De-simplifying single-tablet antiretroviral treatments for cost savings in France: From the patient perspectives to a 6-month follow-up on generics.

In developed countries, most people living with HIV/AIDS are treated with costly brand single-tablet regimens. Given the economic impact, French guidelines recommend using generic antiretroviral therapy when possible to decrease antiretroviral therapy costs. We aimed to study HIV-infected patients' acceptability to switch from a brand single-tablet regimens [abacavir/lamivudine/dolutegravir (Triumeq®) or emtricitabine/tenofovir disoproxil fumarate/rilpivirine (Eviplera®)] to a treatment comprising of two pills: one is a fixed-dose generic combination of 2 Nucleoside Analogs and the second tablet is the third antiretroviral. This study was a prospective observational study in a French hospital. During their follow-up, patients on stable single-tablet regimens were made aware of the possible cost-saving. They were questioned about their willingness and barriers accepting the substitution. Participants chose between the two regimens, either to remain on single-tablet regimens or switch to the de-simplified regimen. Six months later, a second survey was given to the patient who chose to de-simplify and HIV viral load was controlled. The study included 98 patients: 60 receiving emtricitabine/tenofovir disoproxil fumarate/rilpivirine (Eviplera®) and 38 on abacavir/lamivudine/dolutegravir (Triumeq®). Forty-five patients accepted the de-simplified treatment, 37 refused and 16 were undecided and followed the decision offered by their physician. The main reason for unwillingness to switch is the number of pills (77.3%). In multivariate model analysis, male patients (p = 0.001) who have taken antiretroviral therapy for over 20 years (p = 0.04) and who retrieve their treatment in their community hospital (p = 0.03) are more likely to accept the switch. Fifty-one patients accepted to replace their single-tablet regimens and six months later, the majority was satisfied; only four returned to single-tablet regimens because of suspected side effects. Half of the people living with HIV/AIDS in our cohort accepted to switch from brand single-tablet regimens to a two-tablet regimen containing generic drugs within a process that emphasizes health expenditure savings.

Cost-utility of new film-coated tablet formulation of deferasirox vs deferoxamine among major beta-thalassemia patients in Iran.

OBJECTIVES: Thalassemia is a hereditary disease, which caused economic burden in developing countries. This study evaluated the cost utility of new formulation of deferasirox (Jadenu) vs deferoxamine (Desferal) among B-Thalassemia-major patients from payer perspective in Iran. METHODS: An economic-evaluation through Markov model was performed. A systematic review was conducted in order to evaluate the clinical effectiveness of comparators. Because of chelating therapy is weight-dependent, patients were assumed to be 2 years-old at initiation in first and 18 years-old in second scenario, and model was estimated lifetime costs and utilities. Costs were calculated to the Iran healthcare system through payer perspective and measured effectiveness using quality-adjusted life years (QALYs). One-way sensitivity analysis and budget impact analysis was also employed. RESULTS: The 381 studies were retrieved from systematic searching through databases. After eliminating duplicate and irrelevant studies, 2 studies selected for evaluating the effectiveness. Jadenu was associated with an incremental cost-effectiveness ratio (ICER) of 1470.6 and 2544.7 US$ vs Desferal in first and second scenario respectively. The estimated ICER for Jadenu compared to generic deferoxamine was 2837.0 and 6924.1 US$ for first and second scenario respectively. For all scenarios Jadenu is presumed as cost-effective option based on calculated ICER which was lower than 1 gross domestic product per capita in Iran. Sensitivity analysis showed that different parameters except discount rate and indirect cost did not have impact on results. Based on budget impact analysis the estimated cost for patients using Desferal (based on the market share of brand) was 44,021,478 US$ in 3 years vs 42,452,606 US$ in replacing 33% of brand market share with Jadenu. This replacement corresponded to the cost saving of almost 1,568,872 US$ for the payers in 3 years. The calculated cost of using generic deferoxamine in all patients was 68,948,392 US$. The increase in the cost of using Jadenu for 10% of all patients in this scenario would be 934,427 US$ (1.36%) US$ at the first year. CONCLUSIONS: Based on this analysis, film-coated deferasirox appeared to be cost-effective treatment in comparison with Desferal for managing child and adult chronic iron overload in B-thalassemia major patients of Iran.

