Therapeutic Plasma Concentration Range Research Articles

Modern drug analysis in biological fluids suitable for clinical pharmacokinetics

Therapeutic drug monitoring can provide valuable information to guide clinicians in achieving optimal treatment with selected therapeutic agents. Large intersubject variations in drug response are common. There are many factors that may cause variability in drug disposition and drug plasma levels using standard dosage regimens: (1) Biometric factors: age, height, weight; (2) Absorption and patient compliance; (3) Distribution, cardiac failure; (4) Elimination: hepatic and/or renal failure; (5) Individual capacity in metabolizing drugs; (6) Drug-drug interactions. All these factors demand dosage adjustments for the individual patient and contribute to the observation that the correlation between drug plasma level and response is much better than that between the total dose and response among a given patient population. Pharmacokinetic-pharmacodynamic studies yield information on the therapeutic plasma concentration range of a drug that should be maintained during therapy to achieve maximum benefits. This leads to the concept of the ‘target level’ of a particular drug in plasma, which is important for the application of clinical pharmacokinetics in drug therapy. There are two ways by which ‘target levels’ can be utilized to optimize the individual drug dosage regimen: first, calculation of the dose based on predictive pharmacokinetic models for the individual patient; and second, inclusion of drug level monitoring to correct the predictive model for unaccountable intersubject variation. Predictive pharmacokinetic models are particularly useful for drugs that are mainly eliminated by renal excretion, since good correlations between clinical kidney function tests and drug clearance have been established. Thus dosage adjustments, based on individual kidney functions, are an integral part of modern drug therapy with drugs like

The effect of saturable binding to plasma proteins on the pharmacokinetic properties of disopyramide.

Disopyramide exhibits saturable binding to plasma proteins in the therapeutic plasma concentration range. Because of this property, controversy exists in the literature regarding the pharmacokinetic properties of the drug. The purposes of this study were to reassess the pharmacokinetic properties of disopyramide in humans, taking into consideration both total and unbound concentrations and to use disopyramide as a model compound to study the effect of drug binding on the renal clearance of both total and unbound drug. A single intravenous dose of disopyramide (1.5 mg/kg) was administered to eight normal volunteers. Blood and urine samples were collected for 36 h. Total concentrations of disopyramide in plasma and urine were determined by high pressure liquid chromatography. Binding of disopyramide to plasma proteins was determined by equilibrium dialysis. In all subjects the binding of disopyramide to plasma proteins was saturable, but there were considerable differences in binding between subjects. The volume of distribution, total body clearance, and renal clearances of both total and unbound drug were calculated. Because only the total body clearance and renal clearance of unbound compound are not dependent upon unbound fraction (alpha), these are the only parameters which can be reported without qualification as to the concentration. The mean +/-DS total body clearance of unbound drug in the eight subjects was 5.40 +/- 2.80 ml/min/kg. About 50% of this was due to renal elimination. A statistically significant negative correlation of the renal clearance of total disopyramide with time was observed in seven of eight subjects, whereas a significant correlation between the renal clearance of unbound disopyramide and time was observed in only one subject. This suggests that the renal clearance of unbound disopyramide is independent of alpha, while the renal clearance of total disopyramide is dependent upon alpha.

Saturable metabolism of perhexiline maleate: Correlations with long-term toxicity

