Individual Plasma Profiles Research Articles

Physiologically-Based Pharmacokinetic (PBPK) Modeling of Buprenorphine in Adults, Children and Preterm Neonates.

Buprenorphine plays a crucial role in the therapeutic management of pain in adults, adolescents and pediatric subpopulations. However, only few pharmacokinetic studies of buprenorphine in children, particularly neonates, are available as conducting clinical trials in this population is especially challenging. Physiologically-based pharmacokinetic (PBPK) modeling allows the prediction of drug exposure in pediatrics based on age-related physiological differences. The aim of this study was to predict the pharmacokinetics of buprenorphine in pediatrics with PBPK modeling. Moreover, the drug-drug interaction (DDI) potential of buprenorphine with CYP3A4 and P-glycoprotein perpetrator drugs should be elucidated. A PBPK model of buprenorphine and norbuprenorphine in adults has been developed and scaled to children and preterm neonates, accounting for age-related changes. One-hundred-percent of the predicted AUClast values in adults (geometric mean fold error (GMFE): 1.22), 90% of individual AUClast predictions in children (GMFE: 1.54) and 75% in preterm neonates (GMFE: 1.57) met the 2-fold acceptance criterion. Moreover, the adult model was used to simulate DDI scenarios with clarithromycin, itraconazole and rifampicin. We demonstrate the applicability of scaling adult PBPK models to pediatrics for the prediction of individual plasma profiles. The novel PBPK models could be helpful to further investigate buprenorphine pharmacokinetics in various populations, particularly pediatric subgroups.

Development of a Two-Compartment System In vitro Dissolution Test and Correlation with In vivo Pharmacokinetic Studies for Celecoxib

The objective of this study was to develop a novel open-mode two-compartment system dissolution apparatus to simulate the dissolution and absorption of poorly soluble drugs and to establish an in vitro-in vivo correlation (IVIVC). Celecoxib (CEB) was selected as a model drug, and in vitro dissolution was performed using the novel dissolution apparatus with acetate buffers at pH 4.5 containing Tween 80 (0.15%, w/v), at a flow rate of 30mL/min and an agitation rate of 50rpm. Cumulative release of all formulations was incomplete at approximately 70-80%, which likely reflected in vivo dissolution. Corresponding pharmacokinetic studies were performed in which twelve healthy male subjects from two bioequivalence studies received either one immediate release (IR) dose of the test (test 1 or test 2) or the reference formulation (Celebrex®, 200mg). Individual plasma profiles of the formulations were deconvoluted via the Wanger-Nelson method to obtain the mean absorption fractions. A level A correlation was successfully developed with a good R2. The Weibull equation was used to describe the in vitro dissolution and in vivo absorption kinetics. In vitro dissolution correlated with in vivo absorption was applied successfully to predict the in vivo plasma concentrations-time profiles of the CEB formulations. Compared with conventional methods, the novel dissolution device showed great potential for discriminating the dissolution between formulations and generic drugs, which may provide a tool for making in vivo predictions for next bioequivalence trials.

Effect of Food on the Pharmacokinetics of Gliclazide 60 mg Modified Release Tablet in Healthy Caucasian Volunteers

Abstract Objective: To evaluate the food effect on glicazide disposition in clinical trials conducted on healthy Caucasian volunteers who were given a new modified release oral formulation of Gliclazide 60 mg developed by Sun Pharmaceutical Industries, India. Methods: The studies were designed as open-label, randomized, single-dose, crossover studies that consisted of two periods. During each study, venous blood samples were taken before and after drug administration up to 96 hours. Subsequently, individual plasma profiles were determined and non-compartmental method was employed for the assessment of food effect on the pharmacokinetic profile of gliclazide. The statistical significance of differences for the main pharmacokinetic parameters was evaluated by ANOVA test, for p < 0.05 statistical significance was decided. The relative profiles of absorption of gliclazide were obtained by mathematical deconvolution. All calculation were performed by Phoenix WinNonlin®. Results: High-fat, high-calorie meal decreased gliclazide exposure. The mean maximum plasma concentration decreased with 14%, while the mean total area under the plasma concentration-time profile registered a 17% decrease. The elimination half-lives under fasted and fed conditions were comparable and the time to maximum plasma concentration was shortened under fed condition. Safety evaluation showed that overall gliclazide was well tolerated under both fasted and fed condition. Conclusions: The statistical analysis revealed the lack of food effect on the new modified release tablets of Gliclazide 60 mg. However, before stating a definite conclusion regarding the food effect on gliclazide pharmacokinetic profile, additional studies on patients with type 2 diabetes mellitus should be conducted.

