Narrow Therapeutic Drugs Research Articles

CPhaMAS: An online platform for pharmacokinetic data analysis based on optimized parameter fitting algorithm

Background and objectiveClinical pharmacological modeling and statistical analysis software is an essential basic tool for drug development and personalized drug therapy. The learning curve of current basic tools is steep and unfriendly to beginners. The curve is even more challenging in cases of significant individual differences or measurement errors in data, resulting in difficulties in accurately estimating pharmacokinetic parameters by existing fitting algorithms. Hence, this study aims to explore a new optimized parameter fitting algorithm that reduces the sensitivity of the model to initial values and integrate it into the CPhaMAS platform, a user-friendly online application for pharmacokinetic data analysis. MethodsIn this study, we proposed an optimized Nelder-Mead method that reinitializes simplex vertices when trapped in local solutions and integrated it into the CPhaMAS platform. The CPhaMAS, an online platform for pharmacokinetic data analysis, includes three modules: compartment model analysis, non-compartment analysis (NCA) and bioequivalence/bioavailability (BE/BA) analysis. Our proposed CPhaMAS platform was evaluated and compared with existing WinNonlin. ResultsThe platform was easy to learn and did not require code programming. The accuracy investigation found that the optimized Nelder-Mead method of the CPhaMAS platform showed better accuracy (smaller mean relative error and higher R2) in two-compartment and extravascular administration models when the initial value was set to true and abnormal values (10 times larger or smaller than the true value) compared with the WinNonlin. The mean relative error of the NCA calculation parameters of CPhaMAS and WinNonlin was <0.0001 %. When calculating BE for conventional, high-variability and narrow-therapeutic drugs. The main statistical parameters of the parameters Cmax, AUCt, and AUCinf in CPhaMAS have a mean relative error of <0.01% compared to WinNonLin. ConclusionsIn summary, CPhaMAS is a user-friendly platform with relatively accurate algorithms. It is a powerful tool for analysing pharmacokinetic data for new drug development and precision medicine.

Duloxetine Use in the Management of Stress Urinary Incontinence &amp; Students’ Survey

The goal of this study is to assess the knowledge and opinion of students regarding the off-label use of duloxetine in the treatment of stress urinary incontinence (SUI). The Survey questions were provided during the Drug Information Course at Howard University (HU) College of Pharmacy in a class where first-year pharmacy students learn how to conduct a literature search and a survey. A total of 39 students responded to the survey. There were more females (n=23; 56.1%) with an age range between 18 – 24 years. About two-thirds (n=29; 70.7%) had a four-year degree before starting the pharmacy program. Overall, participants scored less than the passing 70% mark on the knowledge questions, which may call for educators to make a special effort to incorporate off-label and approved indications of medication teaching therapeutic-related courses. For example, more than sixty percent of respondents (n=25; 61%) incorrectly stated that duloxetine is a narrow therapeutic drug. The majority (n=; 34; 82.9%) of the participants responded wrongly that urinary incontinence is more common in women during their childbearing age. The opinion survey showed that most participants (n=25; 61%) did not believe there were many FDA-approved effective drugs for treating SUI. Over sixty percent of participants (n=25; 61%) considered SUI a severe illness and did not agree to use a non-approved drug such as duloxetine, although several published clinical studies support its effective use. Participants were split in their opinion regarding the non-approved use of medications. Study results suggest that students may need encouragement to explore medications with non-FDA approvals.

Assessing Pharmacist Interventions at an Outpatient Renal Transplant Clinic Under a Collaborative Pharmacy Practice Agreement.