VERAPAMIL IN THE TREATMENT OF PRINZMETAL'S VARIANT ANGINA: A LONG-TERM, DOUBLE-BLIND, RANDOMIZED TRIAL. SM Johnson, MD, DR Mauritson, MD, LD Hillis, MD, FACC, JT Willerson, MD, FACC, U of Texas Health Science Center, Dallas, TX. This study was performed to assess the efficacy of verapamil (V) in patients (pts) with variant angina pectoris (VAP). 1n 13 pts (8 men, 5 women, mean age 52 yrs) with VAP, V (38&76 mg/day, meanfSD) was compared to placebo (P) in a double-blind, randomized, double-crossover trial of 9 months duration: 1 month of open-label V followed by four 2-month periods of blinded therapy (V-P-V-P or P-VP-V). Ten of 13 pts were maintained on stable doses of isosorbide dinitrate (128*55 mg/day) throughout the study. During each Z-month period, the following were quantitated: (1)chest pains/week (wk). (2)nitroglycerin (NTG) used/wk, and (3)required hospitalizations (HOS) for clinical instability. During the 4 months of V, the number of chest pains/wk (2.0f3.5) and the number of NTG/wk (2.5* 4.5) were less (pcO.01) than during P (12.1*27.8 pains/wk, 15.7f37.5 NTG/wk). None of 13 required HOS during V, but 4/13 required a total of 5 HOS during P (pcO.05). Of the 13 pts, 6 had clinical activity throughout the study, but the other 7 (54X) had prolonged periods of inactivity which, in 6/7, lasted the entire 8 months. In the 6 active pts V had a marked salutary effect (3.8f3.1 pains/wk, 4.645.7 NTG/wk) h w en compared to P (24.7f36.2 painslwk, 3O.lf49.8 NTG/wk, p<O.Ol). V was well tolerated, causing only minor constipation not requiring a change,of dosage. Thus, (1)many patients with variant angina have prolonged periods of clinical quiescence even without calcium antagonists, emphasizing the need for properly-designed studies of potential therapeutic agents; and (2)in a long-term, double-blind, randomized study, verapamil is safe and efficacious in the treatment of variant angina and is especially beneficial in those with clinically-active disease. SATURABLE HETABOCISH OF PERHEXILINE MALEATE: CORRELATIONS WITH LONG-TERM TOXICITY John D. Horowitz, MB; Pamela M. Morris, BSc; Olaf Drummer, MSc; Alan J. Goble, MD; and William J. Louis, MD, Departments of Cardiology and Clinical Pharmacology,Austin Hospital, Heidelberg, Victoria, Australia. Perhexiline maleate (Px) is a calcium channel antagonist which is an effective prophylactic anti-angina1 a‘gent, with minimal cardiovascular adverse effects. However, the chronic administration of Px may cause hepatitis or peripheral neuropathy, limiting the clinical usefulness of Px, which is cleared largely by hepatic hydroxylation. The current investigation examines the possibility of a pharmacokinetic basis for these adverse effects. Single-dose pharmacokinetic studies were performed in six patients with severe angina pectoris using oral Px doses of 150 and 300 mg. A sensitive (threshold 5 ng/ml) and specific high performance liquid chromatographic assay was used. Doubling of the Px dose was associated with a prolongation of mean elimination half-life (from ll.Zf2.1 S.E.M. to 19.1 k-2.8 hours; p<O.Ol) and a disproportionate increase (mean 5.3-fold)in area under the plasma concentration-time curve suggesting saturable hepatic hydroxylation of Px. Steadystate studies in 17 patients treated with Px indicated a therapeutic plasma concentration range of approximately 150 to 600 ng/ml. Five cases of Px toxicity (2 of peripheral neuropathy, one each of hepatitis, blurred vision and nausea) were all associated with Px levels above 700 ng/ml (mean 15702370 ng/ml), and were reversible with readjustment of Px dosage. We conclude that Px is a longacting calcium channel antagonist which is prone to accumulate in some patients due to limited capacity for hepatic Px metabolism. Monitoring of plasma Px concentrations at regular intervals will permit optimization of long-term therapy with Px. BENEFITS OF ADDED NIFEDIPINE IN UNSTABLE ANGINA PERSISTING DESPITE BETA BLOCKADE AND ISOSORBIDE DINITRATE Frans Hagemeijer, MD, FACC, Sint Franciscus Gasthus and Thoraxcenter, Erasmus University, Rotterdam, The Nether-

Clinical pharmacokinetics of valproic acid.

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.

Tocainide kinetics after intravenous and oral administration in healthy subjects and in patients with acute myocardial infarction.

Tocainide is structurally related to lidocaine but may be used orally as well as intravenously. A therapeutic plasma concentration range of 25 to 45 mumole/l has been suggested. Tocainide kinetics were studied in 6 healthy subjects and 16 patients with acute myocardial infarction. There was good accordance in kinetics of healthy subjects and patients. After intravenous administration the mean t1/2 was about 14 hr, volume of distribution about 3.0 l/kg, and corrected renal clearance about 140 ml/min. An average of 35% of the dose was recovered unchanged in urine. After oral administration the absorption rate was rapid relative to the elimination rate, extent of bioavailability was complete, and the apparent volume of distribution was the same as that after intravenous injection. A dose regimen of 750 mg intravenously directly followed by 800 mg orally and subsequently 400 mg 3 times daily resulted in therapeutic plasma levels within 15 min. The plasma levels remained within the therapeutic range throughout a period of observation from 48 to 168 hr.

Therapeutic monitoring of antiarrhythmic drugs.

Antiarrhythmic drugs are potent agents which generally have narrow therapeutic indices. The consequences of administering either too little or too much can be life-threatening. Consequently, monitoring of plasma concentrations of these agents is an important part of rational antiarrhythmic therapy. In using therapeutic plasma concentration range guidelines, one must be conscious of the fact that the relationship between measured plasma concentration and therapeutic response is influenced by several factors. The influence of active metabolites and variability in the degree of plasma protein binding are two important factors. In treating arrhythmias, one must take into account the pharmacokinetics of the particular drug being used and the factors which modulate its plasma concentration-response relationship.

Divergence in pharmacokinetic parameters of quinidine obtained by specific and nonspecific assay methods.

