, Bcr-Abl, and Src family kinases multitarget inhibitor have been approved for chronic myelogenous leukemia (CML) and Ph-positive acute lymphocytic leukemia (Ph+ ALL). Apigenin (APG) has a long history of human usage in food, herbs, health supplements, and traditional medicine, and it poses low risk of damage. The concomitant use of APG containing herbs/foods and traditional medicine may alter the pharmacokinetics of DAS, that probably lead to possible herb-drug interactions. The pharmacokinetic interaction of APG pretreatment with DAS in rat plasma following single and co-oral dosing was successfully deliberated using the UPLC-MS/MS method. The in vivo pharmacokinetics and protein expression of CYP3A2, Pgp-MDR1, and BCPR/ABCG2 demonstrate that APG pretreatment has potential to drastically changed the DAS pharmacokinetics where escalation in the Cmax, AUC(0-t), AUMC(0-inf_obs), T1/2, Tmax, and MRT and reduction in Kel, Vd, and Cl significantly in rats pretreated with APG 40 mg/kg, thus escalating systemic bioavailability and increasing the rate of absorption via modulation of CYP3A2, Pgp-MDR1, and BCPR/ABCG2 protein expression. Therefore, the concomitant consumption of APG containing food or traditional herb with DAS may cause serious life-threatening drug interactions and more systematic clinical study on herb-drug interactions is required, as well as adequate regulation in herbal safety and efficacy.

Anticoagulation Management in Patients Receiving Warfarin at Private Cardiac Centers in Addis Ababa, Ethiopia.

Anticoagulants are the cornerstone therapy for thromboembolism prevention and treatment. Warfarin is the frequently prescribed drug and remains the oral anticoagulant of choice in low- and middle-income countries, including Ethiopia. It is a narrow therapeutic index drug that needs high-quality anticoagulation monitoring with frequent international normalization ratio (INR) testing. The study aimed to assess anticoagulation management with warfarin among adult outpatients at two selected private cardiac centers in Addis Ababa, Ethiopia. A hospital-based retrospective study design that enrolled 374 patients receiving warfarin was employed at two private cardiac centres in Addis Ababa, Ethiopia. The time in the therapeutic range (TTR) was calculated using the Rosendaal method. The data were analyzed using Statistical Package for Social Science version 25. The mean age of the patients was 57 years, and 218 (58.3%) participants were females. Out of 3384 INR tests, 1562 (46.5%) were within the therapeutic range and the mean percentage of TTR was 47.24%. Only 25.67% of the patients spent their TTR ≥ 65%. The present study revealed that dose adjustments were required 1764 times. In non-therapeutic INR values of 1764 that required warfarin dose adjustment, 59.7% of the doses were adjusted. About 262 (70.1%) of co-prescribed medications had interaction with warfarin. Sixty-four patients (17.11%) experienced bleeding events. Anticoagulation management with warfarin was suboptimal in private cardiac Addis Ababa, Ethiopia, private cardiac centers. Warfarin adjustment practice for nontherapeutic INR values was not minimal, and many patients encountered bleeding during their course of therapy.

Warfarin-Induced Limb Contusion Section and Haematoma

Warfarin is a narrow therapeutic index drug with high potential to cause adverse effects. It is generally a preferred drug for the management of venous thrombosis. This case is an unusual presentation of left arm contusion and limb haematoma secondary to long-term warfarin use. A 32-year-old male patient was admitted with the complaints of left lower limb oedema and left upper arm oedema. He was on warfarin for dural sinus thrombosis for two years. The integrative analysis of patient clinical presentation, medication history, International Normalized Ratio (INR) level, Ultrasonography (USG) scan and Naranjo assessment showed the probable case of warfarin-induced left arm contusion and limb haematoma. The patient was successively managed with the administration of vitamin K, injection heparin, packed red blood cell and other supportive therapy after the withdrawal of the culprit drug. Thus, patients prescribed with warfarin should be looked at for this typical adverse event. Monitoring of anticoagulant therapy is vital for the positive clinical outcome and minimisation of adverse events. Clinical pharmacists have a key role to play in the patient safety and their inputs can fertilise the concept of pharmacist led anticoagulation clinic in India.