Background: Collaborative pharmacist practice agreements (CPPAs) advance the role of pharmacists by granting prescriptive authority without direct oversight from participating physicians. Objective: To assess the quantity of prescriptions authorized by pharmacists and frequency and types of interventions performed under a CPPA in an outpatient renal transplant clinic. Practice description: Clinical pharmacists in the outpatient renal transplant clinic began prescribing medications under a CPPA in March 2017. Practice innovation: Under the CPPA, pharmacists perform interventions to improve medication management. After identifying gaps in medication therapy, pharmacists tracked their interventions to improve patient care. Methods: An ambispective cohort study evaluated the number of prescriptions and interventions performed under a CPPA. Patients with a prescription generated by pharmacists between January 2019 through June 2019 were included. Pharmacists prospectively collected the number and types of interventions performed; the number of pharmacist-generated prescriptions was retrospectively collected. Interventions were categorized into three groups: medical record assessments, medication counseling, and resolution of barriers to medication continuation. Results: Pharmacists under a CPPA placed 5793 prescriptions and performed 3852 interventions for 1233 patients. The most common intervention categories were medical record assessments, medication counseling, and resolution of barriers to medication continuation. Conclusion: Pharmacists within a CPPA performed medical record assessments to identify untreated or under treated health conditions, eliminate duplicate therapy, and monitor narrow therapeutic drugs. Expanding pharmacists' prescriptive authority within the renal transplant clinic is a successful strategy to ensure patients are taking medications correctly and to avoid barriers to medication persistence.

Drug Utilization Evaluation Study and Dose Adjustment in Patients with Kidney Disease in Tertiary Care Hospital

INTRODUCTION: Kidney disease is becoming a worldwide public health problem with an increase in incidence and prevalence, poor outcomes and high cost. Rational prescription is necessary in kidney disease patients. These patients are at higher risk of developing drug related problems since they need complex therapeutic regimens that include comorbid conditions like diabetes mellitus, hypertension, coronary artery disease and infection that require frequent monitoring and dosage adjustment. Inappropriate use of medications can increase adverse drug effects, which can be reflected by excessive length of hospital stays, excessive health care utilization and cost. OBJECTIVES: The objective of the study was to assess, evaluate and analyze the prescribing pattern of drugs in kidney disease and their dose adjustments in medicine and emergency department of tertiary care teaching hospital. METHODOLOGY: The study was conducted for a period of 6 months. Ethical clearance was obtained from Institutional Ethical Committee of S C S College of Pharmacy, Harapanahalli. Collected data was analyzed to identify the current prescribing trend and dosage regimen in the management of renal failure patients and to know whether the prescribing rationality was obtained in Medicine and Emergency unit in hospital by using KDIGO guidelines. RESULTS: A total of 140 patients were enrolled in the study according to the inclusion criteria in which 104 were males and 36 were females. 134 CKD cases and 6 AKI cases were found. In the study, 105 (75%) patients were hypertensive, 62 (44.28%) patients were anemic, 54 (38.57%) patients were diabetic and dyslipidemia was associated with 21 (15%) patients. 87 patients were on hemodialysis. On the basis of ATC classification of drugs, cardiovascular system (35.7%) class of drugs was the commonly prescribed followed by drugs for alimentary tract and metabolism (25.97%), anti-infective (10.11%) and blood and blood forming agents (7.97%). Out of 1028 studied drugs, only 105 (10.21%) required dose adjustment where 76 (72.38%) were adjusted and 29 (27.61%) were not adjusted. CONCLUSION: This study illustrates the need for proper dose adjustment and drug utilization pattern in patients with renal failure. Appropriate dosing of antibiotics as well as other drugs, including narrow therapeutic drugs play a vital role in preventing dose related adverse reactions and toxicities. This study will provide an outline for management strategies and will influence the decision making process in clinical practice.

