Dose

Abstract: The glycopeptide antibacterial teicoplanin has become increasingly popular in the last decade with the rise in infections related to methicillin-resistant Staphylococcus aureus. Teicoplanin has 6 major and 4 minor components. It is predominantly (90%) bound to plasma proteins. Of the several methods available to measure concentrations in serum, fluorescence polarisation immunoassay has high reliability and specificity. Teicoplanin is not absorbed orally, but intravenous and intramuscular administration are well tolerated. Teicoplanin is eliminated predominantly by the kidneys and only 2 to 3% of an intravenously administered dose is metabolised. Total clearance is 11 ml/h/kg. Steady state is reached only slowly, 93% after 14 days of repeated administration. Elimination is triexponential, with half-lives of 0.4 to 1.0, 9.7 to 15.4 and 83 to 168 hours. Volumes of distribution are 0.07 to 0.11 (initial phase), 1.3 to 1.5 (distribution phase) and 0.9 to 1.6 (steady state) L/kg. A standard dosage regimen of 6 mg/kg every 12 hours for 3 doses, then daily, will produce therapeutic serum concentrations of ≥10 mg/L in most patients. Higher dosages may be required in certain patients, for example intravenous drug abusers or those with burns, because of unpredictable clearance. Concentrations in bone reach 7 mg/L at 12 hours after a dose of teicoplanin 6 mg/kg, but reach only 3.5 mg/L in the cartilage. Doses of 10 mg/kg are necessary to achieve adequate bone concentrations. There is little penetration into cerebrospinal fluid or the aqueous or vitreous humour. In fat, concentrations may be subtherapeutic (0.5 to 5 mg/L) after a dose of 400mg. A single prophylactic dose of 12 mg/kg is sufficient to maintain therapeutic concentrations during cardiopulmonary bypass or burns surgery. High loading doses reduce the delay to attaining therapeutic concentrations. Premature neonates require a loading dose of 15 mg/kg and a maintenance dosage of 8 mg/kg daily to ensure therapeutic serum concentrations. Children need loading with 10 mg/kg every 12 hours for 3 doses followed by maintenance with 10 mg/kg/day. Clearance is reduced predictably in renal failure, and dosage adjustments can be based on the ratio of impaired clearance to normal clearance. In patients on haemodialysis, 3 loading doses of 6 mg/kg at 12-hour intervals followed by maintenance doses every 72 hours produced trough plasma concentrations of 8 mg/L in most patients at 48 hours. The monitoring of serum concentrations is not necessary to avoid toxicity, but can be helpful in certain patient groups to ensure therapeutic concentrations are present, especially in those not responding to treatment.

Abstract: After a single dose, lithium, usually given as carbonate, reaches a peak plasma concentration at 1.0-2.0 hours for standard-release dosage forms, and 4-5 hours for sustained-release forms. Its bioavailability is 80-100%, its total clearance 10-40 mL/min and its elimination half-life is 18-36 hours. Use of the sustained-release formulation results in 30-50% reductions in peak plasma concentrations without major changes in the area under the plasma concentration curve. Lithium distribution to the brain, evaluated using 7Li magnetic resonance spectroscopy, showed brain concentrations to be approximately half those in serum, occasionally increasing to 75-80%. Brain concentrations were weakly correlated with serum concentrations. Lithium is almost exclusively excreted via the kidney as a free ion and lithium clearance is considered to decrease with aging. No gender- or race-related differences in kinetics have been demonstrated. Renal insufficiency is associated with a considerable reduction in renal clearance of lithium and is considered a contraindication to its use, especially if a sodium-poor diet is required. During the last months of pregnancy, lithium clearance increases by 30-50% as a result of an increase in glomerular filtration rate. Lithium also passes freely from maternal plasma into breast milk. Numerous kinetic interactions have been described for lithium, usually involving a decrease in the drug's clearance and therefore increasing its potential toxicity. Clinical pharmacology studies performed in healthy volunteers have investigated a possible effect of lithium on cognitive functions. Most of these studies reported a slight, negative effect on vigilance, alertness, learning and short-term memory after long-term administration only. Because of the narrow therapeutic range of lithium, therapeutic monitoring is the basis for optimal use and administration of this drug. Lithium dosages should be adjusted on the basis of the serum concentration drawn (optimally) 12 hours after the last dose. In patients receiving once-daily administration, the serum concentration at 24 hours should serve as the control value. The efficacy of lithium is clearly dose-dependent and reliably correlates with serum concentrations. It is now generally accepted that concentrations should be maintained between 0.6 and 0.8 mmol/L, although some authors still favour 0.8-1.2 mmol/L. With sustained-release preparations, and because of the later peak of serum lithium concentration, it is advised to keep serum concentrations within the upper range (0.8-1 mmol/L), rather than 0.6-0.8 mmol/L for standard formulations. It is controversial whether a reduced concentration is required in elderly people. The usual maintenance daily dose is 25-35 mmol (lithium carbonate 925-1300 mg) for patients aged 60 years. The initial recommended dose is usually 12-24 mmol (450-900 mg) per day, depending on age and bodyweight. The classical administration schedule is two or three times daily, although there is no strong evidence in favour of a three-times-daily schedule, and compliance with the midday dose is questionable. With a modern sustained-release preparation, the twice-daily schedule is well established, although one single evening dose is being recommended by a number of expert panels.