Previously published estimates of pharmacokinetic characteristics of quinidine can be shown to be dependent on whether the investigators have used analytical methods which are specific for quinidine. Areas under the plasma concentration-time curve and peak plasma concentrations after administration of the drug were higher and clearance values consequently lower in studies utilizing nonspecific assays unable to distinguish quinidine from its metabolities. The error introduced is larger after oral administration as a result of marked first-pass metabolism of quinidine. The absolute oral bioavailabilities from pharmaceutical preparations might therefore be estimated higher in studies with assays including metabolites in the determination. Although the pharmacodynamic response to quinidine is related to the plasma concentration, the therapeutic window of drug concentrations has been defined only using nonspecific assays. In light of the availability of newly developed specific assays, redefinition of the range of therapeutic plasma concentrations is opportune.

Comparison of Two Spectrofluorometric Procedures for Quinidine Determination in Biological Fluids

Different methods for the spectrofluorometric determination of quinidine in plasma and urine were studied. The alkaline washings of plasma and urine extracts remove fluorescent metabolites, as shown by TLC analysis of urine extracts, and do not lead to a significant loss of alkaloids. The spectrofluorometric assays without alkaline washings of the benzene extract averaged 18% higher than the assays with alkaline washings. Since unchanged quinidine and hydroquinidine are responsible for antiarrhythmic activity, the method with alkaline washing is more appropriate for the control of quinidinemia than are other methods. The therapeutic plasma concentration range becomes 0.8–2.5μg/ml with this method.

Therapeutic control of plasma concentrations and long-term effect of nortriptyline in recurrent affective disorders.

Based on the evidence that therapeutic plasma concentration range in fact exists for the tricyclic antidepressant drug, Nortriptyline (range 50-150 ng/ml), three different investigations were under taken in order to clarify some clinical pharmacological problems during long-term treatment with this drug. The possible prophlactic effect of the drug in recurrent affective disorders was specially examined in a group of patients with a high risk of episodes in their unipolar manic-depressive disease. The results highly demonstrate the value of monitoring plasma levels in achieving therapeutic control. Depressive relapses during treatment, for months and years, were only related to therapeutic insufficient plasma levels of the drug.

Clinical pharmacokinetics of anticonvulsants.

Anticonvulsant therapy was among the first areas to benefit from clinical pharmacokinetic studies. The most important advantage is that the frequent interindividual variation in the plasma level/dose ratio for these drugs can be circumvented by plasma level monitoring. For several anticonvulsants the brain concentration is shown to parallel the plasma concentration. Phenytoin (diphenylhydantoin) is stil the most important anticonvulsant and the one for which kinetics have been thoroughly investigated in man. These investigations have revealed several reasons for the wellknown difficulties in using this drug clinically. The absorption rate and fraction are very much dependent on the pharmaceutical preparation, and changes of brand may alter the plasma level of phenytoin in spite of unaltered dose. The elimination capacity is saturable causing dose dependent kinetics, which again means disproportional changes in plasma level with changes in dose. Great individual variations exist in the rate of metabolism, and several pharmacokinetic drug interactions are known. As an optimum therapeutic plasma concentration range has been established monitoring plasma levels must be strongly advocated. Interpretation of plasma levels in uraemic patients must take into account decreased protein binding of the drug. Carbamazepine is probably as effective as phenytoin. The elimination is a first order process, but the rate of metabolism increases after a few weeks' treatment. An active metabolite (epoxide) may be the cause of some side-effects. Combined treatment with other anticonvulsant drugs decreases the half-life and more frequent dosing may be necessary. An optimum therapeutic concentration range has been suggested and plasma monitoring is advocated, along with that of the active metabolite, the epoxide. Phenobarbitone is still much used but its kinetics have been investigated to a lesser extent. The main problem is the variability in the rate of elimination. In children the half-life of phenobarbitone is only half of that in adults. An optimum therapeutic plasma range has been established and monitoring is recommended. Primidone may have an anticonvulsant activity in itself, but its main metabolite is phenobarbitone. The relatively rapid elimination of primidone is offset by the long half-life of phenobarbitone. An optimum therapeutic range has been suggested, but plasma level monitoring must include determination of phenobarbitone. Ethosuximide. The clinical pharmacokinetics of this important petit mal anticonvulsant is not well known. It has a relatively long half-life (in adults 2 to 3 days; in children shorter). An optimum therapeutic range has been suggested, and routine monitoring of plasma levels may be recommended. Diazepam exerts a repid anticonvulsant activity when the plasma concentration exceeds approximately 500ng/ml after intravenous injection. The kinetic pattern is complex in man. Clonazepam. The clinical pharmacokinetics are still not fully investigated but a therapeutic range has been suggested...