Relationship between Amount of Drugs Taken and Warfarin Adherence

&lt;p&gt;Warfarin is a narrow therapeutic drug that needs to be monitored its use. Warfarin adherence is expected to improve warfarin control. However, the amount of drug taken can cause complications in its use which in turn can impact warfarin adherence. Therefore, this study aims to determine the relationship between the amount of medication taken with warfarin adherence. This study is an analytical observational study with a cross sectional design. The subjects of this study were adult patients (&amp;gt; 18 years old) at the cardiac clinic of PKU Muhammadiyah Yogyakarta Hospital who received warfarin and were willing to be a prescription. The number of research samples obtained was 35 patients. Measurement of adherence using a questionnaire Medication Adherence Rating Scale (MARS). Chi Square analysis was used to determine the relationship between the amount of medication taken and adherence to drinking warfarin. The results showed that there were 19 patients (54.3%) who took 4 drugs (54.3%) and 16 patients (45.7%) who took&amp;gt; 4 drugs. Patient adherence was divided into low and high adherence. A total of 18 patients (51.4%) had high adherence and 17 patients (48.6%) had low adherence. Based on the chi square analysis, there is a relationship between the number of drugs taken and adherence to taking warfarin (p = 0.04 &amp;lt;0.05).&lt;/p&gt;

Pomegranate Juice does not Affect the Bioavailability of Cyclosporine in Healthy Thai Volunteers.

BackgroundIt is still controversial whether pomegranate causes drug interactions. Pomegranate juice has been shown to inhibit CYP3A in-vitro and animal studies. The co-administration of pomegranate juice with cyclosporine, a narrow therapeutic drug that is the substrate of CYP3A, might lead to drug toxicity. The objective of this study is to investigate the effect of pomegranate juice on the pharmacokinetics of cyclosporine in healthy Thai volunteers.MethodsThe study design was an open-label, randomized, single dose, crossover study with a 2-week washout period. Each fasting subject received 2 microemulsion tablets of 100 mg of cyclosporine with 500 ml of pomegranate juice (test) or 500 ml of water (control). Serial blood samples were collected up to 24 h after dosing, and blood samples were analyzed for cyclosporine concentrations by using chemiluminescent microparticle immunoassay. Fourteen healthy volunteers completed the study.ResultsThe 90% confidence intervals for the test/control ratio using logarithmically transformed data of area under the concentration-time curve (AUC) from time zero until the last measured concentration (AUC0-t), AUC from time zero to infinity (AUC0-∞), and maximum concentration (Cmax) were 91.6-105.6, 92.0-105.2 and 82.3-102.5, respectively. The results were within the accepted bioequivalence range for narrow therapeutic index drugs (90-111% for AUC and 80-125% for Cmax). There were no differences in adverse event between the groups.ConclusionSingle dose administration of pomegranate juice with cyclosporine did not significantly affect the oral bioavailability of cyclosporine. However, further work is needed to thoroughly evaluate the effect of pomegranate on narrow therapeutic drugs.

CASE REPORT ON SEIZURE WITH CO ADMINISTRATION OF LEVOFLOXACIN AND THEOPHYLINE

Case Summary: An 84-year-old man was admitted to the hospital due to seizure episodes. One week before the patient was admitted to the same hospital with complaints of COPD exacerbation and was discharged with a prescription of levofloxacin, theophylline ceftriaxone, pantaprazole, montelukast, methylprednisolone, budesonide nebulization, ipratropium bromide nebulization, and syrup codylex. After receiving one dose of oral levofloxacin, the patient experienced a seizure. The patient was hyperglycaemic at the time of admission and had no history of a seizure disorder. Discussion: Here the cause of seizure could be a drug-drug interaction (between theophylline and levofloxacin) with CYP1A2 substrates with no epileptogenic effects which could augment the concentration of levofloxacin and consequently results in seizures. In spite of that, it has to be kept in mind that the drug-drug interactions originate at various pharmacodynamic and pharmacokinetic levels and that drugs CYP affinities are rarely completely CYP-specific. Thus levofloxacin may have drug interactions at the level of CYPs other than CYP1A2. Conclusion: the clinicians are advised to closely monitor the possibility of seizures in COPD patients who+ are taking both levofloxacin and theophylline. The physicians should also be encouraged to use the techniques of TDM to individualize the dose of narrow therapeutic drugs to avoid serious adverse effects.

The role of single nucleotide polymorphisms of CYP3A and ABCB1 on tacrolimus predose concentration in kidney transplant recipients.

