Revolutionizing pharmacokinetics: the dawn of AI-powered analysis.

This editorial explores how artificial intelligence (AI) is revolutionizing the science of pharmacokinetics (PK). It discusses the challenges of conventional PK analysis and how AI has transformed this area. It highlights the promise of artificial intelligence (AI) in predicting pharmacokinetic profiles from chemical structures and its application in several aspects of pharmacology, including dosage customization and drug interactions. Additionally, it emphasizes how important ethical issues and openness are to AI applications, especially when it comes to pharmacokinetic prediction and dataset adaptation. Future directions for AI in PK are discussed, with the creation of all-inclusive AI pharmacokinetics/pharmacometrics software being envisioned. Drug discovery and patient care could be transformed toward more individualized and effective healthcare solutions with the help of this software, which could handle tasks such as data cleaning, model selection, and regulatory report preparation. The editorial highlights the importance of AI in improving pharmaceutical sciences while urging caution and teamwork in navigating its possible uses in pharmacokinetics.

The efficacy and effectiveness of COVID-19 vaccines around the world: a mini-review and meta-analysis.

OBJECTIVES: This meta-analysis evaluated the Efficacy and Effectiveness of several COVID-19 vaccines, including AstraZeneca, Pfizer, Moderna, Bharat, and Johnson & Johnson, to better estimate their immunogenicity, benefits, or side effects. METHODS: Studies reporting the Efficacy and Effectiveness of COVID-19 vaccines from November 2020 to April 2022 were included. The pooled Effectiveness/Efficacy with a 95% confidence interval (95% CI) with Metaprop order was calculated. The results were presented in forest plots. Predefined subgroup analyses and sensitivity analyses were also performed. RESULTS: A total of twenty articles were included in this meta-analysis. After the first dose of the vaccine, the total effectiveness of all COVID-19 vaccines in our study was 71% (95% CI 0.65, 0.78). The total effectiveness of vaccines after the second dose was 91% (95% CI 0.88, 0.94)). The total efficacy of vaccines after the first and second doses was 81% (95% CI 0.70, 0.91) and 71% (95% CI 0.62, 0.79), respectively. The effectiveness of the Moderna vaccine after the first and second dose was the highest among other studied vaccines ((74% (95% CI, 0.65, 0.83) and 93% (95% CI, 0.89, 0.97), respectively). The highest first dose overall effectiveness of the studied vaccines was against the Gamma variant (74% (95% CI, 0.73, 0.75)), and the highest effectiveness after the second dose was observed against the Beta variant (96% (95% CI, 0.96, 0.96)). The Efficacy for AstraZeneca and Pfizer vaccines after the first dose was 78% (95% CI, 0.62, 0.95) and 84% (95% CI, 0.77, 0.92), respectively. The second dose Efficacy for AstraZeneca, Pfizer, and Bharat was 67% (95% CI, 0.54, 0.80), 93% (95% CI, 0.85, 1.00), and 71% (95% CI, 0.61, 0.82), respectively. The overall efficacy of first and second dose vaccination against the Alfa variant was 84% (95% CI, 0.84, 0.84) and 77% (95% CI, 0.57, 0.97), respectively, the highest among other variants. CONCLUSION: mRNA-based vaccines against COVID-19 showed the highest total efficacy and effectiveness than other vaccines. In general, administering the second dose produced a more reliable response and higher effectiveness than a single dose.

In Vitro Permeability, Irritability, and Release Evaluation of Commonly Used Topical Diclofenac Gel Preparations (1%, 5%, and 10%).

Recently, there has been an increase in the use of compounded topical pain preparations, raising concerns that clinicians and patients may not be aware of the potential safety risks. Topical diclofenac is one of the most widely used pain medications, often used for joint ailments such as osteoarthritis and other musculoskeletal pain. Systemic exposure to diclofenac has a dose-related risk for gastrointestinal, cardiovascular, and renal adverse events, particularly in elderly patients. Topical diclofenac preparations are frequently compounded in pharmacies at the concentrations of 1% to 10% (or higher) with or without other active ingredients such as camphor. Considering the significantly higher strengths of the compounded preparations as compared to the commercially available products (1% to 3%) and the frequency of application (sometimes up to six times a day), concerns arise as to the levels of absorption with these formulations and their potential toxicity. The objective of this initial study was formulated in an attempt to shed light on safety concerns of topical diclofenac preparations. A study was designed to evaluate the in vitro release, irritability, and permeability of three different concentrations of compounded diclofenac gels (1%, 5%, and 10%) in PLO GEL MEDIFLO and VersaPro Gel bases. Using MatTek's EpiDerm system, skin irritability and the in vitro permeation of compounded diclofenac gels were evaluated. Additionally, the in vitro release profile, drug content, content uniformity, and physical properties of the compounded gels (pH, homogeneity) were assessed. In all cases, the drug content, content uniformity, physical properties, and preparation stability during the recommended beyond-use dating (90 days) were acceptable. The release profiles of all tested preparations followed the Higuchi model. The in vitro skin irritation evaluation of the tested formulations indicated no irritant preparation. The permeability assessment of the formulated gels revealed that there is a correlation between drug release and percutaneous absorption. VersaPro Gelbased preparations, which showed a lower percentage of drug release over the experiment time, showed a significantly lower average flux at steady-state and the average percentage of absorbed dose after 24 hours. The percentage absorption (%abs) from different formulations ranged from 11.18% to 19.6% depending on the gel base. The permeability coefficient, kp, (cm/hr) ranged from 0.019 to 0.037, and the average flux (µg/cm2/hr) ranged from 8.7 to 103 depending on the gel base and the diclofenac concentration. Based on our findings and previously reported data, the possibility exists that higher diclofenac concentrations in compounded topical preparations may lead to significantly higher blood concentrations as compared to commercially available products, which in turn may also lead to serious side effects. Accordingly, there is a need for clinical studies to evaluate the safety of compounded diclofenac preparations with higher diclofenac contents than United States Food and Drug Administrationapproved formulations.

