Peter K. Honig

Concomitant Risk Factors in Reports of Torsades de Pointes Associated with Macrolide Use: Review of the United States Food and Drug Administration Adverse Event Reporting System

In this case series, we examined concomitant risk factors mentioned in reports of torsades de pointes, a rare ventricular arrhythmia, that occurred in association with administration of macrolide antimicrobials (e.g., azithromycin, clarithromycin, dirithromycin, and erythromycin). Increasing age, female sex, and concomitant diseases and drug administration believed to increase risks for torsades de pointes were commonly reported.

Temporal decline in filling prescriptions for terfenadine closely in time with those for either ketoconazole or erythromycin

Temporal changes in the rates of filling terfenadine prescriptions within 2 days of those for either oral erythromycin or oral ketoconazole were described with use of paid pharmacy claims data from 1988 through 1994 in state Medicaid programs from Michigan and Ohio and in a large health maintenance organization. There were rapid and significant declines in the rates of filling prescriptions for either erythromycin or ketoconazole within 2 days of prescriptions for terfenadine in all three databases that coincided with 1992 publicity about the cardiovascular risk of terfenadine. These findings suggest that the use of terfenadine with contraindicated medications has declined in response to relabeling and publicity concerning the safe use of terfenadine. Further study is necessary to estimate the absolute level of concurrent use of terfenadine with contraindicated medications.

Clinical Pharmacology Studies in Patients with Renal Impairment: Past Experience and Regulatory Perspectives

The objective of this report is to provide a regulatory perspective on the quality of pharmacokinetic studies in renal impairment (RI) studies submitted in support of new drug applications (NBAs) or supplements to NDAs (sNDAs) submitted to the Food and Drug Administration (FDA). Fifty‐one NDA and 20 sNDA submissions reviewed between 1996 and 1997 by the Office of Clinical Pharmacology and Biopharmaceutics were evaluated for the following: (1) whether an RI study was conducted; (2) contribution of the renal clearance to the overall clearance in subjects without renal impairment; (3) degree of plasma protein binding (%PB) in subjects without renal impairment; (4) dose proportionality of single and multiple doses; (5) study design, including dosing regimen; (6) definition of renal impairment; (7) stratification of renal functions; (8) number of subjects/group; (9) data analysis and interpretation; and (10) impact on labeling. Results of the analysis indicated that 67% of the NDAs and 30% of supplemental NDAs contained RI studies (34/51 for NDAs and 6/20 for sNDAs). No obvious differences in the pharmacokinetic characteristics (e.g., percentage excreted unchanged in urine and %PB) were observed between drugs for which RI studies were conducted versus those not conducted. Most studies conducted were designed as single dose (70%). Seventy‐five percent of the studies used doses within the therapeutic dosage range of the drug. The measured 24‐hour creatinine clearance was most often used to assess the renal function. Stratification of renal function ranged from one to five groups, with 6 to 8 subjects enrolled per group. In most studies conducted (38/40), data were analyzed by point estimate using ANOVA. Results of RI studies were adequately reflected in the labeling. The survey reveals that RI study design can be improved for regulatory review purposes. In part based on this analysis, the FDA has prepared a guidance that provides recommendations on the design, analysis, and impact on dosing and labeling for RI studies to include recommendations on when RI studies do not need to be performed. The guidance proposes an equivalence approach with confidence intervals, as opposed to a point estimate approach, to assess the impact of RI on systemic exposure measures.

Clinical pharmacology studies in patients with renal impairment (RI): Past experience and regulatory perspectives

Clinical Pharmacology & Therapeutics (1999) 65, 201–201; doi:

DRUG METABOLISM IN DRUG DEVELOPMENT: A DIA TUTORIAL FOR REGULATORY AFFAIRS SPECIALISTS*

Many drug metabolism, drug-drug interaction, and pharmacogenetics meetings are held each year and are well attended by scientists from the pharmaceutical industry, academia, and worldwide regulatory agencies. Personal communication indicated that large amounts of drug metabolism information passed across the desks of the regulatory affairs specialists either as reports being submitted to or as information requests from regulatory agencies and that, unlike other preclinical or clinical data, there was little appreciation of the meaning or relevance of such information to the overall drug development campaign. The purpose of the tutorial described here was to allow regulatory affairs specialists to gain a working appreciation of the nomenclature, techniques, and usefulness of in vitro and in vivo drug metabolism studies.