Tacrolimus has a narrow therapeutic drug window but high inter- and intrapatient variability. Our aim is to construct a model able to predict optimal maintenance tacrolimus predose concentration (C0) in kidney transplant patients. Here we present our study design and genotype and variant allele frequencies for the selected single nucleotide polymorphisms of genes involved in tacrolimus metabolism in our national cohort of kidney transplant recipients. In the observational part of the study, we intend to determine allelic variants of <italic>CYP3A4</italic>, <italic>CYP3A5,</italic> and <italic>ABCB1</italic> gene in a national cohort of 700 kidney transplants recipients. Clinical and laboratory data of this historic cohort will be added to assess patient's immunologic risk. Based on these data, a prediction model will be constructed that will be validated in a prospective randomized study in 60 de-novo kidney transplant recipients. Our interim cross-sectional observational results show higher variability of <italic>ABCB1</italic> genotypes when compared to <italic>CYP3A</italic> genes, with more than two thirds of the population carrying at least one polymorphic allele. On the other hand, less than 1% of our transplant recipients possess the <italic>CYP3A</italic> genotype, which requires high daily tacrolimus dose. Due to high inter- and intrapatient tacrolimus variability, a patient-tailored approach to define the optimal maintenance tacrolimus C0 for each individual patient is needed. Our model will rely on individual pharmacogenomic and clinical data to cover different patient-specific risk factors for adverse outcomes. .

Future direction of immunosuppression in lung transplantation.

Immunosuppression regimens have helped improve rejection episodes following lung transplantation, but long-term outcomes are still not comparable with cardiac, hepatic, or renal transplantation. This review summarizes the immunobiology that contributes to rejection events and future opportunities in outcomes on the basis of providing optimized delivery of the immunosuppression based on immune-monitoring techniques, taking into account individual patient pharmacokinetics and phenotypic variance. Drug toxicities, narrow therapeutic drug monitoring windows, and current immunoassays currently do not assist in detecting the global degree of immunosuppression. The currently available randomized control trials for induction therapy or maintenance therapies do not provide additional benefits compared with previously reported retrospective trials. To push beyond the current barriers, transplant teams are focusing on the role of pharmacokinetics, assessing phenotypic variable to potentially modify to quadruple therapy and using extracorporeal photopheresis. Conventional practice for the choices of immunosuppression is being evaluated on the basis of randomized control trials as opposed to retrospective studies or single-center trials. The future direction of immunosuppression will be continued by dynamic processes taking into consideration measures to improve tolerance, reducing treatment burden, and providing the best level of evidence while accounting for rejection, infections, renal function, and other comorbidities.

Comparative inhibitory potential of selected dietary bioactive polyphenols, phytosterols on CYP3A4 and CYP2D6 with fluorometric high-throughput screening.

Cytochrome P450 (CYP450) inhibition by the bioactive molecules of dietary supplements or herbal products leading to greater potential for toxicity of co-administered drugs. The present study was aimed to compare the inhibitory potential of selected common dietary bioactive molecules (Gallic acid, Ellagic acid, β-Sitosterol, Stigmasterol, Quercetin and Rutin) on CYP3A4 and CYP2D6 to assess safety through its inhibitory potency and to predict interaction potential with co-administered drugs. CYP450-CO complex assay was carried out for all the selected dietary bioactive molecules in isolated rat microsomes. CYP450 concentration of the rat liver microsome was found to be 0.474nmol/mg protein, quercetin in DMSO has shown maximum inhibition on CYP450 (51.02 ± 1.24%) but less when compared with positive control (79.02 ± 1.61%). In high throughput fluorometric assay, IC50 value of quercetin (49.08 ± 1.02-54.36 ± 0.85μg/ml) and gallic acid (78.46 ± 1.32-83.84 ± 1.06μg/ml) was lower than other bioactive compounds on CYP3A4 and CYP2D6 respectively but it was higher than positive controls (06.28 ± 1.76-07.74 ± 1.32μg/ml). In comparison of in vitro inhibitory potential on CYP3A4 and CYP2D6, consumption of food or herbal or dietary supplements containing quercetin and gallic acid without any limitation should be carefully considered when narrow therapeutic drugs are administered together.