Does splitting a tablet obtain the accurate dose?: A systematic review protocol.

BACKGROUND: Physical manipulation of the manufactured dose form is a common practice, with almost a quarter of all drugs administered in primary care having their dose altered. Splitting a tablet can be advantageous as it facilitates swallowing, allows for dose flexibility and provides cost reductions. However, there are concerns these physical changes can lead to inaccurate portions resulting in significant variations from the prescribed dose. Thus, the review described in this protocol aims to summarise the literature assessing the effect of tablet splitting on dose accuracy. METHODS: Relevant studies will be identified through electronic searches in databases including EMBASE, MEDLINE, CINAHL, and the Cochrane Library, from the beginning of databases until January 2020. Studies investigating any drug, where the tablet was split, will be potentially eligible. Two reviewers will independently screen studies and extract data using standardised forms. Data extracted will include general study information, characteristics of the study, intervention characteristics and outcomes. Primary outcome is to assess dose accuracy of a split tablet measured by drug content or weight variability. Assessment of risk of bias will be dependent upon study design. If deemed feasible, meta-analysis will be performed. RESULTS: The study described within this protocol will provide a synthesis of current evidence assessing the effect of tablet splitting on dose accuracy. CONCLUSION: The conclusion of our study will provide evidence to judge whether splitting a tablet results in an accurate half dose. ETHICS AND DISSEMINATION: Ethics approval was not required for this study. The results of the systematic review described will be published in a peer-reviewed journal. REGISTRATION DETAILS: PROSPERO CRD42018106252.

Desimplification of Single Tablet Antiretroviral (ART) Regimens-A Practical Cost-Savings Strategy?

INTRODUCTION: The use of lifelong antiretroviral therapy (ART) results in increased costs of care; the ability to finance and control sustained costs of ART needs to be discussed. APPROACH: The Southern Alberta Clinic initiated a practical cost savings approach that switched select patients from a branded ART to a less expensive generic variation. Our approach surveyed physicians and patients on their acceptance of switching and then launched a program asking patients if they would switch to generic variations for cost control purposes. RESULTS: Our early findings found >50% of patients approached agreed to switch. We found no evidence of increased risk of viral breakthrough, resistance, side effects, or displeasure with generic drugs. Measured cost savings in the first year were >$1.1 million with annual projected savings of between $4.3 million and $2.6 million (in 2017 Cdn$). CONCLUSION: Our approach can provide an option for controlling costs of HIV care without compromising quality.

Challenges of dispensing costly tablets with short shelf-life.

Afatinib, trametinib and regorafenib are three costly oral oncology drugs with a short shelf-life after the original container has been opened. Their short shelf-lives are due to degradation on exposure to moisture. Therefore, manufacturers recommend them to be dispensed in the original packaging with the desiccant. However, the prescribed quantities do not always match the quantities in the original packaging, usually because of dose modifications for toxicities. This leads to potentially significant drug wastage and financial losses. We describe some potential approaches to this issue.

Cost-Effectiveness of Posaconazole Tablets for Invasive Fungal Infections Prevention in Acute Myelogenous Leukemia or Myelodysplastic Syndrome Patients in Spain.

INTRODUCTION: Posaconazole is superior to fluconazole (FLU) and itraconazole (ITRA) in the prevention of invasive fungal diseases (IFDs) in neutropenic patients with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). A new tablet formulation of posaconazole with improved pharmacokinetic and pharmacodynamic properties compared to posaconazole oral solution has recently been approved. The objective of this study is to estimate the cost-effectiveness of the newly developed posaconazole tablets versus FLU oral suspension or ITRA oral solution for preventing IFDs in high-risk neutropenic patients with AML or MDS and from the perspective of the Spanish National Health System (NHS). METHODS: A previously validated economic model was used. The probabilities of experiencing an IFD, an IFD-related death or death from other causes over 100 days were based on clinical trial data and input into a decision tree. Surviving patients were entered into a Markov model to calculate total costs, number of IFDs and number of life-years gained per patient over a lifetime horizon in each disease and treatment group. Two health states, alive and dead, were considered. Health effects were discounted using a rate of 3%. Univariate and probabilistic sensitivity analyses were conducted. RESULTS: During the first 100 days, posaconazole tablets were associated with a lower risk of IFDs (0.046 vs. 0.111), longer life expectancy (2.92 vs. 2.69 years) and lower total costs (€5906.06 vs. €7847.20 per patient) over the patients' lifetimes compared to FLU or ITRA treatments. Thus, posaconazole tablets were more effective and less costly than FLU or ITRA. Probabilistic sensitivity analysis indicated that there was a 79.9% probability of posaconazole tablets being cost-saving compared to FLU or ITRA. CONCLUSION: From the Spanish NHS perspective, posaconazole tablets are cost-effective compared to FLU or ITRA in AML or MSD patients with chemotherapy-induced neutropenia and at high risk for IFDs. FUNDING: MSD Sharp & Dohme.

