First-time-in-human dose selection: allometric thoughts and perspectives.

Some of the many factors that influence dose selection in first-time-in-human studies are examined. These include animal toxicology, toxicokinetics, allometric scaling, pharmacokinetics, body surface area correlations, and integration of preclinical pharmacologic and toxicologic data. Appropriate preclinical evaluation and analysis may reduce the frequency and severity of unexpected toxic events arising during single-dose, phase I testing. However, significant intrinsic uncertainties in this process presently exist and will continue to exist well into the foreseeable future. With our present state of knowledge, we cannot provide a realistic and reasonable algorithm for ascertaining first-time-in-human doses: any decision tree would be too unwieldy. There are several rules of thumb that do have a place in the evaluation and decision-making process, however.

Comparative kinetics of sematilide in four species.

The goals of this retrospective study with the novel class III antiarrhythmic sematilide HCI were to investigate: a) whether there existed interspecies correlations and b) whether reliable animal-to-human predictions were possible for the main pharmacokinetics parameters. Information on plasma concentrations after intravenous administration was available in rats, rabbits, dogs, and humans. Except for the rabbit, data on the urinary amounts of drug excreted were also available in these species. The drug concentrations in plasma and urine were assayed by a specific HPLC method with UV or electrochemical detection or liquid scintillation spectrometry. In the interspecies correlations and in the animal-to-human predictions, an allometric approach was used with log-log linear regressions of the pharmacokinetic parameters steady-state volume of distribution (Vss), total clearance (CL), mean residence time (t), and terminal disposition half life (t1/2 lambda z), on body weight. The results showed that significant interspecies correlations exist for the tested in vivo pharmacokinetic parameters for sematilide. Reliable animal-to-human predictions with errors < 60% were found for Vss, CL, t1/2 lambda z, and t. In rats, dogs, and humans, sematilide's renal elimination includes glomerular filtration and net tubular secretion. The relative contributions of the renal mechanisms are similar in all three species studied. There were no important species differences observed in the in vitro determined parameters, fraction unbound in plasma, and blood-to-plasma concentration ratio between rats, dogs, and humans.

The pharmacokinetics of oral isradipine in normal volunteers.

The pharmacokinetics and relative bioavailability of oral isradipine, a dihydropyridine calcium channel blocking agent, were determined in 42 normal male volunteers participating in two separate studies. Eighteen of the subjects received 2.5-, 5-, and 10-mg oral doses of isradipine solution (Study 1). The remaining 24 subjects received four 2.5-mg capsules, one 10-mg capsule, and 10 mg of isradipine as an oral solution (Study 2). Venous blood samples were obtained prior to and at frequent intervals after administration of each dose form. Plasma isradipine concentrations were measured by radioimmunoassay. No significant dose effect occurred with respect to any pharmacokinetic parameter except AUC and Cmax in Study 1. In Study 2, Cmax, tmax, and MRT were significantly different after the solution compared with the capsular formulations. The respective pharmacokinetic parameters (mean +/- SD) for the 10-mg solution and 10-mg capsule in Study 2 were time to maximum concentration, 0.40 +/- .28 and 1.57 +/- 0.44 hours; oral clearance, 284.9 +/- 105.3 and 317.0 +/- 138.4 L/hr; elimination half-life, 5.36 +/- 1.8 and 6.63 +/- 2.4 hrs, respectively. Headache, dizziness, and tachycardia were the most frequent adverse effects in both studies.