Abstract: A pharmacokinetic comparison of the two recommended dosages of vancomycin given as multiple doses has not been previously performed. Eleven adult subjects with normal renal function randomly received 500 mg every 6 h (five doses) and, later, 1,000 mg every 12 h (three doses). Each dose was infused over 1 h, and regimens were separated by 1 week. Compared with the two-compartment fit, a three-compartment fit significantly reduced the residual weighted sums of squares. Accumulation occurred for both regimens after repeated dosing and was independent of dose. At steady state, concentrations in serum at 1 h showed little variation for the 1,000- or the 500-mg dose regimen (33.7 +/- 3.8 versus 22.6 +/- 3.2 micrograms/ml); trough concentrations were 7.9 +/- 1.7 versus 11.2 +/- 2.2 micrograms/ml, respectively. With the 1,000-mg dose, the terminal half-life was 7.7 +/- 1.8 h, steady-state area under the curve for the dose interval was 227 +/- 28.3 micrograms X h/ml, and total body clearance was 86.1 +/- 8.9 ml/min per 1.73 m2. The red-man syndrome occurred in 9 of 11 volunteers who received 1,000-mg doses and in none of those who received 500-mg doses. We concluded that vancomycin disposition in healthy adults with normal renal function is best described by a three-compartment model, there is relatively little variation in vancomycin disposition in normal volunteers, significant accumulation occurs with multiple dosing, it is inappropriate to use the same therapeutic window for both regimens, and the pharmacokinetics of vancomycin justify a 12-h dose interval; however, a 1-g dose is associated with a significantly greater incidence of the red-man syndrome.

Abstract: Purpose: A phase I clinical trial in patients with advanced carcinomas was conducted using the orally available neurotrophin receptor-linked tyrosine kinase receptor inhibitor, CEP-701. The objectives were to determine the maximum tolerated dose (MTD), dose-limiting toxicities, and pharmacokinetic profile of this orally administered agent. Patients and methods: A total of 30 patients were accrued to receive escalating BID doses of CEP-701 in cycles lasting 28 days. Between 3 and 6 patients were enrolled at each dose level. Once the MTD was determined, nine de novo patients were recruited to receive that level of drug. Pharmacokinetic studies were performed after the first dose, with additional sampling to assess intraindividual variability. Results: The dosages ranged from 5 mg BID to 160 mg BID. While the criteria for MTD were not met at the dose levels administered, DLTs were observed at 80 and 120 mg BID. Treatment related adverse events, especially of the gastrointestinal system, made CEP-701 poorly tolerated at dosages above 40 mg BID. While CEP-701 did not produce an objective tumor response in any patient, 7 of the 30 patients received treatment for 3 months or more, including 3 who were on study with stable disease for more than 6 months. Orally administered CEP-701 was rapidly absorbed, with a mean t max between 1 and 3 hours. At higher dose levels, serum drug levels showed greater than dose-proportional increases by Day 28 versus Day 1. Conclusion: CEP-701 40 mg BID was well tolerated by patients with advanced malignancy and is the recommended dose level for planned phase II trials. Further study is necessary to determine the clinical efficacy of this novel new chemotherapeutic agent.