Linking the Gastrointestinal Behavior of Ibuprofen with the Systemic Exposure between and within Humans-Part 2: Fed State.

Exploring the intraluminal behavior of an oral drug product in the human gastrointestinal (GI) tract remains challenging. Many in vivo techniques are available to investigate the impact of GI physiology on oral drug behavior in fasting state conditions. However, little is known about the intraluminal behavior of a drug in postprandial conditions. In a previous report, we described the mean solution and total concentrations of ibuprofen after oral administration of an immediate-release (IR) tablet in fed state conditions. In parallel, blood samples were taken to assess systemic concentrations. The purpose of this work was to statistically evaluate the impact of GI physiology (e.g., pH, contractile events) within and between individuals (intra and intersubject variability) for a total of 17 healthy subjects. In addition, a pharmacokinetic (PK) analysis was performed by noncompartmental analysis, and PK parameters were correlated with underlying physiological factors (pH, time to phase III contractions postdose) and study parameters (e.g., ingested amount of calories, coadministered water). Moreover, individual plasma profiles were deconvoluted to assess the fraction absorbed as a function of time, demonstrating the link between intraluminal and systemic behavior of the drug. The results demonstrated that the in vivo dissolution of ibuprofen depends on the present gastric pH and motility events at the time of administration. Both intraluminal factors were responsible for explaining 63% of plasma Cmax variability among all individuals. For the first time, an in-depth analysis was performed on a large data set derived from an aspiration/motility study, quantifying the impact of physiology on systemic behavior of an orally administered drug product in fed state conditions. The data obtained from this study will help us to develop an in vitro biorelevant dissolution approach and optimize in silico tools in order to predict the in vivo performance of orally administered drug products, especially in fed state conditions.

Mechanistic investigation of the negative food effect of modified release zolpidem

AimsWhen administered orally as either an immediate or modified release dosage form, zolpidem demonstrates a negative food effect, i.e. decrease in Cmax and AUC. The aim of the study was to arrive at a better understanding of the absorption of this BCS class I compound in vivo and to simulate the observed plasma profiles using in vitro and in silico methods. MethodsPharmacokinetic profiles of zolpidem are presented from a bioavailability (8mg intravenous; 10mg immediate release Stilnox®; 10mg and 12.5mg modified release Ambien® CR) and from a food effect study (12.5mg modified release Ambien® CR). The dissolution behavior of the 12.5mg strength was investigated using compendial methods in the USP apparatus II and using biorelevant methods in the USP apparatus III and IV. The mean plasma profiles as well as selected individual plasma profiles were simulated with Simcyp® and GastroPlus™. The absorption behavior was additionally investigated using the Qgut model, which entails algebraic deconvolution of all individual profiles, incorporating both first pass gut and liver extraction. ResultsIt was possible to simulate the mean plasma profiles using a “middle-out” approach, based on in vitro data combined with pharmacokinetic parameters obtained after intravenous administration, using PBPK software (Simcyp® and GastroPlus™), resulting in average fold error (AFE) values <1.5. Deconvolution verified that the in vivo absorption rate from the modified release formulation is controlled by the formulation in the fasted state, whereas in the fed state, the absorption rate is mainly controlled by gastric emptying. One-stage in vitro tests suggested that interactions with meal components, resulting in incomplete release, may be the source of the negative food effect for both the immediate and modified release formulations. ConclusionsThe present study demonstrated that a combination of biorelevant dissolution testing with modeling approaches enables a mechanistic understanding of the absorption of zolpidem from various formulations and can serve as a useful biopharmaceutical approach for the development of modified release solid oral dosage forms.