Solid oral forms availability in children: a cost saving investigation.

AIM: To assess the suitability and potential cost savings, from both the hospital and community perspective, of prescribed oral liquid medicine substitution with acceptable solid forms for children over 2 years. METHOD: Oral liquid medicines dispensed from a paediatric hospital (UK) in 1 week were assessed by screening for existence of the solid form alternative and evaluating the acceptability of the available solid form, firstly related to the prescribed dose and secondly to acceptable size depending on the child's age. Costs were calculated based on providing treatment for 28 days or prescribed duration for short term treatments. RESULTS: Over 90% (440/476) of liquid formulations were available as a marketed solid form. Considering dosage acceptability (maximum of 10% deviation from prescribed dosage or 0% for narrow therapeutic range drugs, maximum tablet divisions into quarters) 80% of liquids could be substituted with a solid form. The main limitation for liquid substitution would be solid form size. However, two-thirds of prescribed liquids could have been substituted with a suitable solid form for dosage and size, with estimated savings being of £5K and £8K in 1 week, respectively based on hospital and community costs, corresponding to a projected annual saving of £238K and £410K (single institution). CONCLUSION: Whilst not all children over 2 years will be able to swallow tablets, drug cost savings if oral liquid formulations were substituted with suitable solid dosage forms would be considerable. Given the numerous advantages of solid forms compared with liquids, this study may provide a theoretical basis for investing in supporting children to swallow tablets/capsules.

Should vitamin B12 tablets be included in more Canadian drug formularies? An economic model of the cost-saving potential from increased utilisation of oral versus intramuscular vitamin B12 maintenance therapy for Alberta seniors.

OBJECTIVE: The aim of this study was to estimate the cost-savings attainable if all patients aged ≥65 years in Alberta, Canada, currently on intramuscular therapy were switched to oral therapy, from the perspective of a provincial ministry of health. SETTING: Primary care setting in Alberta, Canada. PARTICIPANTS: Seniors of age 65 years and older currently receiving intramuscular vitamin B12 therapy. INTERVENTION: Oral vitamin B12 therapy at 1000 µg/day versus intramuscular therapy at 1000 µg/month. PRIMARY AND SECONDARY OUTCOME MEASURES: Cost saving from oral therapy over intramuscular therapy, from the perspective of the Alberta Ministry of Health, including drug costs, dispensing fees, injection administration fees, additional laboratory monitoring and physician visit fees. RESULTS: Over 5 years, if all Albertans aged 65 years and older who currently receive intramuscular B12 are switched to oral therapy, our model found that $C13 975 883 can be saved. Even if no additional physician visits are billed for among patients receiving intramuscular therapy, $C8 444 346 could be saved from reduced administration costs alone. CONCLUSIONS: Oral B12 therapy has been shown to be an effective therapeutic option for patients with vitamin B12 deficiency, yet only three provinces and the Non-Insured Health Benefits program include oral tablets on their formulary rather than the parenteral preparation. To ensure judicious use of limited health resources, clinicians and formulary committees are encouraged to adopt oral B12 therapy as a clinically and cost-effective first-line therapy for vitamin B12 deficiency.

Design and evaluation of an economic taste-masked dispersible tablet of pyridostigmine bromide, a highly soluble drug with an extremely bitter taste.