Releasing fast and slow: Non-destructive prediction of density and drug release from SLS 3D printed tablets using NIR spectroscopy

Selective laser sintering (SLS) 3D printing is a revolutionary 3D printing technology that has been found capable of creating drug products with varied release profiles by changing the laser scanning speed. Here, SLS 3D printed formulations (printlets) loaded with a narrow therapeutic index drug (theophylline) were produced using SLS 3D printing at varying laser scanning speeds (100–180 mm/s). The use of reflectance Fourier Transform – Near Infrared (FT-NIR) spectroscopy was evaluated as a non-destructive approach to predicting 3D printed tablet density and drug release at 2 h and 4 h. The printed drug products formulated with a higher laser speed exhibited an accelerated drug release and reduced density compared with the slower laser scanning speeds. Univariate calibration models were developed based on a baseline shift in the spectra in the third overtone region upon changing physical properties. For density prediction, the developed univariate model had high linearity (R2 value = 0.9335) and accuracy (error < 0.029 mg/mm3). For drug release prediction at 2 h and 4 h, the developed univariate models demonstrated a linear correlation (R2 values of 0.9383 and 0.9167, respectively) and accuracy (error < 4.4%). The predicted vs. actual dissolution profiles were found to be statistically similar (f2 > 50) for all of the test printlets. Overall, this article demonstrates the feasibility of SLS 3D printing to produce drug products containing a narrow therapeutic index drug across a range of drug release profiles, as well as the potential for FT-NIR spectroscopy to predict the physical characteristics of SLS 3D printed drug products (drug release and density) as a non-destructive quality control method at the point-of-care.

188: PHARMACOKINETIC ANALYSIS OF ANTIMICROBIAL THERAPY IN VENTRICULAR ASSIST DEVICE-SUPPORTED PATIENTS

Introduction: As a result of underlying heart failure, the utilization of left ventricular assist devices (VAD) has increased as a means of offloading the failing ventricle to improve cardiac output. Importantly, after device implantation and once end-organ perfusion has been enhanced, new pharmacokinetic alterations may acutely develop which may require pre-emptive dose adjustments for several pharmacotherapies. Currently, there are limited data in patients with VADs to determine patient and population-specific antimicrobial disposition. The purpose of this study is to assess perioperative pharmacokinetic changes in patients during VAD implantation receiving prophylactic antibiotics. Methods: Patients will be prospectively enrolled to collect blood samples peri-operatively and post-operatively. Blood samples will be used to analyze the antimicrobial concentrations using a validated high-performance liquid chromatography (HPLC-UV) assay. Results: To date, 11 patients have been enrolled in this study. Enrollees are on average 63 years of age, predominately male (82%), with nonischemic cardiomyopathy (64%). LVAD implantation consisted of HeartMate3 (n=9), and HVAD devices (n=2). Standard prophylactic regimens for LVAD implantation include ceftazidime and vancomycin. Intra-operatively, all patients received one prophylactic dose of ceftazidime 2 grams from which samples were collected thereafter. The median samples collected intra-operatively was 4 (IQR 3,6). Post-operatively, ceftazidime prophylaxis was continued for 36 hours, and samples were typically collected after the third ceftazidime dose. The median samples collected post-operatively was 4 (IQR 4,5). Antimicrobial plasma concentrations are currently pending processing and analysis. The drug concentration in the serum will be analyzed to determine the maximum concentration, area under the concentration-time profile for the dosing interval, half-life, clearance, and volume of distribution. Conclusions: In this medically complex heart failure patient population, use of narrow therapeutic index drugs can have detrimental consequences if they are not dosed appropriately. This study will provide practitioners more insight in perioperative dosing regimens for VAD patients by understanding how serum drug levels may be altered with VAD therapy.

Evaluation of a Proposed Approach for the Determination of the Bioequivalence Acceptance Range for Narrow Therapeutic Index Drugs in the European Union.

Bioequivalence (BE) of products containing narrow therapeutic index (NTI) drugs in the European Union is currently established by demonstrating that the 90% confidence interval for the ratio of the population geometric means of the test compared to the reference product’s AUC, and in certain cases Cmax, is included within the tighter acceptance range of 90.00−111.11%. An alternative criterion, consisting of narrowed limits based on the within-subject variability of the reference product, was recently proposed. Its performance for a three-period partial replicate design was tested by simulation in terms of power to show BE, type I error (T1E) and sample size requirements. A new condition, a constraint on the test-to-reference geometric mean ratio (cGMR) to be contained within the range of 90.00−111.11%, was also tested. The probability of showing BE when the products differ more than 10% was increased, but only if the reference product’s within-subject variability was moderate-to-high. The inclusion of the additional cGMR limited this. An increase in the T1E (<7%) was observed. The inclusion of the additional cGMR did not change the highest inflation of the T1E. Finally, a significant sample size reduction was observed and the inclusion of the cGMR usually did not increase the required sample size.