Deficiencies of the FDA in Evaluating Generic Formulations: Addressing Narrow Therapeutic Index Drugs

Generic drugs represent a significant portion of the medical arsenal in treating disease. As copies of originator drugs, these drugs have been permitted abbreviated approval under the Hatch-Waxman Act. Yet with the current cost focus upon generic formulations, potential safety issues with generics have arisen. Although there is an established criterion of "bioequivalence" that generic formulations must demonstrate, narrow-therapeutic index drugs for sensitive clinical circumstances such as epilepsy, antiplatelet therapies, and mental health treatments may require different regulatory treatment than other generic drugs. Further, in these circumstances, differences in generic formulations may lead to adverse clinical outcomes due to less stringent bioequivalence tolerances. Yet there is no mandate for comparison between different generic formulations. Countries outside the United States advocate for narrowing tolerance ranges for these high risk health situations and the drugs for their treatment. We argue in this paper that additional patient safety matters must be taken into account for narrow therapeutic disease drugs, and regulatory bodies should emphasize greater tightness in bioequivalence before these narrow-therapeutic drug generic formulations are approved.

Future Challenges: Changing Health Care Delivery and Advancing Patient Care

Our current health care system involves multidisciplinary groups of practitioners who function as freestanding silos and in which a “team” approach means an awareness and tolerance of other disciplines as patients are handed from one practitioner to another. Pharmacy has advanced from clinical pharmacy through pharmaceutical care to the dawning of medication therapy management services. With each step pharmacy has become more focused on direct patient care. As technology and technicians improve the dispensing process and as electronic databases evolve, the pharmacist will increasingly be positioned to be more available and better equipped to provide direct patient care and medication therapy management services. Over the next decade, I see pharmacy and other health care providers moving to an interdisciplinary team approach in which decisions are made by consensus and through which each discipline has an equal opportunity for input.1 To accommodate such a change, I envision a new health care delivery model based on the following components: n Wellness and prevention services as the entry point into the system. n An interdisciplinary delivery model with providers having shared borders (a model in which our professional boundaries become blurred or overlap, and health care professionals share a common knowledge base, a common professional interest, and an instinct to help the patient). n “Physician extenders” providing disease and medication management services using evidenced-based medicine. n Systems that are outcomes driven and outcomes justified. n A broader acceptance and use of complementary and alternative medicine within the delivery model. All of the above components are evolving or already exist in the current environment. The challenge to the system is to integrate them into successful delivery models. The challenge to the pharmacist is to identify, embrace, Future Challenges: Changing Health Care Delivery and Advancing Patient Care and drive their evolving roles within this new health care delivery model.

Comparison of genotypic and phenotypic strategies for individualized therapy with the narrow therapeutic drug warfarin

CYP2C9 metabolizes a wide variety of drugs, including losartan and (S)-warfarin. CYP2C9 is polymorphic and correlation between warfarin clearance and CYP2C9 genotypes has been demonstrated in healthy volunteers and selected patients. The overall objective of our study was to determine, in patients with a multiple drug regimen, correlations between required doses of warfarin and 1) CYP2C9 genotypes, or 2) CYP2C9 phenotype (losartan metabolic ratio). Losartan and its main metabolite EXP 3174 were analysed by HPLC in 6-hour urine samples collected from 77 subjects after a single 12.5 mg oral dose of losartan. The three most common CYP2C9 allelic variants were analysed by PCR-RFLP using genomic DNA of 121 patients. Mean urinary metabolic ratios of losartan were 3.9±3.7 for CYP2C9*1/*1 (n=49), 4.0±5.4 for *1/*2 (n=13), 5.4±4.5 for *1/*3 (n=8), 5.2 for *2/*2 (n=2) and 12.8 for *2/*3 (n=1). A multiple linear regression analysis model was developed using phenotype, age, weight, gender and amiodarone treatment as cofactors. This model explains up to 40% of variability in warfarin dose. In contrast, a genotype analysis correlated with phenotype values only in patients carrying two copies of variant alleles. Our results indicate that in more than 90% of patients, a genotypic approach does not predict required doses of warfarin. On the other hand, CYP2C9 phenotype, when feasible, could represent a more favourable approach to explain intersubject variability in warfarin disposition. Clinical Pharmacology & Therapeutics (2004) 75, P60–P60; doi: 10.1016/j.clpt.2003.11.230

