Value of preapproval safety data in predicting postapproval hepatic safety and assessing the legitimacy of class warning.

OBJECTIVE: The objective of this study was to systematically evaluate whether preapproval safety data for nonhepatotoxic drugs and hepatotoxic drugs can be compared to improve preapproval prediction of postapproval hepatic safety and to assess the legitimacy of applying class warnings. METHODS: Drugs within a therapeutic class that included at least one drug that had been withdrawn from the market because of liver toxicity or had a warning of potential liver toxicity issued by major regulatory agencies, and at least one drug free from such regulatory action, were identified and divided into two groups: drugs with and drugs without regulatory action. Preapproval clinical data [including the elevation rates of alanine aminotransferse (ALT) and withdrawal due to liver toxicity, the number of patients with combined elevation of ALT and bilirubin, and liver failure] and nonclinical data (including chemical structures, metabolic pathways, and other significant findings in animal studies) were compared between the two groups. RESULTS: Six drug classes were assessed in this study: thiazolidinediones, cyclooxygenase-2 inhibitors, fluoroquinolones, catechol-O-methyltransferase (COMT) inhibitors, leukotriene receptor inhibitors, and endothelin receptor antagonists. In two classes (COMT inhibitors and endothelin receptor antagonists), drugs with regulatory action had significantly higher rates of ALT elevation of more than threefold and greater numbers of patients with combined elevation of ALT and bilirubin than drugs without regulatory action. Drugs with regulatory action also had chemical structures or metabolic pathways associated with the toxicity. The legitimacy of class warnings was refuted in all six classes of drugs. CONCLUSION: Preapproval safety data may help predict postapproval hepatic safety and can be used to assess the legitimacy of applying class warnings.

Electrophysiologic, pharmacokinetic, and pharmacodynamic values indicating a higher risk of torsades de pointes.

Torsades de pointes (TdP) is a major safety concern with drugs that are submitted for regulatory approval. The study aimed to identify the electrophysiological, pharmacokinetic, and pharmacodynamic values indicating a higher risk of TdP. A number of QT-prolonging drugs were assigned to 2 groups. Group 1 consisted of drugs that had been withdrawn or suspended from the market because of unacceptable TdP risk or for which numerous reports of TdP had been published. Group 2 included drugs for which there had been isolated reports or no report. The results showed that drugs in group 1 induced greater inhibition of human ether-a-go-go-related gene (HERG) potassium current or the rapid component of the delayed rectifier potassium current (I(kr)), had lower half-maximal inhibitory concentration (IC50) values for inhibition of HERG/I(kr), and induced greater QTc increases in humans. The cutoff values indicating a higher risk of TdP included an increase in action potential duration greater than 10% at concentration lower than 300 nM, inhibition of HERG/I(kr) greater than 30% at therapeutic concentration, IC50 lower than 2 µM, a mean QTc increase greater than 15.5 milliseconds in monotherapy and 12.0 milliseconds with concurrent use of metabolic inhibitors, and an upper bound of its 95% confidence interval greater than 21 milliseconds in monotherapy and 19.4 milliseconds in the presence of metabolic inhibition.

Electrocardiographic monitoring for QT prolongation in patients treated with ziprasidone--a claims database approach.

PURPOSE: Drug-induced cardiac arrhythmia is a major safety concern for drugs with a potential to prolong the QT interval. The purpose of the study is to examine whether timely electrocardiographic (ECG) monitoring has been performed for patients treated with ziprasidone. METHODS: Out-patient pharmacy claims data abstracted from Taiwan's National Health Insurance Research Database were used to identify patients treated with ziprasidone. Based on the dataset sorted by the encrypted patient identifier and by date, the rates of ECG performed before and during treatment were examined. The intervals between treatment beginning and ECG examination during therapy were calculated. RESULTS: Among 4789 patients ever treated with zipasidone, 229 (4.8%) had ECG performed before treatment. Among 2052 patients treated with a longer duration of ziprasidone, 394 (19.2%) had ECG performed during treatment. They included 64 (3.1%) patients who had it performed within the first 30 days of treatment, 124 (6.0%) within 60 days and 178 (8.7%) within 90 days. The mean interval was 157.4 days (95% confidence interval (CI), 143.0-171.8) between treatment beginning and the first on-therapy ECG examination and was 210.4 days (95%CI, 178.6-242.2) between treatment beginning and the second ECG. CONCLUSIONS: Low rates of ECG examination before and during therapy were noted among patients treated with ziprasidone. It took significant length of time to perform ECG monitoring after treatment was started. Although the patients studied had few risk factors for cardiac arrhythmia, ECG monitoring for patients using ziprasdione could be improved.

Magnitude of QT prolongation associated with a higher risk of Torsades de Pointes.

PURPOSE: Drug induced Torsades de Pointes (TdP) is a major concern for new drugs seeking regulatory approval. Prolongation of QT intervals greater than 60 millisecond or to longer than 500 millisecond in an individual patient has been considered to be associated with a higher risk. The purpose of this study is to identify values inferred from a population that predict a stronger potential for TdP. METHODS: Prolongation data of 30 non-antiarrhythmic QT prolonging drugs were analysed. Depending on how strong the drugs were associated with TdP, they were categorized as strong or borderline torsadogens. The differences in mean QTc increases between the two groups were compared and cut-off values that distinguished strong from borderline drugs were searched for. RESULTS: The average QTc increase of 19.3 millisecond of strong torsadogens was significantly greater than the 8.0 millisecond of borderline torsadogens. Prolongation greater than 12 millisecond in the context of monotherapy or 25 millisecond in the presence of metabolic inhibition and an upper bound of 95% confidence interval (CI) for the mean QTc increase greater than 14 millisecond in monotherapy or 30.1 millisecond in combination therapy with metabolic inhibitors favoured a stronger association with TdP. CONCLUSIONS: Drugs strongly associated with TdP have greater QTc increases than those with less concern. Several cut-off values have been noted to distinguish between them. These values may be helpful for evaluation of TdP risk for future QT prolonging drugs.