Stability of levothyroxine tablets in blister packaging versus bottles and vials under simulated in-use conditions

IntroductionLevothyroxine, the standard-of-care treatment for hypothyroidism, is susceptible to degradation when exposed to light and moisture and is an FDA-designated narrow therapeutic index drug. In this report, we examined how different packaging (e.g., cold form blister packs, manufacturer’s bottles, or pharmacy amber vials) affects the physicochemical integrity and potency of levothyroxine in conditions simulating real-world patient use.MethodsIn part 1 of this study, we evaluated changes in the physicochemical properties (e.g., moisture gain, hardness, and disintegration time) of levothyroxine tablets stored in high-density polyethylene (HDPE) bottles, amber vials, and blister packs when exposed intermittently to different relative humidities (RH), 25 °C/75% RH and 25 °C/90% RH for 90 days, or 54 °C/75% RH continuously for 2 days. In part 2 of the study, we compared the potency of levothyroxine tablets in bottles and aluminum/aluminum cold form blister packs exposed to 28 °C/65% RH intermittently over 105 days and continuously over 30 days.ResultsMoisture content, hardness, and disintegration time were relatively unchanged for blister-packaged levothyroxine tablets under all conditions studied. Conversely, the physicochemical properties of tablets stored in amber vials and bottles were altered over time. Levothyroxine potency remained relatively consistent for blister-packaged tablets (100.8% at baseline, 99.6% at day 105) and decreased for bottled levothyroxine (101.4% at baseline to 93.9% at day 105).ConclusionLevothyroxine packaging can influence tablet integrity. Blister packages preserved physicochemical properties and potency better than bulk bottles. Additional studies are needed to determine the impact of packaging and changes in tablet integrity on patient outcomes.

NIR Spectroscopy as an Online PAT Tool for a Narrow Therapeutic Index Drug: Toward a Platform Approach Across Lab and Pilot Scales for Development of a Powder Blending Monitoring Method and Endpoint Determination.

An online near-infrared (NIR) spectroscopy platform system for real-time powder blending monitoring and blend endpoint determination was tested for a phenytoin sodium formulation. The study utilized robust experimental design and multiple sensors to investigate multivariate data acquisition, model development, and model scale-up from lab to manufacturing. The impact of the selection of various blend endpoint algorithms on predicted blend endpoint (i.e., mixing time) was explored. Spectral data collected at two process scales using two NIR spectrometers was incorporated in a single (global) calibration model. Unique endpoints were obtained with different algorithms based on standard deviation, average, and distributions of concentration prediction for major components of the formulation. Control over phenytoin sodium's distribution was considered critical due to its narrow therapeutic index nature. It was found that algorithms sensitive to deviation from target concentration offered the simplest interpretation and consistent trends. In contrast, algorithms sensitive to global homogeneity of active and excipients yielded the longest mixing time to achieve blending endpoint. However, they were potentially more sensitive to subtle uniformity variations. Qualitative algorithms using principal component analysis (PCA) of spectral data yielded the prediction of shortest mixing time for blending endpoint. The hybrid approach of combining NIR data from different scales presents several advantages. It enables simplifying the chemometrics model building process and reduces the cost of model building compared to the approach of using data solely from commercial scale. Success of such a hybrid approach depends on the spectroscopic variability captured at different scales and their relative contributions in the final NIR model.

Interchangeability between Generic and Reference Products: Limits of Average Bioequivalence Methodology.