Kinetic Analysis of Drug Release from Compounded Slow-release Capsules of Liothyronine Sodium (T3).

The purpose of this study was to formulate extemporaneously compounded Liothyronine Sodium (T3) slow-release capsules and to evaluate their in vitro drug release performance. Twenty-one formulations containing T3 (7.5 µg) with various compositions of two different grades of Methocel E4M and K100M premium (30% to 90%), and/or SimpleCap/Lactose (10% to 70%) were examined. Quality assessment of the capsules was conducted by standard quality control criteria of the United States Pharmacopeia (i.e., weight variation, content uniformity) to ensure their compliance. The dissolution release profile of the formulations was evaluated using United States Pharmacopeia Apparatus type II (paddle method) at a speed of 50 rpm and temperature of 37°C in phosphate buffered saline media ( pH = 7.2 to 7.4). Aliquots from the media were taken periodically up to 24 hours and analyzed using a validated enzyme-linked immunosorbent assay method. The cumulative percentage of drug release for each formulation was fitted to eleven major release kinetic equations to determine the best-fit model of drug release, as well as the mechanism of release. Assay sensitivity was as low as 1 ng/mL and the optimal calibration range was found to be between 0 ng/mL and 7.5 ng/mL, which corresponded well with the average physiological plasma concentrations of T3. Liothyronine sodium with either SimpleCap (100%) or Methocel E4M (100%) exhibited slowrelease kinetic patterns of Peppas and Zero Order, respectively. The formulation with SimpleCap (100%) had a higher percentage of drug release (as compared to 100% Methocel E4M) within the first four hours; this formulation released 80% of the drug within 12 hours when the release was plateaued thereafter. The formulation with 30% Methocel E4M and 70% SimpleCap released 100% of the drug within the initial 12 hours and exhibited a Zero Order slow-release kinetic pattern. In general, the release kinetic rate of the formulations containing Methocel K100M appeared to be slower than Methocel E4M. This alteration may be due to a higher molecular weight and apparent viscosity of Methocel K100M. While most of the formulations were fitted to a slow-release kinetic pattern, several others including Methocel E4M 100%, 30% Methocel E4M+ 70% Simple Cap, 40% Methocel K100M+ 60% SimpleCap, 50% Methocel K100M+ 50% SimpleCap, 30% Methocel E4M+ 70% Lactose, 90% Methocel E4M+ 10% Lactose, 40% Methocel K100M+ 60% Lactose, and 50% Methocel K100M+ 50% Lactose followed an ideal slow-release kinetic pattern of Zero Order or Higuchi. The results of this study successfully demonstrated the optiomal composition of slow-release compounded capsules of T3. Future studies are warranted to evaluate the in vivo performance of the optimal formulations and to establish an in vitro-in vivo correlation.

Microvesicle removal of anticancer drugs contributes to drug resistance in human pancreatic cancer cells.

High mortality in pancreatic cancer patients is partly due to resistance to chemotherapy. We describe that human pancreatic cancer cells acquire drug resistance by a novel mechanism in which they expel and remove chemotherapeutic drugs from the microenvironment via microvesicles (MVs). Using human pancreatic cancer cells that exhibit varied sensitivity to gemcitabine (GEM), we show that GEM exposure triggers the cancer cells to release MVs in an amount that correlates with that cell line's sensitivity to GEM. The importance of MV-release in gaining drug resistance in GEM-resistant pancreatic cancer cells was confirmed when the inhibition of MV-release sensitized the cells to GEM treatment, both in vitro and in vivo. Mechanistically, MVs remove drugs that are internalized into the cells and that are in the microenvironment. The differences between the drug-resistant and drug-sensitive pancreatic cancer cell lines tested here are explained based on the variable content of influx/efflux proteins present on MVs, which directly dictates the ability of MVs either to trap GEM or to allow GEM to flow back to the microenvironment.

Time and concentration dependency of P-gp, MRP1 and MRP5 induction in response to gemcitabine uptake in Capan-2 pancreatic cancer cells.

1. Influx and efflux proteins play a major role in the overall uptake and efficacy of chemotherapeutic agents and cellular chemo-resistance. 2. The present study investigated the time course and dose dependency of the induction of three efflux proteins, P-gp, MRP1 and MRP5, in response to gemcitabine exposure in Capan-2 pancreatic cancer cell line at transcriptional and translational levels. The influence of exposure on the influx protein (ENT1), the net cellular uptake of the gemcitabine, the overall ATPase activity and the cell death rate were also measured. 3. The time course of the expression exhibited an initial rise, toward a plateau level. The estimated Km and Vmax confirmed that MRP5 and to a lesser extent MRP1 are the prominent proteins for efflux of gemcitabine. Both mRNA and protein expression demonstrated the time and concentration dependency of the induction; and the elevated ATPase activity validated that the induced efflux proteins are functionally active. 4. The results of the study revealed that the efficacy window of gemcitabine as it relates to the function of the efflux proteins is concentration and temporal dependent and is well correlated to the first 60 min of exposure.