Predictive Potential of Cmax Bioequivalence in Pilot Bioavailability/Bioequivalence Studies, through the Alternative ƒ2 Similarity Factor Method.

Pilot bioavailability/bioequivalence (BA/BE) studies are downsized trials that can be conducted prior to the definitive pivotal trial. In these trials, 12 to 18 subjects are usually enrolled, although, in principle, a sample size is not formally calculated. In a previous work, authors recommended the use of an alternative approach to the average bioequivalence methodology to evaluate pilot studies' data, using the geometric mean (Gmean) ƒ2 factor with a cut off of 35, which has shown to be an appropriate method to assess the potential bioequivalence for the maximum observed concentration (Cmax) metric under the assumptions of a true Test-to-Reference Geometric Mean Ratio (GMR) of 100% and an inter-occasion variability (IOV) in the range of 10% to 45%. In this work, the authors evaluated the proposed ƒ2 factor in comparison with the standard average bioequivalence in more extreme scenarios, using a true GMR of 90% or 111% for truly bioequivalent formulations, and 80% or 125% for truly bioinequivalent formulations, in order to better derive conclusions on the potential of this analysis method. Several scenarios of pilot BA/BE crossover studies were simulated through population pharmacokinetic modelling, accounting for different IOV levels. A redefined decision tree is proposed, suggesting a fixed sample size of 20 subjects for pilot studies in the case of intra-subject coefficient of variation (ISCV%) > 20% or unknown variability, and suggesting the assessment of study results through the average bioequivalence analysis, and additionally through Gmean ƒ2 factor method in the case of the 90% confidence interval (CI) for GMR is outside the regulatory acceptance bioequivalence interval of [80.00-125.00]%. Using this alternative approach, the certainty levels to proceed with pivotal studies, depending on Gmean ƒ2 values and variability scenarios tested (20-60% IOV), were assessed, which is expected to be helpful in terms of the decision to proceed with pivotal bioequivalence studies.

Alternative Analysis Approaches for the Assessment of Pilot Bioavailability/Bioequivalence Studies.

Pilot bioavailability/bioequivalence (BA/BE) studies are usually conducted and analysed similarly to pivotal studies. Their analysis and interpretation of results usually rely on the application of the average bioequivalence approach. However, due to the small study size, pilot studies are inarguably more sensitive to variability. The aim of this work is to propose alternative approaches to the average bioequivalence methodology, in a way to overcome and reduce the uncertainty on the conclusions of these studies and on the potential of test formulations. Several scenarios of pilot BA/BE crossover studies were simulated through population pharmacokinetic modelling. Each simulated BA/BE trial was analysed using the average bioequivalence approach. As alternative analyses, the centrality of the test-to-reference geometric least square means ratio (GMR), bootstrap bioequivalence analysis, and arithmetic (Amean) and geometric (Gmean) mean ƒ2 factor approaches were investigated. Methods performance was measured with a confusion matrix. The Gmean ƒ2 factor using a cut-off of 35 was the most appropriate method in the simulation conditions frame, enabling to more accurately conclude the potential of test formulations, with a reduced sample size. For simplification, a decision tree is also proposed for appropriate planning of the sample size and subsequent analysis approach to be followed in pilot BA/BE trials.

Untangling Absorption Mechanisms and Variability in Bioequivalence Studies Using Population Analysis.

PURPOSE: Both inter-individual (IIV) and inter-occasion (IOV) variabilities are observed in bioequivalence studies. High IOV may be a cause of problems on the demonstration of bioequivalence, despite strict measures are taken to control it. The objective of this study is to investigate further means of controlling IIV by optimizing study design of crossover studies. METHODS: Data from 18 bioequivalence studies were used to develop population pharmacokinetics (popPK) models to characterize the absorption and disposition processes of 14 drugs, to estimate IOV for each drug substance and to evaluate possible correlations with biopharmaceutical properties of drug substances, classified in accordance to the Biopharmaceutics Drug Disposition Classification System (BDDCS). RESULTS: Plasma-pharmacokinetics profiles for the 14 drugs analyzed were successfully described using popPK. The pharmacokinetic parameters that showed greater variability were first-order rate constant of absorption, duration of the zero-order absorption process, relative bioavailability and time of latency. ISCV% estimated for Cmax seems to correlate with the log-Dose-Number for Class 1, 2 and 3, despite no direct correlation was observed between popPK model residual variability (RUV) and ISCV%. Nevertheless, higher RUV estimates were observed for Class 2 drugs in comparison to Class 1 and 3. CONCLUSION: Pharmacokinetic parameters related to drug absorption showed greater variability. Ingestion of the IMP along with 240 mL of water showed to standardize gastric emptying. Given the dependency between Cmax variability and dose-solubility ratio, for classes 2 and 4, ad libitum water intake may increase Cmax and AUC ISCV%. A water ingestion standardization until the expected Tmax of the drug is suggested.