Marketing authorisation of generic drugs is based on a demonstration of the "average" bioequivalence (ABE), with acceptance limits of 0.8-1.25 for the 90% confidence interval (CI) of the ratio (generic versus reference) of geometric means of exposure (whole blood, serum or plasma drug concentration). However, when interchangeability of reference by one generic is considered during treatment of a given patient, such methodology cannot guarantee the lack of therapeutic impact especially for drugs with narrow therapeutic index. This review article describes the basis and limits of ABE methodology, and the adaptations that have been proposed by regulatory agencies. For highly variable drugs, given their large therapeutic margin, regulatory agencies even allow widening of the bioequivalence acceptance limits. For drugs with a narrow therapeutic index, the average bioequivalence methodology has been amended differently by regulatory agencies. The European Medicine Agency only requires the narrowing of the ABE acceptance limits to the 0.9-1.10 range. The US Food and Drug Administration (FDA) has proposed to narrow the ABE acceptance limits according to the reference within-subject variance. The FDA requires a fully replicate cross-over study (with four periods) which allows one to compare the within-subject variance between generic and reference drug, and to detect any subject-by-formulation interaction. Indeed, any within-subject variance difference or subject by formulation interactionis an obstacle to interchangeability at the individual level. These amendments for the ABE do not fundamentally change the fact that individual ratios of exposure (generic/reference) will vary to a larger extent than the ratio of their means. For these reasons, since true individual bioequivalence studies cannot be performed for practical reasons and statistical issues, one can suggest that, in addition to the usual average bioequivalence criteria, the limits of the 95% confidence interval of the individual generic/reference exposure ratios could be used to allow interchangeability during treatment (at least for narrow therapeutic index drugs). Limit values of such CI for interchangeability acceptance should be scaled to the therapeutic margin of the reference drug. Regulatory agencies could conduct calculations based on real datasets of bioequivalence studies to determine if such criteria could be acceptable to allow interchangeability.

Effect of Oral Administration of Valerian Extract at Different Doses on Pharmacokinetic Parameters of Carbamazepine in Rabbits

Carbamazepine (CBZ) is a narrow therapeutic index drug used in the treatment of trigeminal neuralgia and psychiatric disorders. Valerian (VAL) is a popular herbal product which should be prescribed to treat insomnia and anxiety. The study was designed to investigate the presence of significant pharmacokinetic (PK) interaction between Valerian (VAL) at different concentrations on Carbamazepine (CBZ) pharmacokinetic parameters in healthy male rabbits. In an in vivo, parallel-randomized controlled trial, the rabbits in three groups "first (control), second and third" were given oral doses of CBZ (50 mg/kg), for "second and third" groups (as test groups) rabbits were given (20 and 40 mg/kg/day) of the VAL respectively, as suspension in normal saline for eight consecutive days. On the eighth day, CBZ was co-administered an hour after adding the last dose of VAL suspension. Venous blood samples (1.0-1.5 mL) were obtained from rabbits' ears' marginal vein at predetermined different periods. The plasma of this blood separation was done using centrifugation and stored at -80°C, prior to analysis by using CBZ chemiluminescent enzyme immunoassay detection kit. Different PK parameters such as Cmax, tmax, t½, ke, AUC0-24 and AUC0-∞ were determined for the three groups, applying Statistical testing (ANOVA). The results showed statistical insignificant differences for all PK parameters among the three groups with (p˃0.05). The findings showed that VAL at both concentrations is not likely to interfere with PK parameters related to CBZ, Further confirmation in humans shoud be done before these findings are applied to patient care.

Tacrolimus dose adjustment is not necessary in dose to dose conversion from a twice daily to a prolonged release once daily dose form

