Retrospective analysis of the biopharmaceutics characteristics of solid oral Modified-Release drug products in approved US FDA NDAs designated as Extended-Release or Delayed-Release formulations.

BACKGROUND: Modified Release (MR) orally administered drugs products [Extended-Release (ER) and Delayed-Release (DR)] differ from Immediate-Release (IR) drug products in their drug release site and/or rate to offer therapeutic advantages. It is important to understand the biopharmaceutics factors that determine how a drug works in the gastrointestinal tract and the various pharmacokinetic properties that determine a drug's rate of absorption and release in the human body. To better understand the biopharmaceutics characteristics of ER and DR drug products, this study retrospectively analyzed submissions approved by the US Food and Drug Administration (FDA), from 2001 to 2021, and their corresponding review documents. This review work is expected to enhance the readers' understanding regarding the biopharmaceutics properties that supported approval of these products' ER claims, as per 21 CFR 320.25(f), and DR claims. METHODS: A comprehensive search was conducted using the FDA's internal New Drug Application (NDA) database for ER and DR oral drug products approved between 2001 and 2021. The search yielded 87 ER applications (23 ER capsules and 64 ER tablets) and 21 DR applications (10 DR capsules, 11 DR tablets) for which electronic records were accessible. These products were analyzed for overall drug product design, dosing frequency compared to the reference (if applicable), degree of fluctuation, dissolution method, and alcohol dose-dumping. RESULTS: Out of 87 total applications for ER drug products that were assessed, 62% of the ER tablets contained a polymer matrix formulation, and hypromellose (HPMC) was used in 50% of these products. 52% of the ER capsules consisted of polymer beads while about half of the DR drug products contained a non-bead formulation with a combination of polymers. The majority of ER drug products were found to have a reduction in dosing frequency and a decrease in the degree of fluctuation when compared to the IR reference product. The 13 ER drug products that exhibited an increase in degree of fluctuation exhibited general and pharmacodynamic benefits, such as reduced dosing frequency and reduced pill burden. The majority of DR formulations were developed to prevent drug degradation in the stomach, followed by to decrease potential stomach irritation, and lastly for localized release in the colon. The majority of ER drug products had 1:1 ratios of dissolution duration compared to dosing frequency (i.e., the majority of ER drug products had a dissolution duration of 24 h and were dosed every 24 h while those with a dissolution duration of 12 h were dosed every 12 h). The majority of ER applications had single-stage dissolution methods while most DR drug products used biphasic dissolution methods. All of the DR dissolution methods incorporated an acid stage of 2 h and a buffer stage with various timeframes. 53% the DR drug products had a ratio of dissolution duration to dosing frequency of 1:4 (e.g. a dissolution duration of 2 h to a dosing frequency of 8 h) or 1:8 (e.g. a dissolution duration of 2 h to a dosing frequency of 16 h). Of the ER tablets and DR drug products, 72% exhibited no alcohol dose-dumping under in vitro testing conditions. ER capsules, however, did not yield similar results-most of which exhibited alcohol induced dose-dumping. Alcohol dose dumping was mitigated by either in vivo studies or warnings on the drug product label. CONCLUSION: The results of this study help the reader understand the design, characteristics, and pharmacological advantages of the ER and DR drug products for patient benefit; as well as the regulations governing the FDA's assessment of ER claims.

Contrasting the potential benefits of early invasive coronary angiography in acute and chronic myocardial injury patterns.

BACKGROUND: In cases of evolving myocardial injury not definitively attributed to coronary ischaemia precipitated by plaque rupture, referral for invasive coronary angiography (ICA) may be influenced by observed troponin profiles. We sought to explore association between early ICA and elevated high-sensitivity troponin T (hs-cTnT) concentrations with and without dynamic changes, to examine if there may be a hs-cTnT threshold associated with benefit from an initial ICA strategy. METHODS: Using published studies (hs-cTnT study n = 1937, RAPID-TnT study n = 3270) and the Fourth Universal Definition of Myocardial Infarction (MI), index presentations of patients with hs-cTnT concentrations 5-14ng/L were classified as 'non-elevated' (NE). Hs-cTnT greater than upper reference limit (14ng/L) were classified as 'elevated hs-cTnT with dynamic change' (encompassing acute myocardial injury, Type 1 MI, and Type 2 MI), or 'non-dynamic hs-cTnT elevation' (chronic myocardial injury). Patients with hs-cTnT <5ng/L and/or eGFR<15mmol/L/1.73m2 were excluded. ICA was performed within 30 days of admission. Primary outcome was defined as composite endpoint of death, MI, or unstable angina at 12 months. RESULTS: Altogether, 3620 patients comprising 837 (23.1%) with non-dynamic hs-cTnT elevations and 332 (9.2%) with dynamic hs-cTnT elevations were included. Primary outcome was significantly higher with dynamic and non-dynamic hs-cTnT elevations (Dynamic: HR: 4.13 95%CI:2.92-5.82; p<0.001 Non-dynamic: HR: 2.39 95% confidence interval [CI]:1.74-3.28, p<0.001). Hs-cTnT thresholds where benefit from initial ICA strategy appeared to emerge was observed at 110ng/L and 50ng/L in dynamic and non-dynamic elevations, respectively. CONCLUSION: Early ICA appears to portend benefit in hs-cTnT elevations with and without dynamic changes, and at lower hs-cTnT threshold in non-dynamic hs-cTnT elevation. Differences compel further investigation.

