Assessment of the impact of partial area under the curve in a bioavailability/bioequivalence study on generic prolonged-release formulations.

The requirement for multiple-dose bioequivalence studies for the approval of generic prolonged-release (PR) formulations is not agreed upon by the EMA and FDA. While the EMA requests these studies, the FDA has no specific requirement, nor does ANVISA. Additional metrics are suggested for the assessment of prolonged-release products, and the partial Area Under the Curve (pAUC) metric has received increasing regulatory recognition. The objective of this work was to investigate whether the evaluation of the partial AUC in studies assessed by ANVISA can detect differences between 2 prolonged-release formulations that have demonstrated bioequivalence by the usual metrics. Twenty-four studies in a total of 117, which were already approved by ANVISA considering the usual metrics in the last 14 years, failed to demonstrate bioequivalence for partial AUC, which is related to 33.9% of evaluated PR products. For 76.92% of the studies, there was no significant increase in the intrasubject variability observed in the partial AUC analysis compared to the usual metrics, with a CV < 30% for both cases, calculated individually for each study, indicating that there is no need to increase the sample size to perform such analysis. The results of this paper demonstrate that the current criteria for assessing the bioequivalence of some prolonged-release formulations are insufficient and that the evaluation of partial AUC could be useful to assure the therapeutic parity of two products.

Medically Ill hospitalized Patients for COVID-19 THrombosis Extended ProphyLaxis with rivaroxaban ThErapy: Rationale and Design of the MICHELLE Trial.

BACKGROUND: The devastating Coronavirus disease (COVID-19) pandemic is associated with a high prothrombotic state. It is unclear if the coagulation abnormalities occur because of the direct effect of SARS-CoV-2 or indirectly by the cytokine storm and endothelial damage or by a combination of mechanisms. There is a clear indication of in-hospital pharmacological thromboprophylaxis for every patient with COVID-19 after bleed risk assessment. However, there is much debate regarding the best dosage regimen, and there is no consensus on the role of extended thromboprophylaxis. DESIGN: This study aims to evaluate the safety and efficacy of rivaroxaban 10 mg once daily for 35 ± 4 days versus no intervention after hospital discharge in COVID-19 patients who were at increased risk for VTE and have received standard parenteral VTE prophylaxis during hospitalization. The composite efficacy endpoint is a combination of symptomatic VTE, VTE-related death, VTE detected by bilateral lower limbs venous duplex scan and computed tomography pulmonary angiogram on day 35 ± 4 posthospital discharge and symptomatic arterial thromboembolism (myocardial infarction, nonhemorrhagic stroke, major adverse limb events, and cardiovascular death) up to day 35 ± 4 posthospital discharge. The key safety outcome is the incidence of major bleeding according to ISTH criteria. SUMMARY: The MICHELLE trial is expected to provide high-quality evidence around the role of extended thromboprophylaxis in COVID-19 and will help guide medical decisions in clinical practice.1.

Using Physiologically Based Pharmacokinetic Modeling to Assess the Risks of Failing Bioequivalence Criteria: a Tale of Two Ibuprofen Products.

The aims of the proposed study were to develop and verify a quantitative model-based framework to anticipate the in vivo bioequivalence of ibuprofen immediate release formulations. This stepwise approach integrated virtual bioequivalence trials to simulate the test to reference (T/R) ratio for positive (i.e., bioequivalent) and negative (i.e., non-bioequivalent) control formulations containing ibuprofen, approximated distribution of interoccasion variability (IOV) on ibuprofen peak (Cmax) and extent of exposure (AUC) by bootstrapping resampling methods, post hoc incorporation of IOV to simulated T/R ratios, and power curve analysis. After post hoc incorporation of the bootstrapped IOV to the simulated Cmax T/R geometric mean ratios, the resulting 90% confidence intervals overlapped with the in vivo observations for both pairwise comparisons. On the other hand, simulated and observed AUC TNBE/R geometric mean ratios differed, likely due to the lack of propagating clearance-related IOV to the simulations. This approach is in line with modern regulatory initiatives that advocate leveraging quantitative methods and modeling to modernize generic drug development and review. Graphical abstract.

Pharmacist-physician collaborative care model for patients with uncontrolled type 2 diabetes in Brazil: results from a randomized controlled trial.