Twice daily TAC (BID TAC) and prolonged released once daily dose tacrolimus (OD TAC) have different pharmacokinetic (PK) profiles in kidney transplant (KT) recipients. Precise dose adjustment recommendations when converting from BID TAC to OD TAC remain inconclusive. A single center, PK study was conducted in stable KT recipients taking constant doses of TAC, mycophenolic acid, and prednisolone. The area under the concentration–time curve (AUC) 0–24 and Ctrough were measured before and 4 weeks after 1:1 conversion from BID TAC to OD TAC without subsequent dose adjustment. A 90% confidence interval (CI) of geometric mean ratio (GMR) of OD TAC/BID TAC within the range of 0.9–1.11 was utilized to indicate equivalence of the narrow therapeutic index drugs. The roles of CYP3A5 genotypic polymorphism on PK parameters were also assessed. There were 20 patients with median time since transplantation of 18 months. The mean of CKD-EPI eGFR was 60.7 ± 16.43 mL/min/1.73 m2. The median total daily TAC dose of 0.058 mg/kg/day. The geometric means (%CV) of AUC0-24 of OD and BID TAC were 205.16 (36.4%) and 210.3 (32.5%) ng/mL × h, respectively, with a GMR of 0.98 (90%CI 0.91–1.04). The geometric means (%CV) of Ctrough of OD TAC and BID TAC were 5.43 (33.1%) and 6.09 (34.6%) ng/mL, respectively. The GMR of Ctrough was 0.89 (90%CI 0.82–0.98), which was below 0.9. The newly calculated target Ctrough level of OD TAC was 4.8–6.2 ng/mL. The best abbreviated AUC0-24 was AUC = 0.97(C0) + 5.79(C6) + 18.97(C12) − 4.26. The GMR AUC0-24 was within the range of 0.9–1.11 irrespective of CYP3A5 genotypic polymorphism while the GMR of Ctrough was below 0.9 only in the CYP3A5 expressor patients. The 1:1 conversion from BID TAC to OD TAC without subsequent dose adjustment provided similar AUC0-24 regardless of CYP3A5 genotypic polymorphism. However, the Ctrough was lower in the CYP3A5 expressor group. Therefore, it is not necessary to routinely increase the OD TAC dose after conversion.Trial registration: Thai Clinical Trials Registry (TCTR20210715002).

Managing Potential Drug Interactions of Nirmatrelvir/Ritonavir in COVID-19 Patients: A Perspective from an Israeli Cross-Sector Collaboration.

Managing Potential Drug Interactions of Nirmatrelvir/Ritonavir in COVID-19 Patients: A Perspective from an Israeli Cross-Sector Collaboration.

Therapeutic Basis of Generic Substitution of Antiseizure Medications.

More than thirty antiseizure medications (ASMs) are available for treating epilepsy. ASMs differ in their potency and efficacy in controlling seizures by acting on diverse targets in the brain, often with variable pharmacokinetics. Moreover, nearly 30% of people with epilepsy have drug-resistant or intractable seizures. Generic substitution of ASMs is a complex issue. It is thought that frequent generic substitution in people with epilepsy may cause problems because the U.S. Food and Drug Administration (FDA) rules allow too much variability across products. The standard bioequivalence range (80% to 125%) appears too broad for many ASMs, especially those exhibiting little separation between therapeutic and toxic levels. Hence, sub-therapeutic concentration may lead to therapeutic failure with seizure recurrence, which could be life threatening. A supra-therapeutic level could result in adverse effects or compliance issues. There are reported issues with generic substitutions of phenytoin, topiramate, levetiracetam, carbamazepine, and lamotrigine. There is discussion in the epilepsy community about additional guidelines, including designation of generic ASMs as Narrow Therapeutic Index (NTI) drugs and how patient education plays a role in generic substitution. Overall, based on the published evidence on specific generic ASMs, FDA bioequivalence standards are not the cause of problems with generic ASM substitution. Rather, it is imperative that physicians and pharmacists provide adequate patient education on what to expect when switching to generic ASMs, including changes in medication shape and color. Another suggestion would be to consider that all ASMs be considered for inclusion in NTI class to prevent the clinical outcome issues associated with generic ASM switching. SIGNIFICANCE STATEMENT: There are critical aspects to consider when switching from a brand name antiseizure medication (ASM) when a generic becomes available or switching between generics. Generic ASMs are interchanged with little consideration of differences in therapeutic equivalence and other clinical factors. This article describes key issues on generic substitution of ASMs and highlights critical pharmacotherapeutic issues associated with generic ASMs.

Nano optical and electrochemical sensors and biosensors for detection of narrow therapeutic index drugs.

Forthe first time, a comprehensive review is presented on the quantitative determination of narrow therapeutic index drugs (NTIDs) by nano optical and electrochemical sensors and biosensors. NTIDs have a narrow index between their effective doses and those at which they produce adverse toxic effects. Therefore, accurate determination of these drugs is very important for clinicians to provide a clear judgment about drug therapy for patients. Routine analytical techniques have limitations such as being expensive, laborious, and time-consuming, and need a skilled user and therefore the nano/(bio)sensing technologyleads to high interest.

A Proposed Approach for the Determination of the Bioequivalence Acceptance Range for Narrow Therapeutic Index Drugs in the European Union.

