In vivo drug-drug interaction studies--a survey of all new molecular entities approved from 1987 to 1997.

Ninety-eight new molecular entities applications approved between 1987 to 1991 (period I) and 193 applications for new molecular entities between 1992 to 1997 (period II) were surveyed for drug-drug interaction studies. In period I (used as a comparator), 32 applications contained drug-drug interaction studies for a total of 117 studies. In period II, 106 applications reported drug-drug interaction studies, and the number of studies per new molecular entity ranged from 0 to 15. Most studies (77%) were performed in healthy subjects, with 44% using crossover designs, 7% using parallel designs, and the remaining using fixed sequence designs. The most common dosing scheme for new molecular entities/interacting drug was multiple dose (47%), whereas single dose/multiple dose was used in 31% of studies, and single dose/single dose was used in 18% of studies. Of the 540 drug-drug interaction studies submitted in period II, 80 (15%) resulted in clinically significant labeling statements. Submissions for new molecular entities to the Center for Drug Evaluation and Research divisions most likely to include drug-drug interaction studies were neuropharmacology, cardiorenal, antiviral, and antiinfective drugs. Some drug classes such as oncology drug products and radioimaging products were least likely to include drug-drug interaction studies in their submissions. We conclude that the use of drug-drug interaction studies in the drug development process has increased between the two periods.

Utilisation of pharmacokinetic-pharmacodynamic modelling and simulation in regulatory decision-making.

Modelling and simulation (M&S) play an important role in regulatory decision-making that affects both the public and industry. Technological advances in various fields related to drug development call for more focus on ways to optimise current drug development practices. Recognition of the potential of M&S by regulatory agencies inevitably has a substantial impact on drug development. The objective of the current review is to present the various regulatory initiatives for application of M&S to clinical drug development. The relevant parts of the various recommendations issued by the US Food and Drug Administration (FDA), via guidance documents and advisory committee meeting proceedings, are highlighted. Application of M&S to a variety of activities, such as integrating pharmacokinetic-pharmacodynamic knowledge across a new drug application and designing efficient trials, is discussed. Some of the challenges that pharmaceutical institutions currently face when implementing M&S projects, such as team structure, communication with regulators, training and time constraints, are also presented, and solutions are proposed.

Red blood cell partitioning, protein binding and lipophilicity of six phenothiazines.

Hexane-water partition coefficients, pKa values, protein binding and red blood cell partitioning were studied with six phenothiazine drugs. Red cell partitioning was independent of drug concentration, and there was no correlation between partitioning and physicochemical characteristics. Red cell partitioning could be used indirectly to estimate protein binding, but two potential pitfalls of general importance were found. Failure to consider drug binding of glassware and haematocrit changes were shown to induce incorrect estimates of both red cell partitioning and protein binding, as well as hexane-water partition coefficients.

Pharmacokinetics and pharmacodynamics of acepromazine in horses.

A specific, sensitive, reverse-phase high-performance liquid chromatographic assay for acepromazine, with analytic sensitivity as low as 5 ng/ml of plasma, and electrochemical detection with an oxidation potential of 0.7 V, was used to study the pharmacokinetics of acepromazine given at a dosage of 0.15 mg/kg of body weight in horses. The relation between effect and pharmacokinetics of the drug was examined. The effects studied included those on blood pressure, pulse, PCV, measures of respiration function, and sedation. Intravenously administered doses led to a biphasic concentration decay pattern with an alpha-phase distribution half-life of < 3 minutes. The beta-phase half-life was in the range of 50 to 150 minutes. The CNS effects peaked at 20 minutes after administration, and the hemodynamic effects peaked at 100 minutes. In all horses, the most sensitive variable was the PCV, which decreased by up to 20% (P < 0.0001). Systolic, diastolic, and mean blood pressures decreased (P < 0.0001); heart rate was unchanged (P > 0.05). Neither blood gas tensions nor blood pH changed noticeably (P > 0.05). In all horses studied, acepromazine had a significant (P < 0.0001) sedative effect, as observed by posture and alertness. None of the observed pharmacodynamic effects correlated well with plasma acepromazine concentration. These effects persisted beyond the time of detectable acepromazine concentration, indicating that they might be caused by active metabolites, or that their timing could result from complex pharmacokinetic compartment influences.