Therapeutic drug monitoring (TDM) is the quantification and interpretation of drug concentrations in blood to optimize pharmacotherapy. It considers the interindividual variability of pharmacokinetics and thus enables personalized pharmacotherapy. In psychiatry and neurology, patient populations that may particularly benefit from TDM are children and adolescents, pregnant women, elderly patients, individuals with intellectual disabilities, patients with substance abuse disorders, forensic psychiatric patients or patients with known or suspected pharmacokinetic abnormalities. Non-response at therapeutic doses, uncertain drug adherence, suboptimal tolerability, or pharmacokinetic drug-drug interactions are typical indications for TDM. However, the potential benefits of TDM to optimize pharmacotherapy can only be obtained if the method is adequately integrated in the clinical treatment process. To supply treating physicians and laboratories with valid information on TDM, the TDM task force of the Arbeitsgemeinschaft fur Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued their first guidelines for TDM in psychiatry in 2004. After an update in 2011, it was time for the next update. Following the new guidelines holds the potential to improve neuropsychopharmacotherapy, accelerate the recovery of many patients, and reduce health care costs.

/pdf/consensus-guidelines-for-therapeutic-drug-monitoring-in-18b8y5mu39.pdf

Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017.

Therapeutic drug monitoring (TDM), i. e., the quantification of serum or plasma concentrations of medications for dose optimization, has proven a valuable tool for the patient-matched psychopharmacotherapy. Uncertain drug adherence, suboptimal tolerability, non-response at therapeutic doses, or pharmacokinetic drug-drug interactions are typical situations when measurement of medication concentrations is helpful. Patient populations that may predominantly benefit from TDM in psychiatry are children, pregnant women, elderly patients, individuals with intelligence disabilities, forensic patients, patients with known or suspected genetically determined pharmacokinetic abnormalities or individuals with pharmacokinetically relevant comorbidities. However, the potential benefits of TDM for optimization of pharmacotherapy can only be obtained if the method is adequately integrated into the clinical treatment process. To promote an appropriate use of TDM, the TDM expert group of the Arbeitsgemeinschaft fur Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued guidelines for TDM in psychiatry in 2004. Since then, knowledge has advanced significantly, and new psychopharmacologic agents have been introduced that are also candidates for TDM. Therefore the TDM consensus guidelines were updated and extended to 128 neuropsychiatric drugs. 4 levels of recommendation for using TDM were defined ranging from “strongly recommended” to “potentially useful”. Evidence-based “therapeutic reference ranges” and “dose related reference ranges” were elaborated after an extensive literature search and a structured internal review process. A “laboratory alert level” was introduced, i. e., a plasma level at or above which the laboratory should immediately inform the treating physician. Supportive information such as cytochrome P450 substrate- and inhibitor properties of medications, normal ranges of ratios of concentrations of drug metabolite to parent drug and recommendations for the interpretative services are given. Recommendations when to combine TDM with pharmacogenetic tests are also provided. Following the guidelines will help to improve the outcomes of psychopharmacotherapy of many patients especially in case of pharmacokinetic problems. Thereby, one should never forget that TDM is an interdisciplinary task that sometimes requires the respectful discussion of apparently discrepant data so that, ultimately, the patient can profit from such a joint effort.

/pdf/agnp-consensus-guidelines-for-therapeutic-drug-monitoring-in-18q2ciintb.pdf

AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Psychiatry: Update 2011

Valproic acid is rapidly absorbed from the gastrointestinal tract, peak concentrations being attained 1 to 2 hours after administration of the conventional tablet, but later with the enteric-coated tablets. The bioavailability of valproic acid is complete and independent of the preparation used. The apparent volume of distribution is relatively small (0.1 to 0.4 L/kg), due to high plasma protein binding. Protein binding is decreased in patients with renal insufficiency, in patients with chronic liver disease, and possibly in the presence of other displacing agents. The total plasma clearance of valproic acid is in the range of 5 to 10ml/min. Plasma elimination half-life is between 10 and 16 hours, and does not change after continued treatment with valproic acid alone. In combination therapy with other antiepileptic drugs, the half- life can be as short as 6 to 8 hours due to liver enzyme induction. Renal excretion of unchanged valproic acid accounts for only 1 to 3% of the total dose. Valproic acid is present in cerebrospinal fluid in concentrations equal to the unbound drug in plasma (around 10% of the total concentration). Valproic acid concentration in saliva is less than and unrelated to the free drug concentration in plasma. The drug is excreted into breast milk and evidence suggests that it also crosses the placenta. Four independent metabolic pathways — glucuronidation, β-oxidation and ω-oxidation (ω1, and ω2) have been demonstrated in man. Analytical difficulties caused by the similarity of the metabolites with many normal endogenous compounds and by chemical lability of several metabolites impede the isolation, identification and especially the quantification of valproic acid metabolites. Quantitative aspects of metabolism are essential for the understanding of drug effects in patients. The main metabolite 3-oxo-valproic acid shows comparable pharmacological activity to valproic acid itself in mice; unsaturated metabolites also show some activity. In young infants under 2 months of age valproic acid elimination half-life can be 60 hours, but in older children, plasma elimination appears to be identical to the adult situation. Valproic acid elimination is impaired in acute viral hepatitis and in liver cirrhosis. No information is available on valproic acid kinetics in renal insufficiency. Phenobarbitone plasma concentrations rise under combination therapy with valproic acid, because phenobarbitone elimination is impaired. Valproic acid lowers total plasma concentrations of phenytoin by displacing it from its plasma albumin binding site, but free phenytoin concentrations remain unchanged and phenytoin doses need not be modified. Valproic acid elimination is enhanced in the presence of inducing drugs like phenobarbitone, primidone, phenytoin and carbamazepine. The valproic acid dose-plasma concentration relationship is curvilinear, since valproic acid protein binding decreases with higher concentrations. Therefore, the increase in the plasma concentration is smaller than expected from the dose increase. The lower value of the therapeutic plasma concentration range of valproic acid is around 50μg/ml. Because of low clinical toxicity the upper value of the therapeutic range has yet to be determined.