Twelve-Month Outcomes of Patients With Myocardial Injury not Due to Type-1 Myocardial Infarction.

BACKGROUND: Diagnosis of acute myocardial infarction (AMI) requires a combination of elevated cardiac troponins, and clinical or echocardiographic evidence of coronary ischaemia. Identification of patients with a high likelihood of coronary plaque rupture (Type 1 myocardial infarction [MI]) is crucial as it is these patients for whom coronary intervention has been well-established to provide benefit and reduce subsequent coronary ischemic events. However, high-sensitivity cardiac troponin (hs-cTn) assays have increasingly identified patients with hs-cTn elevations not due to Type 1 MI where recommendations for ongoing care are currently limited. Understanding the profile and clinical outcomes for these patients may inform the development of an emerging evidence-base. METHODS: Using two previously published studies (hs-cTnT study n=1,937, RAPID-TnT study n=3,270) and the Fourth Universal Definition of MI, index presentations of patients to South Australian emergency departments with suspected AMI, defined by high sensitivity cardiac troponin T (hs-cTnT) greater than the upper reference limit (14 ng/L) and without obvious corresponding ischaemia on electrocardiogram (ECG), were classified as either Type 1 MI (T1MI), Type 2 MI (T2MI), acute myocardial injury (AI), or chronic myocardial injury (CI). Patients with non-elevated hs-cTnT (defined as <14 ng/L) were excluded. Outcomes assessed included death, MI, unstable angina, and non-coronary cardiovascular events within 12 months. RESULTS: In total, 1,192 patients comprising 164 (13.8%) T1MI, 173 (14.5%) T2MI/AI, and 855 (71.7%) CI were included. The rate of death or recurrent acute coronary syndrome was greatest in patients with T1MI, but also occurred with moderate frequency in Type 2 MI/AI and CI (T1MI: 32/164 [19.5%]; T2MI/AI: 24/173 [13.1%]; CI:116/885 [13.6%]; p=0.008). Of all the deaths observed, 74% occurred among those with an initial index diagnostic classification of CI. After adjusting for age, gender and baseline comorbidities, the relative hazard ratios for non-coronary cardiovascular readmissions were similar across all groups: Type 2 MI/AI: 1.30 (95% confidence interval 0.99-1.72, p=0.062); CI: 1.10 (95% confidence interval 0.61-2.00, p=0.75). CONCLUSIONS: Non-T1MI accounted for the majority of patients presenting with elevated hs-cTnT without ischaemia on ECG. Patients with T1MI had the highest rates of death or recurrent AMI; however patients with T2MI/AI and CI experienced a substantial rate of non-coronary cardiovascular re-hospitalisations.

A systematic description of the post-EMR defect to identify risk factors for clinically significant post-EMR bleeding in the colon.

BACKGROUND AND AIMS: Clinically significant post-EMR bleeding (CSPEB) is the most-frequent serious adverse event after EMR of large laterally spreading colonic lesions (LSLs). There is no proven prophylactic therapy, and it remains a significant drawback of EMR. We aimed to systematically describe and evaluate the features of the post-EMR mucosal defect (PED) and their relationship to CSPEB. METHODS: A prospective study of LSLs referred for EMR at a tertiary center was performed. PEDs without visible features were recorded as bland blue. Nonbland blue (NBB) PED features included size, number, and herniation of submucosal vessels and presence of submucosal hemorrhage, fibrosis, fat, and exposed muscle. NBB PEDs were analyzed for association with CSPEB, defined as bleeding occurring after completion of the procedure necessitating readmission or reintervention. RESULTS: From April 2012 to May 2017, 501 lesions in 501 patients were eligible for analysis. The frequency of CSPEB was 30 of 501 (6.0%). More than or equal to 3 visible vessels was a significant predictor of CSPEB (P = .016). None of the following showed a significant correlation with CSPEB: presence of visible vessels, their diameter, herniation, or other nonvascular PED features. Submucosal vessels were more common in the left-sided colon segment (88.6% vs 78.3%, P = .004) and were significantly larger (20.8% vs 12.1% ≥1 mm, P = .037), more numerous (median 4 vessels [interquartile range, 2-7] vs 2 vessels [interquartile range, 1-4], P < .001), and more often herniated (32% vs 22.2%, P = .022). CONCLUSIONS: More than or equal to 3 visible vessels within the PED may be predictive for CSPEB and may define a target group for real-time prophylactic intervention. No other endoscopically visible features of the PEDs were predictive of CSPEB. (Clinical trial registration number: NCT03117400.).