Pyridostigmine bromide (PTB) is a highly soluble and extremely bitter drug. Here, an economic complexation technology combined with direct tablet compression method has been developed to meet the requirements of a patient friendly dosage known as taste-masked dispersible tablets loaded PTB (TPDPTs): (1) TPDPTs should have optimal disintegration and good physical resistance (hardness); (2) a low-cost, simple but practical preparation method suitable for industrial production is preferred from a cost perspective. Physicochemical properties of the inclusion complex of PTB with beta-cyclodextrin were investigated by Fourier transformed infrared spectroscopy, differential scanning calorimetry and UV spectroscopy. An orthogonal design was chosen to properly formulate TPDPTs. All volunteers regarded acceptable bitterness of TPDPTs. The properties including disintegration time, weight variation, friability, hardness, dispersible uniformity and drug content of TPDPTs were evaluated. The dissolution profile of TPDPTs in distilled water exhibited a fast rate. Pharmacokinetic results demonstrated that TPDPTs and the commercial tablets were bioequivalent.

Tablet splitting: a review of the clinical and economic outcomes and patient acceptance. Second of a 2-part series. Part 1 was published in May 2012 (Consult Pharm 2012;27:239-53).

OBJECTIVE: To describe the clinical outcomes, patient acceptance, and economic effect associated with tablet splitting. DATA SOURCES: PubMed (1966-June 2011) and International Pharmaceutical Abstract (1975-June 2011) searches were conducted using tablet splitting as the search terms. STUDY SELECTION: All studies that evaluated the clinical outcome (n = 4), patient acceptance (n = 5), and economic effects (n = 8) of tablet splitting were included. DATA EXTRACTION: The American Pharmacists Association guidelines, recommendations from the Food and Drug Administration, and clinical trial data were evaluated. DATA SYNTHESIS: The majority of trials conducted evaluating clinical outcomes associated with tablet splitting were evaluated in patients receiving statins and antihypertensives. Clinical outcomes associated with risperidone were assessed. No adverse clinical outcomes were observed with therapy. Most studies evaluating the economic effects of tablet splitting have revealed a cost savings associated with this process; however, many studies were subject to limitations. The first part of this two-part series reviewed the weight and content uniformity in tablet splitting. CONCLUSION: Tablet splitting does not seem to significantly affect clinical outcomes related to management of hypertension, cholesterol, or psychiatric disorders, nor influence overall patient adherence.

Tablet splitting: a review of weight and content uniformity.

OBJECTIVE: To describe the product integrity and ethical/ legal issues associated with tablet splitting. DATA SOURCES: PubMed (1966-June 2011), International Pharmaceutical Abstract (1975-June 2011), and bibliographic searches were conducted. STUDY SELECTION: All studies that evaluated the weight/dose variations (N = 13) of split tablets were included. DATA EXTRACTION: The American Pharmacists Association guidelines, recommendations from the Food and Drug Administration, and clinical studies evaluating product integrity of split tablets were used to provide an overview of issues related to this practice. Legal considerations from various sources were also included. DATA SYNTHESIS: The practice of tablet splitting is increasing and is associated with variations in drug distributions related to the tablet-splitting technique and other causes. The first part of this two-part series will evaluate the product integrity and practice-related issues associated with tablet splitting. CONCLUSION: The majority of the studies associated with tablet splitting reveal large fluctuations in weight/dosage, but few studies evaluate variability with narrow therapeutic index medications. Therefore, the clinical impact of these variations is not globally applicable across medication classes. Although tablet splitting has the potential to save patients and health care organizations a significant amount of money, appropriateness of tablet splitting should be determined for individual medications and individual patients. Assessments should include an evaluation of patient understanding and physical abilities for tablet splitting.

Cost-effectiveness of several atypical antipsychotics in orally disintegrating tablets compared with standard oral tablets in the treatment of schizophrenia in the United States.