PhRMA perspective on population and individual bioequivalence.

The Food and Drug Administration (FDA) issued a second-draft guidance in August 1999 on the subject of in vivo bioequivalence, which is based on the concepts of individual and population bioequivalence (IBE and PBE, respectively). The intention of this guidance is to replace the 1992 guidance that requires that in vivo bioequivalence be demonstrated by average bioequivalence (ABE). Although the concepts of population and individual bioequivalence are intuitively reasonable, a detailed review of the literature has not uncovered clinical evidence to justify the additional burden to the innovator and generic companies as well as the consumer that the new guidelines would impose. The criteria for bioequivalence described in the draft guidance employ aggregate statistics that combine information about differences in bioavailability between formulation means and differences in bioavailability variation of formulations between and within subjects. The purely technical aspects of the statistical approach are reasonably sound. However, PhRMA believes that important operational issues remain that need to be resolved before any changes to current practice are implemented. PhRMA believes that the ideals of prescribability and switchability are intuitively reasonable, but it is uncertain of the extent to which the proposed guidance can achieve these goals. It is not clear whether the attainment of such goals is necessary in the evaluation of bioequivalence given the role this plays in drug development, and the lack of clinical evidence argues against a pressing need to change current practice. PhRMA is concerned that the trade-off offered by the aggregate criteria may ultimately represent more harm than good to the public interest. PhRMA recommends more rigorous evaluation of methods based on two-way crossover designs before moving to methods that require more complex designs. One such method is identified herein and contains procedures for estimating prescribability and switchability. The possibility of a phase-in or trial period to collect replicate crossover data to further evaluate IBE and PBE and possibly allow market access based on these criteria as they are being evaluated has been proposed. PhRMA believes this is unprecedented and will offer little additional information beyond that which can be obtained by simulation or has already been collected by the FDA. Simulation studies have the advantage of allowing evaluation of the sensitivity of various procedures to represent the data patterns as created within the simulation. Operating characteristics by which proposed criteria can be adequately judged have not yet been defined. The limitations of ABE for highly variable drugs and narrow therapeutic drugs are well appreciated and may be addressed by means other than a wholesale change in the current criteria.

Warfarin responses in total joint and hip fracture patients

Warfarin is considered as a narrow therapeutic drug—an agent for which small changes in dosage can lead to significant changes in response. The precision of warfarin treatment is especially relevant in an acute-care setting. In this study, we examined the effect of various risk factors on warfarin response in the early postoperative period after total joint arthroplasty and hip fracture fixation. A total of 260 patients placed on warfarin for thrombosis prophylaxis were retrospectively studied. Risk factors for warfarin sensitivity include age 80 years or older and hip fracture fixation. Patients aged 80 years or older who had hip fracture fixation were 4.7 times more likely to experience an international normalized ratio (INR) at or greater than 4.0 than other patients (therapeutic target range of INR, 1.8–2.2). The largest subtherapeutic risk group in this study were men weighing 180 lb or more. They were 5.7 times less likely to achieve an INR of 1.6 than the other patients. Factors such as body weight, age, and gender should be considered when ordering warfarin therapy. Current hospital warfarin sliding scales should be reviewed for their efficacy to ensure that the target outcome is achieved.