Interindividual Variability Of Pharmacokinetic Parameters Research Articles

Alfentanil‐Induced Miosis Clearance as a Liver CYP3A4 and 3A5 Activity Measure in Healthy Volunteers: Improvement of Experimental Conditions

The aims of this study were to demonstrate the correlation between alfentanil-induced miosis evaluation and alfentanil pharmacokinetics (PK) as a CYP3A4 and 3A5 activity probe in volunteers and to explain the variability in pupilar response and in alfentanil PK. In ambient light, the miosis kinetic parameters were significantly correlated with PK (CLs: r = 0.9, P = .00; AUCs: r = 0.8, P = .01). In dark, a similar correlation was observed between miosis and alfentanil clearances (r = 0.85, P = .03). In 6 volunteers, the sigmoid E(max) model was applicable (average E(max) = 2.5 +/- 0.7 mm, gamma = 2.5 +/- 1.6 and EC(50) = 76.8 +/- 22.3 ng/mL), and in 3, the simple E(max) model was applicable (average E(max) = 2.8 +/- 0.3 mm and EC(50) = 19.9 +/- 8.5 ng/mL). There was a large interindividual variability in PK parameters (coefficient of variation = 19.7%-31.2%). Free drug fraction concentrations were negatively correlated with plasma alpha(1)-AGP (r = -0.9, P = .04) and albumin levels (r = -0.94, P = .02). Alfentanil-induced miosis clearance as a noninvasive CYP3A4 and 3A5 activity measure can be done in both ambient and dark conditions. Drug free fraction may be responsible for large intersubject variability in alfentanil PK.

Population pharmacokinetics of melphalan, infused over a 24-hour period, in patients with advanced malignancies

The objective of the present study was to characterize the population pharmacokinetics of melphalan infused over a 24-h period in patients with advanced malignancies. Enrolled in the study were 64 patients (144 courses). The population pharmacokinetic analysis was performed using NONMEM through the graphical interface Visual-NM. Population characteristics were computed from an initial group of 43 patients (99 courses), and 21 additional patients (45 courses) were used for model validation. With the use of a one-compartment model, the influence of demographic and biological characteristics was examined. The basic parameters were total clearance (CL) and volume of distribution (V). The interoccasion variability was taken into account in the model. The drug exposure was estimated for each patient and correlated with markers of efficacy and toxicity. Data analysis was performed using a three-step approach. In step 2, a close relationship was found between creatinine clearance, gender and melphalan CL. The inclusion of this second stage model significantly improved the fit. Melphalan CL was higher in male patients (14.3+/-4.5 l/h per m2) than in female patients (12.3+/-4.5 l/h per m2). CL was also reduced somewhat in patients with decreased creatinine clearance. Large interindividual variability in pharmacokinetic parameters occurred (CL varied from 4.4 to 30.6 l/h per m2). The percentage intrapatient variability in clearance between courses was 25.4%. For determining melphalan AUC in clinical routine from one sample drawn at steady state, Bayesian methodology allowed a more accurate estimation of CL than the classical formula. Neutropenia and thrombocytopenia were the main haematological toxicities encountered; grade 4 was observed in 34 and 22 courses over a total of 144 courses, respectively. No significant relationship between AUC and haematological toxicity was found. In patients with prostatic cancer a weak relationship was observed between the decrease in PSA levels and AUC (P=0.0457), while in patients with ovarian cancer no relationship was found between AUC and CA125 levels. The population pharmacokinetic approach developed in this study should allow dosage to be individualized in order to decrease toxicity while maintaining good efficacy.

An application of population kinetics analysis to estimate pharmacokinetic parameters of sodium tungstate after multiple-dose during preclinical studies in rats.

The purpose of this study was to use a population approach in the preclinical development program of sodium tungstate in the rat in order i) to compute individual pharmacokinetic parameters of this compound after repeated oral administrations, until the 4-week toxicology study, using an empirical Bayes methodology; and ii) to study the influence of the administered dose, of the gender and of the duration of treatment on the pharmacokinetic parameters. Four studies were used representing a mixture of single intravenous administration and multiple oral administrations. The treatment duration ranged from 7 to 28 days. Intravenous dose was 9 mg/kg; three different oral doses were tested, 50, 100 and 200 mg/kg/day. Plasma concentration profiles versus time were compatible with a two-compartment model. A significant gender effect was found on bioavailability. The duration of treatment and the administered dose did not significantly explain part of the interindividual variability of pharmacokinetic parameters. The absorption of tungsten was rapid (1-3 hr). Total plasma clearance and elimination half-life averaged 2.8 ml/min/kg and 3.04 hr in males, and 3 ml/min/kg and 2.74 hr in females. The bioavailability was on an average 70%; being significantly higher in females than in males (0.78 versus 0.61). This compartmental approach should be considered as complementary to the usual non-compartmental approach used for analysis of preclinical data and should be a valuable tool to characterise the pharacokinetic/pharmacodynamic behaviour of a drug.

PH-Dependent dissolving nano- and microparticles for improved peroral delivery of a highly lipophilic compound in dogs.