Clinical Pharmacokinetics of Valproic Acid

Carbamazepine is a first-line drug in the treatment of most forms of epilepsy and also the drug of first choice in trigeminal neuralgia. Furthermore, it is now frequently used in bipolar depression.

Clinical pharmacokinetics and pharmacological effects of carbamazepine and carbamazepine-10,11-epoxide. An update

Carbamazepine seems to as effect as phenytoin in the treatment of grand mal and psychomotor epilepsy. It is the drug of first choice in trigeminal neuralgia. After single oral doses of carbamazepine, the absorption is fairly complete and the elimination half-life is about 35 hours (range 18 to 65 hours). During multiple dosing, the half-life is decreased to 10-20 hours, probably due to autoinduction of the oxidative metabolism of the drug. Phenytoin and barbiturates also induce the metabolism of carbamazepine. After single doses of carbamazepine, elimination follows dose-dependent first order kinetics. Carbamazepine is metabolised by oxidation before excretion in the urine. In experimental animals, the metabolite carbamazepine-10,11-epoxide has anticonvulsant activity comparable with that of the parent drug. The plasma concentration of the metabolite during long-term treatment of epileptic patients varies between 5 and 81% of that of the parent drug. The plasma protein binding of the metabolite is about 50% compared with about 75% for the parent drug. Less than 50% of a given carbamazepine doses has been identified as metabolites in the urine. The quantitatively most important metabolites is the trans-10,11-dihydro-10,11-diol. The kinetics of carbamazepine have been explored to some extent in pregnant women, newborns and children. Plasma levels of carbamazepine seem to decrease during pregnancy, possibly as a result of increased metabolism. The drug readily crosses the placenta and the levels measured in newborns are comparable with maternal plasma concentrations. In newborns exposed to the drug during fetal life, the plasma half-lives were relatively short (8.2 to 28.1 hours) indicating an induction of carbamazepine metabolism during gestation. The pharmacokinetics of carbamazepine in children aged 0.3 to 15 years are comparable with that in adults. A single daily dose of carbamazepine is insufficient; 2 doses per day are appropriate in most cases, but some patients may benefit from more frequent dosing to avoid side-effects. Compared with phenytoin, for example, very few controlled studies have been performed to establish the plasma level range of carbamazepine associated with the best therapeutic outcome. However, the best anticonvulsant effect of carbamazepine seems to be obtained at plasma levels of about 5 to 10microgram/ml (20 to 40mumol/L). Side-effects are most frequent at higher levels but may also be seen at lower levels.

Clinical Pharmacokinetics of Carbamazepine

Plasma levels of DPA and CNP and associated antiepileptic drugs were measured in groups of respectively 106 and 30 epileptic patients aged from 3 to 49 years. A poor correlation between daily oral dose and plasma levels of both drug was observed when the whole group of patients was considered. A better correlation was seen in a group of adult patients who received DPA and PB. Children below 10 years of age disposed both drugs faster than adults and the difference was significant (p less than 0.01) in groups receiving PB as associated drug. Patients medicated with PB and DPA or CNP showed lower plasma levels of both drugs; on the other hand DPA appeared to cause a decrease of PB clearance which was more marked in children. The clinical significance of the fluctuations of daily plasma levels of both drugs are discussed in relationship to the schedule of administration and plasma sampling. Observations on the therapeutic ranges and adverse effect of the drugs are reported.

Plasma levels of di-no-propylacetate and clonazepam in epileptic patients.

1 Carbamazepine (CBZ) brain and plasma concentrations were measured in twenty-one patients undergoing brain surgery for tumour removal. The drug was administered prophylactically at doses ranging from 6.9 to 14.8 mg/kg for 4-5 days before the intervention. 2 In seventeen cases where sample were collected 10-14 h after dosing, CBZ brain levels ranged from 2.2-14.5 microgram/g. A significant linear relationship (p less than 0.01) was observed between brain and plasma concentrations with a brain/plasma ratio of 1.1 +/- 0.1. 3 Carbamazepine 10,11-epoxide (CBZ-Epox), present in all samples, could be quantified in three brain specimens. Its brain concentrations ranged from 1.5-2.7 microgram/g with a brain/plasma ratio of 1.1-1.2. 4 Parieto-occipital areas tended to show higher CBZ concentrations while lower values were found in temporal regions. Very low CBZ levels were found in two gliomas while in meningiomas CBZ levels were similar to those observed in normal tissue. 5 The data, showing a linear relationship between brain and plasma concentrations of both CBZ and its epoxide, give additional significance to the plasma level monitoring of antiepileptic drugs.

/pdf/carbamazepine-and-carbamazepine-10-11-epoxide-concentrations-2zwmi1o73p.pdf

Carbamazepine and carbamazepine-10, 11-epoxide concentrations in human brain.

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Plasma levels of di-no-propylacetate and clonazepam in epileptic patients.

Carbamazepine and carbamazepine-10, 11-epoxide concentrations in human brain.