The current regulatory criterion for bioequivalence of narrow therapeutic index (NTI) drugs in the European Union requires that the 90% confidence interval for the ratio of the population geometric means of the test product compared with the reference for area under the plasma concentration-time curve (AUC), and in certain cases maximum plasma drug concentration (Cmax ), to be included within the tighter acceptance range of 90.00-111.11%. As a consequence, sponsors need to recruit a higher number of subjects to demonstrate bioequivalence and this may be seen as increasing the burden for the development of generics. This "one-size-fits-all" criterion is particularly questionable when the within-subject variability of the reference product is moderate to high. As an alternative, we propose a further refined statistical approach where the acceptance range is narrowed based on the within-subject variability of the reference product of the NTI drug, similar to the one used for widening the standard 80.00-125.00% acceptance range for highly variable drugs. The 80.00-125.00% acceptance range is narrowed, only if the within-subject variability is lower than 30%, down to the current NTI acceptance range of 90.00-111.11% when the within-subject variability is 13.93% or lower. Examples within the current European Medicines Agency list of NTI drugs show a considerable reduction in required sample size for drugs like tacrolimus and colchicine, where the predicted within-subject variability is 20-30%. In these cases, this approach is less sample size demanding without any expected increase in the therapeutic risks, since patients treated with reference products with moderate to high within-subject variability are frequently exposed to bioavailability differences larger than 10%.

Clinical and Molecular Perspectives on Inflammation-Mediated Regulation of Drug Metabolism and Transport.

Inflammation is a possible cause of variability in drug response and toxicity due to altered regulation in drug-metabolizing enzymes and transporters (DMETs) in humans. Here, we evaluate the clinical and in vitro evidence on inflammation-mediated modulation of DMETs, and the impact on drug metabolism in humans. Furthermore, we identify and discuss the gaps in our current knowledge. A systematic literature search on PubMed, Embase, and grey literature was performed in the period of February to September 2020. A total of 203 papers was included. In vitro studies in primary human hepatocytes revealed strong evidence that CYP3A4 is strongly downregulated by inflammatory cytokines IL-6 and IL-1β. CYP1A2, CYP2C9, CYP2C19, and CYP2D6 were downregulated to a lesser extent. In clinical studies, acute and chronic inflammatory diseases were observed to cause downregulation of CYP enzymes in a similar pattern. However, there is no clear correlation between in vitro studies and clinical studies, mainly because most in vitro studies use supraphysiological cytokine doses. Moreover, clinical studies demonstrate considerable variability in terms of methodology and inconsistencies in evaluation of the inflammatory state. In conclusion, we find inflammation and pro-inflammatory cytokines to be important factors in regulation of drug-metabolizing enzymes and transporters. The observed downregulation is clinically relevant, and we emphasize caution when treating patients in an inflammatory state with narrow therapeutic index drugs. Further research is needed to identify the full extent of inflammation-mediated changes in DMETs and to further support personalized medicine.

Inflammation Suppresses Patients' Ability to Metabolize Cytochrome P450 Substrate Drugs.

To assess the impact of inflammation on cytochrome P450 (CYP) drug metabolism in human subjects. A PubMed search was done from 1980 to July 2021 limited to human subjects and English language using a search strategy of (((phase I metabolism) OR (CYP) OR (cytochrome P450)) AND (inflammatory OR inflammation)). Narrative review of human studies assessing the impact of inflammation or inflammatory suppression with biologic drugs on CYP drug metabolism were used. Patients with inflammatory conditions ranging from fungal, viral, or bacterial infections to noninfectious causes (critical illness, surgical procedure, cancer, or transplantation of stem cells or organs) have suppressed drug metabolism. Markers of inflammation such as C-reactive protein or α-1-acid glycoprotein are correlated with reduced clearance through CYP3A4, CYP1A2, and CYP2C19. Elevated interleukin-6 concentrations are also associated or correlated with reduced clearance for CYP3A4 and CYP2C-19 isoenzymes. There was insufficient information to properly assess CYP2D6. Health professionals should appreciate that patients with acute or chronic inflammation from infectious or noninfectious causes could have suppressed drug metabolism through CYP3A4, CYP1A2, and CYP2C19. For narrow therapeutic index drugs, such as many of the drugs assessed in this review, that means more judicious drug monitoring to prevent adverse events. Like other types of drug-drug or drug-disease interactions, inflammation can alter the steady-state concentration of CYP metabolized drugs.