RATIONALE, AIMS AND OBJECTIVES: This study aimed to evaluate the effect of a pharmacist-physician collaborative care model on clinical outcomes in patients with uncontrolled type 2 diabetes and determine characteristics that influence this effect. METHODS: A randomized controlled trial was conducted in a secondary care clinic for 80 patients with type 2 diabetes, aged 40-79 years and glycosylated haemoglobin (A1C) level ≥ 7.0%. The intervention group received individual, face-to-face pharmaceutical consultations and remote telephone support after a routine visit. The main measures were clinical outcomes (A1C, blood pressure, LDL cholesterol) and process indicators (medication adherence, medication regimen complexity, use of medicines). Multiple regression models were used to determine the variables that could explain the reduction and individualized control of A1C. RESULTS: From the initial sample of 80 patients, 73 completed this study. Compared with usual care, patients in the intervention group showed greater reduction in A1C (-0.79 vs. -0.16; P = 0.010); and an increase in the percentage of patients achieving the individualized goal of A1C (25.0% vs. 5.4%; P = 0.020). In addition, there was an increase in the percentage of adherent patients and in the average scores of medication adherence. Participation in the intervention group, higher baseline A1C levels and greater change in medication adherence were all significant predictors of improvement in A1C levels. CONCLUSIONS: The results suggest that the collaborative care model proposed is feasible and more effective than the usual care in the reduction and individualized control of A1C levels in patients with uncontrolled type 2 diabetes.

Effect of Different Sampling Schedules on Results of Bioavailability and Bioequivalence Studies: Evaluation by Means of Monte Carlo Simulations.

Bioavailability and bioequivalence study is one of the most frequently performed investigations in clinical trials. Bioequivalence testing is based on the assumption that 2 drug products will be therapeutically equivalent when they are equivalent in the rate and extent to which the active drug ingredient or therapeutic moiety is absorbed and becomes available at the site of drug action. In recent years there has been a significant growth in published papers that use in silico studies based on mathematical simulations to analyze pharmacokinetic and pharmacodynamic properties of drugs, including bioavailability and bioequivalence aspects. The goal of this study is to evaluate the usefulness of in silico studies as a tool in the planning of bioequivalence, bioavailability and other pharmacokinetic assays, e.g., to determine an appropriate sampling schedule. Monte Carlo simulations were used to define adequate blood sampling schedules for a bioequivalence assay comparing 2 different formulations of cefadroxil oral suspensions. In silico bioequivalence studies comparing different formulation of cefadroxil oral suspensions using various sampling schedules were performed using models. An in vivo study was conducted to confirm in silico results. The results of in silico and in vivo bioequivalence studies demonstrated that schedules with fewer sampling times are as efficient as schedules with larger numbers of sampling times in the assessment of bioequivalence, but only if Tmax is included as a sampling time. It was also concluded that in silico studies are useful tools in the planning of bioequivalence, bioavailability and other pharmacokinetic in vivo assays.

A comparative analysis of biopharmaceutics classification system and biopharmaceutics drug disposition classification system: a cross-sectional survey with 500 bioequivalence studies.

Although policies of waiving bioequivalence studies are part of the legal framework of various regulatory agencies, there is no harmonization with regard to extension of the biowaiver to drugs other than those with high solubility and high permeability, nor is there any consensus or official endorsement of the biopharmaceutics drug disposition classification system (BDDCS). To better understand the applicability of the biowaiver, we carried out a cross-sectional survey to estimate the relative risk of obtaining nonbioequivalent (non-BE) or bioinequivalent (BIE) results for drug products containing drugs belonging to each of the biopharmaceutics classification system (BCS) and BDDCS classes. Five hundred bioequivalence studies were randomly sampled from a database of the Brazilian Health Surveillance Agency (ANVISA). The drugs were classified according to the BCS and BDDCS, to evaluate how characteristics related to drug and dosage form influence the outcome of bioequivalence studies. The relative risk of obtaining a non-BE result was approximately four times lower for drugs in classes 1 and 3 of BCS or BDDCS when compared with class 2 drugs. Thus, it seems that the final outcome of a bioequivalence study is strongly influenced by the solubility of the drug, but not by its intestinal permeability or extent of metabolism.

Effect of pH, mucin and bovine serum on rifampicin permeability through Caco-2 cells.

Rifampicin, a poorly soluble drug, has great importance in therapeutics as it is the main drug used to treat tuberculosis. The characterization of its permeability and the factors that influence it represent an important tool for predicting its bioavailability. Caco-2 cell monolayers were used as models of the intestinal mucosa to assess the uptake and transport of rifampicin and the effects of various experimental conditions were investigated, in order to establish the influence of these variables on rifampicin permeability. Different pHs (5.8, 6.8 and 7.4) in the apical medium, the presence or absence of mucin (3.0% w/v) in the donor site and the presence or absence of bovine serum albumin (4.0% v/v) in the receptor chamber were the evaluated conditions. The quantification of rifampicin in the apical or basolateral chambers was performed by a validated HPLC-UV method. The change in the donor chamber pH showed that permeability values were greater at pH 6.8, although this increase does not result in an alteration of the qualitative classification of rifampicin, which has high permeability. Mucin and bovine serum showed no effects on the permeability of rifampicin at the concentration tested. Overall, the current study suggests that pH, artificial mucin and bovine serum proteins have no influence on rifampicin permeability.