Dose-plasma level correlation

Phenobarbitone has a long half-life of about 3 days (M7) and plasma levels correlate moderately well with the daily dose (B4, B32, S30). A therapeutic range (Table 2) of 8-21 ju.g/ml has been described (S30), and severe toxic symptoms are rarely encountered in association with plasma levels below 50/tg/ml (Lll). 

No modern studies of the human pharmacokinetics of LSD have been done, largely because human experimentation has virtually stopped. An older study that used a spectrofluorometric technique for measuring plasma concentrations of LSD was done in humans given doses of 2 Mg/kg i.v. After equilibration had occurred in about 30 min, the plasma level was between 6 and 7 ng/ml. Subsequently, plasma levels gradually fell until only a small amount of LSD was present after 8 hr. The half-life of the drug in humans was calculated to be 175 min (2). Subsequent pharmacokinetic analysis of these data indicated that plasma concentrations of LSD were explained by a two-compartment open model. Performance scores were highly correlated with concentration in the tissue (outer) compartment, which was calculated at 11.5% of body weight. The new estimation of half-life for loss of LSD from plasma, based on this model, was 103 min (47). 

A dose-finding study of duloxetine based on duloxetine-associated SERT occupancy was recently reported using PET [61]. SERT occupancies increased dose responsively and correlated well with the plasma concentration of duloxetine. It was found that 40 mg or more duloxetine was needed to attain 80% occupancy, and 60 mg of duloxetine could maintain a high level of SERT occupancy with once-a-day dosing. 

Phase I data were presented at the 95th AACR meeting, March 2004. Normal healthy male volunteers were subjected to bone marrow aspirations prior to and 4 h following a single 25 mg oral dose of the compound or placebo. L21649 achieved plasma concentrations of 103.4 nM at 4 h post-dose. In July 2004, similar clinical data were presented at the 29th National Medicinal Chemistry symposium. The PK/PD correlated well, and at that time, it was believed that the plasma levels should be closer to the EC90 levels for maximal efficacy. 

Clonidine is well absorbed after oral administration. Peak plasma levels occur between 2 and 4 hours after drug administration and correlate well with pharmacological activity. The plasma half-life in patients with normal renal function is 12 hours. Urinary excretion of clonidine and its metabolites accounts for almost 90% of the administered dose, and fecal excretion accounts for the rest. Approximately 50% of an administered dose is excreted unchanged the remainder is oxidatively metabolized in the liver. 

For some psychotropic drugs (e.g., lithium and some antidepressants) a good correlation exists between plasma levels and therapeutic or toxic effects. Optimum steady-state levels can now be predicted from single-dose blood level data of some drugs (lithium, nortriptyline, desipramine). Altered PK behavior in children has to be taken into consideration in using psychotropic drugs. With development of suitable drug... 

The hypothesis that the optimal dose of SSRI may be dependent on HTT variants is intriguing it can be speculated that dose-response correlations differ across genotypes patients with one or two copies of the short variant of the serotonin transporter might respond at lower doses and/or plasma levels of SSRIs than patients with two copies of the long variant. This hypothesis could be tested using flexible-dose placebo-controlled designs coupled with family-based association studies. 

Carbamazepine should be initiated at a dosage of 200 mg twice a day, with increases in increments of 200 mg/day every 3-5 days. Cited plasma levels of 8-12 ng/mL are based on clinical use in patients with seizure disorders and do not correlate with clinical response in patients with psychiatric disorders. We recommend dose titration to achieve clinical response and minimize side effects... 

This section deals with the question of whether there are quantitatively detectable and interpretable correlations between the dose of an administered drug, or the concentration of a drug and its metabolites measured in the blood or plasma (blood or plasma level), and the therapeutic action or side effects observed. Investigations relating to questions of this type are called PK PD (pharmacokinetic pharmacodynamic) studies. The PK PD analysis is a bidirectional approach pharmacokinetics represent what the body does with a drug, and pharmacodynamics describes what a drug does to the body. The PK PD analyses are key elements of early drug development, and PK PD trials are able to answer specific disease-related efficacy and safety questions. 

Substantial interindividual variability is seen in the plasma levels of bupropion, as well as in its three metabolites. There is a correlation between levels of threohydrobupropion and erythrohydrobupropion but not between the levels of these metabolites and those of either the parent drug or hydroxybupropion ( 315). Thus, there can be substantial differences in plasma levels among patients on the same dose of bupropion. 

Although studies have been done with virtually all of the SSRIs attempting to correlate antidepressant efficacy with plasma drug levels, they have consistently failed to find a relationship (121,342, 343, 344, 345, 346, 347 and 348). However, a relationship has been found between the plasma levels of each SSRI achieved on the lowest, usually effective dose and the ability to inhibit approximately 70% to 80% of serotonin uptake ( 25). Thus, patients who have SSRI plasma levels below this threshold have probably not had an optimal trial of the SSRI as a result of rapid clearance, inadequate dose, or noncompliance. 

Fig. 5 shows an example of the plasma levels after administration of the pulsed release system to two volunteers. As can be seen from Fig. 5, in both cases there are two peaks. The first peak is 20pg ml-1 after about lh, and the second is 16-20 pg 1 after 4.5-5 h there is an evident delay in the absorption of the second dose which appears to correlate quite well with the in vitro performance of the pulsed system. 

Another cause of toxicity with diphenylhydantoin can be the result of interactions with other drugs such as isoniazid. This drug is a noncompetitive inhibitor of the aromatic hydroxylation of diphenylhydantoin. Consequently, the elimination of diphenylhydantoin is impaired in the presence of isoniazid, and the plasma level is greater than anticipated for a normal therapeutic dose. Furthermore, it was found that there was a significant correlation... 

Peak plasma levels in pM per mg isoflavone per kg body weight. b Correlation between dose and plasma levels by linear regression. 

Cardiovascular Safety Effects on vascular tone have received the most attention, as a result of toxicities that were identified very early in the development of the first systemically administered PS ODNs. We showed that there was correlation between complement activation and the reported alterations in blood pressure and heart rate in monkeys treated with high doses of PS ODN [40-42], The observation appears to be unique or at least more prominent in monkeys, and that has actually driven the need to characterize the toxicity of oligonucleotide therapeutics in monkeys as the nonrodent species. (Note that complement activation has not proved to be a significant issue in the clinic, although in clinical studies we strive to avoid plasma levels that might be associated anaphylactoid responses in monkeys.)... 

Positive correlations between plasma levels of vanadium and manic depressive psychosis have been observed in a number of laboratories160"163. Symptoms are augmented when patients are administered vanadium for 10 days162, but large doses of ascorbic acid reverses this effect possibly through the reduction of vanadium(V) to van-adium(IV)160. It has been suggested that manic depressives may have a defect in the sodium pump or that vanadium is a factor in controlling the Na+, K+-ATPase activity in this illness. 

---