A Single Dose of Marine Chlorella vulgaris Increases Plasma Concentrations of Lutein, ß-Carotene and Zeaxanthin in Healthy Male Volunteers.

The beneficial health effects of Chlorella vulgaris have been associated with the presence of several nutrients and antioxidants, including carotenoids. However, the in vivo bioavailability of Chlorella is still poorly evaluated. In this work, a human intervention study was conducted in 11 healthy men to evaluate the bioavailability of carotenoids within 3 days after the intake of a single dose (6 g) of dried marine Chlorella vulgaris containing lutein (7.08 mg), ß-carotene (1.88 mg) and zeaxanthin (1.47 mg). Subjects were instructed to follow a low carotenoid diet during the experimental phase, starting 1 week earlier. On the day of the experiment, dried microalgae formulated in vegetarian hard capsules were ingested, and blood samples were collected up to 72 h for the analysis of plasma carotenoids concentration by high-performance liquid chromatography with diode-array detection. For all carotenoids, the estimated AUC and Cmax values were significantly different from zero (p < 0.05), indicating that a single dose of marine Chlorella vulgaris increased plasma concentrations of lutein (Cmin-corrected AUC = 1002 µg·h/L, Cmax = 20.4 µg/L), ß-carotene (AUC = 1302 µg·h/L, Cmax = 34.9 µg/L) and zeaxanthin (AUC = 122.2 µg·h/L, Cmax = 3.4 µg/L). The bioavailability of other compounds, namely, polyunsaturated fatty acids and trace elements, was also assessed post-prandial for the first time, showing that linoleic acid, docosahexaenoic acid and iodine were absorbed after microalgae intake. These findings support the use of Chlorella vulgaris as a source of carotenoids, PUFA and essential trace elements with associated health benefits.

Assessment of pharmacokinetic changes of meropenem during therapy in septic critically ill patients.

BACKGROUND: Meropenem is a carbapenem antibiotic commonly used in critically ill patients to treat severe infections. The available pharmacokinetic (PK) data has been mostly obtained from healthy volunteers as well as from clinical studies addressing selected populations, often excluding the elderly and also patients with renal failure. Our aim was to study PK of meropenem in a broader population of septic critically ill patients. METHODS: We characterized the PK of meropenem in 15 critically ill patients during the first 36 hrs of therapy. Aditionally, whenever possible, we collected a second set of late plasma samples after 5 days of therapy to evaluate PK intra-patient variability and its correlation with clinical course.Patients received meropenem (1 g every 8 hrs IV). Drug plasma profiles were determined by high-performance liquid chromatography. The PK of meropenem was characterized and compared with clinical parameters. RESULTS: Fifteen septic critically ill patients (8 male, median age 73 yrs) were included. The geometric mean of the volume of distribution at the steady state (Vss)/weight was 0.20 (0.15-0.27) L/kg. No correlation of Vss/weight with severity or comorbidity scores was found. However the Sequential Organ Failure Assessment score correlated with the Vss/weight of the peripheral compartment (r2 = 0.55, p = 0.021). The median meropenem clearance (Cl) was 73.3 (45-120) mL/min correlated with the creatinine (Cr) Cl (r2 = 0.35, p = 0.033).After 5 days (N = 7) although Vss remained stable, a decrease in the proportion of the peripheral compartment (Vss2) was found, from 61.3 (42.5-88.5)% to 51.7 (36.6-73.1)%. No drug accumulation was noted. CONCLUSIONS: In this cohort of septic, unselected, critically ill patients, large meropenem PK heterogeneity was noted, although neither underdosing nor accumulation was found. However, Cr Cl correlated to meropenem Cl and the Vss2 decreased with patient's improvement.