Single dose studies

Based on a single-dose study and tissue blood concentration ratios, diisopropyl methylphosphonate is taken up by the lungs of mice, rats, and dogs (Hart 1976). The lung blood concentration ratios are 4.5 for mice, 3.6 for rats, and 2.0 for dogs. There is also some uptake of the [14C]-label by the testes where the testes blood concentration ratios are 2.7 for mice, 2.3 for rats, but only 1.1 for dogs. 

Studies in animals indicate that the effects of lead on heme synthesis occur in many tissues and that the time courses of these effects depends on the tissue, exposure duration, and the chemical and animal species administered. Oral exposure of rats to lead acetate increased liver ALAS activity in a single dose study (Chmielnicka et al. 1994), decreased liver ALAS activity in a chronic study (Silbergeld et al. 

Chronic and subchronic toxicity studies are conducted to define the dose level, when given repeatedly, that cause toxicity, and the dose level that does not lead to toxic findings. In Japan, such studies are referred to as repeated-dose toxicity studies. As with single-dose studies, at least two animal species should be used, one rodent and one nonrodent (rabbit not acceptable). In rodent studies, each group should consist of at least 10 males and 10 females in nonrodent species, 3 of each sex are deemed adequate. Where interim examinations are planned, however, the numbers of animals employed should be increased accordingly. The planned route of administration in human subjects is normally explored. The duration of the study will be dictated by the planned duration of clinical use (Table 2.14). 

Based on these general principles, the first dose in humans should be supported by a single-dose study in an appropriate animal species by the intended clinical... 

Single-dose studies are performed in two species, usually rat and mouse, by two routes of administration, usually intravenous, to ensure systemic exposure, and the proposed clinical route. Following the ICH guidance in November 1991, non-rodent, single-dose tests are no longer required. If the proposed clinical route is intravenous, then one route is usually acceptable. 

Single-dose studies may be performed early in a development programme. The information gained from these studies is rapidly superseded, in terms of its value for risk assessment, by repeat-dose studies. 

Table is to be used for estimation only. Data are compiled from multiple references and may be based on single-dose studies. 

Pharmacokinetics Buspirone is rapidly absorbed and undergoes extensive first-pass metabolism. Approximately 95% of buspirone is plasma protein bound. In a single dose study, 29% to 63% of the dose was excreted in the urine within 24 hours. 

Drug/Food interactions Several case reports and single-dose studies suggest that enteral nutritional therapy may decrease phenytoin concentrations however, this has not been substantiated. 

QTproiongation and potentiai for proarrhythmic effects In single dose studies of apomorphine, changes in QTc ranging from 0 to 7 msec were reported. Some drugs that prolong the QT/QTc interval have been associated with the occurrence of torsades de pointes and with sudden unexplained death. 

Renai/Hepatic function impairment The safety and pharmacokinetics of rimantadine in renal and hepatic insufficiency only have been evaluated after single dose administration. In a single dose study of patients with anuric renal failure, the apparent clearance was approximately 40% lower and the elimination half-life was 1.6-fold greater than that in healthy controls. In a study of 14 people with chronic liver disease (mostly stabilized cirrhotics), no alterations in the pharmacokinetics were observed after a single dose of rimantadine. However, the apparent clearance of rimantadine following a single dose to 10 patients with severe liver dysfunction was 50% lower than that reported for healthy subjects. Because of the potential for accumulation of rimantadine and its metabolites in plasma, exercise caution when patients with renal or hepatic insufficiency are treated with rimantadine. 

Excretion - Of the 99% of the total abacavir dose recovered, 1.2% was excreted unchanged in the urine as abacavir. Fecal elimination accounted for 16% of the dose. In single-dose studies, the observed elimination half-life was approximately 1.54 hours. 

Sometimes there is a reason for changing the opioid in an individual patient. In these circumstances the recommendation has been to switch between opioids according to particular so-called equi-analgesic dose measures. These are often based on single dose studies and therefore have limited applicability in patients who have been treated for a longer time. 

Further complicating the picture is the induction of autoreceptor supersensitivity with chronic neuroleptic administration, as well as the fact that at least one tract-the mesocortical, which projects to the prefrontal cortex-may lack such autoreceptors. Some of the authors conducted preliminary, single-dose studies with apomorphine at a dose that stimulated presynaptic DA autoreceptors that reduced synthesis and NT release, producing a measurable acute antipsychotic effect ( 9, 10). 

Figure 6 Moraxen rectal delivery system. Comparative steady-state simulation of morphine plasma levels after single daily rectal administration of Moraxen with 100 mg morphine compared with twice-daily 50 mg morphine (OSRM) in an oral prolonged-release formulation. The simulation is based on the plasma levels from a single-dose study.

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