Single-dose administration

Chow, H.H. et al., Phase I pharmacokinetic study of tea polyphenols following single-dose administration of epigallocatechin gallate and polyphenon E, Cancer Epidemiol Biomarkers Prev, 10, 53, 2001. 

This reversible HDAC inhibitor has potency in low nanomolar ranges. ° TSA induces cellular differentiation, apoptosis and growth factor unresponsiveness when administered under regimental dosing and not under single dose administration. However, TSA showed poor results in clinical trials, likely due to a combination of poor biodistribu-fion and fast metabolism. 

If after single dose administration, the blood samples are not collected at time intervals, which allow for a description of the whole plasma concentration time course, including the absorption, distribution, and elimination phase, the information obtained is limited. In particular, data should be available in the hrst hours after administration to cover the absorption phase. If measurements of the parent compound and its metabolite(s) are made in this period, this will allow assessment of an extensive first pass effect, i.e., when a substance after oral administration is transported via the portal vein to the liver where metabolism takes place before the substance enters the systemic circulation. 

Children After a single-dose administration of 5 to 15 mg/kg of oxcarbazepine, the dose-adjusted AUC values of MHD were 30% to 40% lower in children younger than 8 years of age than in children older than 8 years of age. The clearance in children older than 8 years of age approaches that of adults. 

Age Cross-study comparison of pharmacokinetic data following single dose administration of 6 mg tizanidine showed that younger subjects cleared the drug 4 times faster than the elderly subjects. Tizanidine has not been evaluated in children. 

Tablets The terminal half-life following a single dose administration is approximately 120 to 170 hours. The total apparent clearance is about 26 L/h. 

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. 

Pharmacokinetics One emtricitabine/tenofovir disoproxil fumarate tablet was bioequivalent to 1 emthcitabine capsule (200 mg) plus 1 tenofovir disoproxil fumarate tablet (300 mg) following single-dose administration to fasting healthy subjects. 

The fact that single-dose administration of benzodiazepines could have marked amnestic effects was first recognized in anesthesiology where these drugs are used to relax and sedate patients prior to surgery. It was found that,... 

Two patients stabilized on a phenytoin regimen suffered a loss of seizure control after taking shankhapushpi, an Ayurvedic antiepileptic medicine, three times a day. There was also a significant decrease in serum phenytoin concentration from 9.6 to 5.1mg/L. To investigate the possible mechanisms, multiple doses of shankhapushpi were administered to rats and resulted in decreased plasma phenytoin concentrations, whereas single-dose administration was reported to interfere with the antiplatelet effect of phenytoin, thereby implying both a pharmacokinetic and pharmacodynamic basis for the interaction (73). 

The pharmacokinetic parameters of approved mAbs with regard to absorption, maximum concentration (Cmax) and tmax after single dose administration, systemically available fractions (F), and the commonly used dosing regimens and routes of administration are summarized in Table 3.4. 

Fig. 12.8 (A) Dose-response relationship for adalimumab following singledose administration in patients with rheumatoid arthritis. (Figure produced from data reported in [78]). (B) Simulated suppression of serum TNF-a following single-dose administration of adalimumab.

Fig. 13.2 Mean concentration-time profiles for tasidotin after single-dose administration for patients enrolled in Study 103.

Pantoprazole is subject to low first-pass hepatic extraction, as reflected in an estimated absolute oral bioavailability of 77%. On repeated oral administration, the pharmacokinetics of pantoprazole (20 and 40 mg once daily) are similar to those after single dose administration [1,18]. The absolute bioavailability was 70% in patients with severe liver cirrhosis, and more than 90% in healthy elderly subjects [18]. 

Pharmacokinetic information gained following single-dose administration can be used to help predict the likely events following chronic dosing, either as a constant-rate infusion or multiple dosing, which often involves giving a fixed dose at set time intervals. 

Study design Single-dose Administration Multiple-dose Administration... 

Study Design Single-Dose Administration (n = 93) Multiple-Dose Administration (n = 34) (Day 7)... 

Preclinical Pharmacology. The pharmacokinetics of total and free platinum were determined following oral gavage of JM216 as part of the schedule dependency antitumor experiments described above [20], At doses of 9.5,40 (day 1), 40 (day 5) and 200 mg/kg, non-linear pharmacokinetics were observed, both in terms of total and ultrafilterable platinum. On comparing doses of 9.5 and 40 mg/kg, the AUCs increased by tenfold and out of proportion to the fourfold increase in dose. Conversely, a further fivefold increase in dose to 200 mg/kg (the maximum tolerated for single-dose administration) was accompanied by only a twofold increase in AUC, consistent with saturable absorption. Similar Cmax and AUC values for total and ultra-filterable platinum were obtained on day 5 vs. day 1 for the 40 mg/kg dose level. 

Figure 9.2 Induction of neopterin by administration of interferon-P to rhesus macaques. Mean neopterin concentration after a single dose administration of inter-feron-P in rhesus monkeys. Concentration over time profile plotted from animals...

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