OBJECTIVE: Although the use of innovative drug delivery systems, like orally disintegrating antipsychotic tablets (ODT), may facilitate medication adherence and help reduce the risk of relapse and hospitalization, no information is available about the comparative cost-effectiveness of standard oral tablets (SOT) vs ODT formulations in the treatment of schizophrenia. This study compared the cost-effectiveness of olanzapine ODT and olanzapine SOT in the usual treatment of outpatients with schizophrenia from a US healthcare perspective. The study also compared olanzapine ODT with risperidone and aripiprazole, two other atypical antipsychotics available in both ODT and SOT formulations. METHODS: Published medical literature and a clinical expert panel were used to populate a 1-year Monte Carlo Micro-simulation model. The model captures clinical and cost parameters including adherence levels, treatment discontinuation by reason, relapse with and without inpatient hospitalization, quality-adjusted life years (QALYs), treatment-emergent adverse events, healthcare resource utilization, and associated costs. Key outcomes were total annual direct cost per treatment, QALY, and incremental cost-effectiveness (ICER) per 1 QALY gained. RESULTS: Based on model projections, olanzapine ODT therapy was more costly ($9808 vs $9533), but more effective in terms of a lower hospitalization rate (15% vs 16%) and better QALYs (0.747 vs 0.733) than olanzapine SOT therapy. Olanzapine ODT was more cost-effective than olanzapine SOT (ICER: $19,643), more cost-effective than risperidone SOT therapy (ICER: $39,966), and dominant (meaning less costly and more effective) than risperidone ODT and aripiprazole in ODT or SOT formulations. LIMITATIONS: Lack of head-to-head randomized studies comparing the three studied atypical antipsychotics required making input assumptions that need further study. CONCLUSIONS: This micro-simulation found that the utilization of olanzapine ODT for the treatment of schizophrenia is predicted to be more cost-effective than any other ODT or SOT formulations of the studied atypical antipsychotic medications.

Novel formulation and drug delivery strategies for the treatment of pediatric poverty-related diseases.

INTRODUCTION: Due to a lack of approved drugs and formulations, children represent the most vulnerable patients. Magistral, unlicensed formulations obtained by the manipulation of solid forms should undergo clinical evaluation to ensure bioequivalence. The development of new pediatric medicines is complex and faces technological, economic and ethical challenges. This phenomenon has contributed to the emergence of an adult-children gap. To improve the situation, the World Health Organization launched the global campaign 'Make medicines child size' and a number of international initiatives have been established. The situation is more critical in the case of poverty-related diseases (PRDs) that mainly affect poor countries. AREAS COVERED: This review critically discusses different strategies to develop pediatric formulations and drug delivery systems (DDS) in PRDs and their potential implementation in the current market. Readers will gain an updated perspective on the development of pediatric medicines for the treatment of PRDs and the proximate challenges and opportunities faced to ensure an effective pharmacotherapy. EXPERT OPINION: There is an urgent need for the development of innovative, scalable and cost-viable formulations to ensure pediatric patients have access to appropriate medications for PRDs. The guidelines of the International Conference on Harmonisation constitute a very good orientation tool, as they emphasize physiological and developmental aspects that need to be considered in pediatric research. It is important to consider cultural, economic and ethical aspects that make developing nations facing PRDs different from the developed world. Thus, the best strategy would probably be to conceive and engage similar initiatives in the developing world, to address unattended therapeutic niches.

Preoperative localization of intracranial lesions with MRI using marking pills.

OBJECTIVE: To describe a simple technique for preoperative surface localization of intracranial lesions. METHODS: 11 pills in total, including Alfarol (alfacalcidol) capsules, were affixed to a phantom with adhesive tape and a MRI scan was performed. The visibility of the pills and any spatial errors in determining their locations were evaluated. Between June 2006 and April 2009, we employed Alfarol capsules as a skin marker in MRI in clinical surgical cases. RESULTS: Alfarol capsules, whose actual size is 5.6 mm in diameter, were identified as a hyperintense spot at a size of 4.2, 4.2, and 4.5mm in diameter in T1-weighted, T2-weighted, and FLAIR (fluid attenuated inversion recovery) sequence images, respectively. The size discrepancies were within 1.4 mm. The average spatial errors were 0.7, 0.6, and 0.7 mm in T1-weighted, T2-weighted, and FLAIR sequence images, respectively. Other pills were not identified in the MRI scans. During this 35-month period, 8 patients underwent preoperative MRI-guided localization at our institution. There were 5 men and 3 women in whom 8 biopsies were performed. In all cases, the result of the biopsy was positive and useful for the treatment that followed. No perioperative complications were encountered. CONCLUSION: Alfarol capsule can be used as an external skin marker. Our simple and inexpensive method is a useful addition to preoperative evaluation of superficial intracranial lesions.

A comprehensive in vitro and in vivo evaluation of thiolated matrix tablets as a gastroretentive delivery system.

