Purpose: Narrow therapeutic index (NTI) drugs must be routinely monitored for their severe effects. These drugs share some common features and criteria that focus on the separation of safety and efficacy in relation to toxicity and efficacy. Methods: There are many factors that contribute to drugs’ high toxicity and lack of efficacy, including the following 5: right drug, right dose, right time, right duration, right age. Results: It’s reviewed over 200 drugs, focusing on NTI drugs’ clinical pharmacology, dose-response relationship, physiochemical properties, and potential drug-drug interactions. It is found that any minor change in therapeutic drug concentrations or doses may have significant consequences for patients, such as bleeding due to warfarin overdose or thrombotic events due to underdose. Conclusions: For NTI drugs, therapeutic drug monitoring (TDM) must be accessible in all hospitals and outpatient clinics to ensure patient safety. These approaches and methods must be done in each patient.

As a clinical pharmacist and clinical pharmacologist for about 25 years at the Food and Drugs Administration (FDA), I have always wondered about the question of splitting the tablet, and especially for tablets for the drugs with Narrow Therapeutic Index (NTI). For these drugs, any small increase in the amount ingested to a severe patient has risky consequences, especially in the elderly. I worked on this NTI project during my tenured year at the FDA. I reviewed over 200 commonly prescribed drugs, from the efficacy and safety perspective. My focus was identifying the Maximum Toxic Concentration (MTC), the Minimum Effective Concentration (MEC), Maximum Dose (Max D), and Minimum Dose (Min D). The therapeutic index (TI) was measured from the following equation: TI =MTC/MEC for all drugs. Also, I identified the various strengths available for each drug product and the scoring (if any). The analysis shows that the mean and standard deviation (SD) for all 64 scored tablets was 5.030 (± 2.79 units) and that all unscored drugs was 9.520 (± 14.22 units). As noted, there was more variability in the unscored tablets. This provided evidence that the drugs tending to be NTI were scored to titrate. However, patients, especially elderly, appear to be confused and having difficulty in accurately breaking the tablet scores. However, it is important to note that acetaminophen represents wide TI, maximum daily dose of 4,000 mg/day, and it is no-scored. However, levothyroxine which represents drug with NTI has 12 strengths and all are scored.

Purpose: If the drugs are routinely required for therapeutic drug monitoring (TDM), they may be considered NTI drugs. By basing some criteria that affect the degree of separation of the concentrations that elicit the therapeutic and the adverse effects, an attempted to avoid the vagaries inherent in preparing a list of individual drugs themselves. Methods: I reviewed over 200 commonly prescribed drugs in the retail and hospital pharmacies in the US. As the Food and Drugs Administration (FDA) clinical pharmacologist and as practicing clinical pharmacist in hospitals for 25 years, there are no drugs that of concern than the Narrow Therapeutic Index (NTI) drugs. Results: NTI drugs are very dangerous in that any small change in the dose or concentration or interaction with any drugs, may end up with major consequences. That is why in hospitals, NTI drugs are routinely monitor such as vancomycin and gentamicin. Similarly, at the FDA, it is essential that labels specify the drug levels for certain conditions or diseases that are being monitoring. Conclusions: The plasma levels sometimes are required for in-patient and out-patient for drugs such as valproic acid, digoxin, and theophylline. It is essential that NTI must be monitored in-patient and out-patient.

Ziprasidone (Geodon®), also known at the time of submission to the Food and Drug Administration (FDA) as Zeldox®. It was submitted initially for the treatment of psychiatric disorders e.g., Schizophrenia. However, there was delay on its approval due to increase of QT prolongation, which was discussed at the FDA Advisory Committee. This review focused on the clinical pharmacology and the pharmacokinetics (PK) of the drug, specifically at the time of submission to the FDA and other related updated references. The sponsor (Pfizer) summitted about 40 clinical pharmacology and PK studies including QT prolongation studies. There were four capsules formulation at that time: 20, 40, 60, and 80 mg and one intramuscular (IM) strength in another New Drug Administration (NDA) that came subsequent to oral route. The drug has to be given with food to increase the bioavailability to 60% (two-fold increase). Ziprasidone is extensively metabolized after oral administration with only a small amount excreted in the urine (<1%) or feces (<4%) as unchanged drug. Approximately 20% of the dose is excreted in the urine, with approximately 66% being eliminated in the feces. Some of its metabolites are active. Ziprasidone has very high, sub nanomolar binding affinity for the human serotonin.