Pharmacokinetics of transdermal buprenorphine patch in the elderly

PurposeTransdermal buprenorphine patches provide comparable pain relief to that of low-potency opioids in elderly individuals. However, specific data on their use in elderly individuals is limited. This study investigated and compared the PK of buprenorphine transdermal patches in elderly (≥75 years) versus younger (50–60 years) individuals.MethodsThis was a multiple-dose, open-label, parallel-group study in healthy volunteers split into two age groups (younger, 50–60 years; elderly, ≥75 years) with 37 individuals in each. Study participants received two consecutive 7-day buprenorphine 5 μg/h transdermal patch applications, and blood samples were collected on the week of the second patch application [day 7 (predose), days 8, 9, 10, 12, and 14] to determine PK at steady state. Pharmacokinetic parameters were determined for buprenorphine and norbuprenorphine. Safety was assessed by analyzing adverse events, hematology, clinical chemistry, urine analysis, vital signs, electrocardiogram (ECG), and physical examinations.ResultsThe area under the plasma concentration-time curve at steady state (AUCtau), measured over one dosing interval, was similar for elderly [mean ± standard deviation (SD) 9,940 pg/h/ml (4,827 pg/h/ml] and younger [mean ± SD 11,309 (3,670 pg/h/ml] individuals. Bioequivalence was not demonstrated between groups, which may be attributable to the relatively high level of variability in individual plasma profiles. More adverse events were reported by younger (216) than elderly (164) study participants.ConclusionsNo dosage alterations are necessary for PK reasons when treating elderly people with buprenorphine transdermal patches.

The effect of antacid on aspirin pharmacokinetics in healthy Thai volunteers.

The effect of antacid on aspirin pharmacokinetics and bioavailability was determined in 10 healthy adult male and female volunteers, aged 20-45 years old. Each subject received 650 mg of aspirin orally after an overnight fast. The wash out period was 14 days and then all subjects were given 650 mg of aspirin 10 minutes after antacid (aluminium hydroxide and magnesium hydroxide). Plasma aspirin, salicylate and salicyluric acid levels were determined by a specific high performance liquid chromatographic analysis. Individual plasma profiles were analysed using compartmental and non-compartmental methods. The results show that antacid affected the relative bioavailability of aspirin since the mean peak concentration (Cmax) of aspirin was significantly higher when antacid was given. However, the time to reach peak concentration (Tmax) and the area under the plasma concentration-time curve (AUC) showed no significant difference between the two treatments. It was, therefore, not possible to conclude that the non-bioequivalence was caused by a difference in rate or amount of aspirin absorption, or both. No significant difference was observed in Cmax, Tmax, AUC, t1/2, Ka, Kel of salicylate and salicyluric acid. However, the rate of total salicylate absorption was increased since the absorption rate constant (Ka) was higher when antacid was given. This may provide a more rapid effect of the drug.

Reproducibility of oxprenolol plasma concentrations in young female volunteers following oral administration of an oxprenolol Oros dosage form.

Plasma oxprenolol concentrations were measured in six young healthy female volunteers after single oral dosing with a 16/260 oxprenolol Oros system on three separate occasions. Reproducibility was assessed by comparing individual plasma profiles, areas under the curve, peak concentrations and times to peak. Plasma concentration-time profiles were consistent with an extended duration of drug release from the Oros system. Individual and mean profiles on the three occasions were similar, and no significant differences in mean plasma levels, or derived pharmacokinetic parameters, were detected. The mean amount of drug in eight systems recovered from faeces corresponded to 11% of the dose. Individual amounts were related to the total transit time of the system through the body. The 16/260 Oros system functioned reproducibly within the gastrointestinal tract, and in vivo absorption mirrored in vitro drug release.