RR01, a new highly lipophilic drug showing extremely low water solubility and poor oral bioavailability, has been incorporated into pH-dependent dissolving particles made of a poly(methacrylic acid-co-ethylacrylate) copolymer. The physicochemical properties of the particles were determined using laser-light-scattering techniques, scanning electron microscopy, high-performance liquid chromatography, and x-ray powder diffraction. Suspension of the free drug in a solution of hydroxypropylcellulose (reference formulation) and aqueous dispersions of pH-sensitive RR01-loaded nanoparticles or microparticles were administered orally to Beagle dogs according to a 2-block Latin square design (n = 6). Plasma samples were obtained over the course of 48 hours and analyzed by gas chromatography/mass spectrometry. The administration of the reference formulation resulted in a particularly high interindividual variability of pharmacokinetic parameters, with low exposure to compound RR01 (AUC0-48h of 6.5 microg x h/mL and coefficient of variation (CV) of 116%) and much higher Tmax, as compared to both pH-sensitive formulations. With respect to exposure and interindividual variability, nanoparticles were superior to microparticles (AUC0-48h of 27.1 microg x h/mL versus 17.7 microg x h/mL with CV of 19% and 40%, respectively), indicating that the particle size may play an important role in the absorption of compound RR01. The performance of pH-sensitive particles is attributed to their ability to release the drug selectively in the upper part of the intestine in a molecular or amorphous form. In conclusion, pH-dependent dissolving particles have a great potential as oral delivery systems for drugs with low water solubility and acceptable permeation properties.

Therapeutic drug monitoring of antiarrhythmic agents.

Therapeutic drug monitoring has come of age in clinical medicine and, in particular, its use with antiarrhythmic agents has flourished. The classic indications for the use of therapeutic drug monitoring are commonly encountered with antiarrhythmic drug use. Most of the currently available antiarrhythmics have a narrow therapeutic index, necessitating careful dose titration. The effectiveness of these agents in clinical use is frequently difficult to determine as a result of marked variability in arrhythmia frequency or infrequent events. Thus, therapeutic drug monitoring seems appropriate for adjusting therapy in arrhythmia prophylaxis or in the prevention of sudden death. Most antiarrhythmic agents appear to have generally accepted therapeutic ranges, a prerequisite for therapeutic drug monitoring. The historical determination of the therapeutic range for each of the antiarrhythmics will be discussed in addition to the numerous factors affecting the definition of this range for any drug, including type of arrhythmia, aetiology of underlying cardiac disease, the concept of true individual dose ranging, adequate control periods, the definition of true drug efficacy and the quantitation of arrhythmia frequency (including 24-hour ECG recording with computer-assisted analysis and the invasive technology of programmable ventricular stimulation), and the roles of protein binding, drug interactions and active metabolites. In addition to these considerations, therapeutic drug monitoring is particularly useful in this drug class because of marked interindividual variability in pharmacokinetic parameters including absorption, clearance and volume of distribution, resulting in variable dose-concentration relationships. This information can be useful in distinguishing between true therapeutic failures and inadequate plasma concentrations. The therapeutic concentration range of quinidine appears to be 1 to 5μg/ml utilising newer, more specific assay techniques, but the accepted range is very dependent on the type of assay. There is wide interindividual variability in the optimal drug concentration with toxicity occurring from 3μg/ml. The effective concentration range for procainamide is 4 to 10μg/ml, with early toxicity commencing at 8 to 10μg/ml and progressively increasing with further increments in plasma concentration. However, some patients may respond to higher concentrations without experiencing toxicity. The therapeutic concentration range for N-acetylprocainamide is not clearly defined, but appears to be greater than 10μg/ml with toxicity occurring over a wide range of concentrations (10 to 40μg/ml). As yet, there is no satisfactory method to deal with combined procainamide and N-acetylprocainamide concentrations. Clinical studies have not carefully defined the effective concentration range of dis-opyramide, but it appears to be 2.5 to 6.0μg/ml with toxicity occurring throughout the therapeutic range. Interpretation of therapeutic drug monitoring information on disopyramide is made difficult by the presence of concentration-dependent protein binding. Lignocaine is effective in the concentration range from 1.5 to 5.5μg/ml with toxicity common at concentrations higher than 5.0μg/ml. Protein binding is probably of greater importance than initially presumed, particularly in patients with acute myocardial infarction who develop enhanced protein binding of this drug. Some patients whose arrhythmia appears refractory at usual concentrations, may respond if the therapeutic range is exceeded. Mexiletine has a very low therapeutic index. Although its therapeutic range has not been carefully defined, effective concentrations appear to vary from 0.5 to 2.0μg/ml. Toxicity can span this entire range, but with marked interindividual variability. There are few studies that have carefully studied the therapeutic concentration range of Phenytoin as an antiarrhythmic agent. Within this context, the therapeutic concentration range appears to be from 10 to 20μg/ml; from the neurology literature toxicity occurs when concentrations exceed 20μg/ml. Few studies have defined the effective antiarrhythmic concentration range of propranolol. Its efficacy appears to be related to its β-blocking properties and accordingly the effective concentration should exceed 20ng/ml. There is evidence that some patients may respond to higher doses and concentrations than are usually necessary to achieve adequate β-blockade. Toxicity does not appear to be related to excessive plasma concentrations, but rather lends to occur early in therapy at low concentrations. In conclusion, therapeutic drug monitoring appears to be of benefit in antiarrhythmic therapy. However, its proper use depends on an intimate understanding of the concepts of effective and toxic ranges, as well as the pharmacokinetic parameters of each agent.