The aim of this study was to investigate the potential of thiolated matrix tablets for gastroretentive delivery systems. Poly(acrylic acid)-cysteine (PAA-Cys) and chitosan-4-thiobuthylamidine (chitosan-TBA) were evaluated as anionic and cationic thiolated polymers and riboflavin was used as a model drug. Tablets were prepared by direct compression and each formulation was characterized in terms of disintegration, swelling, mucoadhesion, and drug release properties. Thereafter, the gastric residence times of tablets were determined with in vivo study in rats. The resulting PAA-Cys and chitosan-TBA conjugates displayed 172.80 ± 30.33 and 371.11 ± 72.74 µmol free thiol groups, respectively. Disintegration studies demonstrated the stability of thiolated tablets up to 24 h, whereas tablets prepared with unmodified PAA and chitosan disintegrated within a time period of 1 h. Mucoadhesion studies showed that mucoadhesion work of PAA-Cys and chitosan-TBA tablets were 1.341- and 2.139-times higher than unmodified ones. The mucoadhesion times of PAA, PAA-Cys, chitosan, and chitosan-TBA tablets were 1.5 ± 0.5, 21 ± 1, 1 ± 0.5, 17 ± 1 h, respectively. These results confirm the theory that thiol groups react with mucin glycoproteins and form covalent bonds to the mucus layer. Release studies indicated that a controlled release was provided with thiolated tablets up to 24 h. These promising in vitro results of thiolated tablets were proved with in vivo studies. The thiolated tablets showed a gastroretention time up to 6 h, whereas unmodified tablets completely disintegrated within 1 h in rat stomach. Consequently, the study suggests that thiolated matrix tablets might be promising formulations for gastroretentive delivery systems.

Cost-effectiveness analysis of prostaglandin E2 gel for the induction of labour at term.

OBJECTIVE: To estimate the cost-effectiveness of prostaglandin E2 (dinoprostone) vaginal gel for the induction of labour at term from the perspective of the UK's National Health Service. DESIGN: Economic evaluation conducted as part of a randomised controlled trial. SETTING: Maternity department at a major teaching hospital in London, UK. POPULATION: A cohort of 165 pregnant women presenting as cephalic between 36(+6) and 41(+6) weeks of gestation, for whom induction of labour was deemed necessary. METHODS: Either 3-mg Prostin E2 vaginal tablets or 1- or 2-mg Prostin E2 vaginal gel were administered at 6-hourly intervals. MAIN OUTCOME MEASURES: Incremental cost per hour prevented between induction and delivery. The nonparametric bootstrap method was used to construct cost-effectiveness acceptability curves and estimate net benefits at alternative cost-effectiveness thresholds. RESULTS: Women receiving the gel accrued nonsignificantly higher costs (incremental cost £630; bootstrap 95% CI -£353, £2320; P = 0.43), and experienced a significantly reduced interval between induction and delivery (median of 1400 versus 1780 minutes; mean of 1711 versus 2765 minutes; P = 0.03). The incremental cost per hour prevented from induction of labour to delivery was estimated at £36. At a cost-effectiveness threshold of £100 per hour of care prevented, the probability that the gel is cost-effective was estimated at 0.83, and the mean net benefit to the health services was estimated at £1121 (bootstrap 95% CI -£1133, £3379). The results were sensitive to the inclusion of neonatal costs in the analysis and the value of the cost-effectiveness threshold. Notably, excluding neonatal costs increased the probability that the gel is cost-effective at a cost-effectiveness threshold of £100 per hour of care prevented to 0.99. CONCLUSIONS: This study suggests that prostaglandin E2 gel is probably more cost-effective than prostaglandin E2 tablets for the induction of labour at term. Given that the results are applicable to the general obstetric population requiring induction of labour at term, decision-makers should consider the likely economic impacts of their implementation.

The paradox of scored tablets: a cost-saving risk.

One of the cornerstones of pharmacotherapy is the proper dose of medicine, which should ideally be tailored to the individual patient. However, even if clinically possible, this is economically not feasible as a too large number of different dosage strengths would be required. Therefore, a balance is required between the patient's benefit/risk and the cost to the individual and society on the other hand. Scored or splitted tablets were, and still are, often used strategies to these opposite interests, enabling more dose-flexibility, but also at the same time increasing the dose-variability as a consequence of the breaking process. The question of how to deal with this paradox was investigated by exploring the prevalence and classification of scored tablets as well as the cost-benefits. A strategy for clinical pharmacologists is presented to improve the outcome of this paradox.