Immediate-release Formulation Research Articles

FDA and EMA Oversight of Disruptive Science on Application of Finite Absorption Time (F.A.T.) Concept in Oral Drug Absorption: Time for Scientific and Regulatory Changes

Background: It has been demonstrated that the concept of infinite absorption time, associated with the absorption rate constant, which drives a drug’s gastrointestinal absorption rate, is not physiologically sound. The recent analysis of oral drug absorption data based on the finite absorption time (F.A.T.) concept and the relevant physiologically based finite-time pharmacokinetic (PBFTPK) models developed provided a better physiologically sound description of oral drug absorption. Methods: In this study, we re-analyzed, using PBFTPK models, seven data sets of ketoprofen, amplodipine, theophylline (three formulations), and two formulations (reference, test) from a levonorgestrel bioequivalence study. Equations for one-compartment-model drugs, for the estimation of fraction of dose absorbed or the bioavailable fraction exclusively from oral data, were developed. Results: In all cases, meaningful estimates for (i) the number of absorption stages, namely, one for ketoprofen and the levonorgestrel formulations, two for amlodipine, the immediate-release theophylline formulation, and the extended-release Theotrim formulation, and three for the extended-release Theodur formulation, (ii) the duration of each absorption stage and the corresponding drug input rate, and (iii) the total duration of drug absorption, which ranged from 0.75 h (ketoprofen) to 11.6 h for Theodur were derived. Estimates for the bioavailable fraction of ketoprofen and two theophylline formulations exhibiting one-compartment-model kinetics were derived. Conclusions: This study provides insights into the detailed characteristics of oral drug absorption. The use of PBFTPK models in drug absorption analysis can be leveraged as a computational framework to discontinue the perpetuation of the mathematical fallacy of classical pharmacokinetic analysis based on the absorption rate constant as well as in the physiologically based pharmacokinetic (PBPK) studies and pharmacometrics. The present study is an additional piece of evidence for the scientific and regulatory changes required to be implemented by the regulatory agencies in the not-too-distant future.

Acute Quetiapine Intoxication: Relationship Between Ingested Dose, Serum Concentration and Clinical Presentation-Structured Literature Review and Analysis.

Over the past decade, quetiapine has become one of the most commonly used psychotropic drugs in acute intoxication events worldwide. A structured literature review and analysis were conducted to assess the relationship between the kinetic and dynamic profiles in acute quetiapine intoxication. The correlation between dose and peak serum concentration (cmax) was determined using Pearson's correlation coefficient. Binary logistic regression was used to evaluate dose and cmax as predictors of the most common clinical events, signs and symptoms. One hundred and thirty-four cases of acute quetiapine ingestion were included in the analysis, with a median ingested dose of 10 g and a median cmax of 4 mg/L. The typical half-life was estimated to be 16.5 h, significantly longer than at therapeutic doses. For the immediate-release formulation, a biphasic disposition could not be excluded. Dose and cmax demonstrated a weak but significant correlation (r = 0.256; N = 63; p = 0.043). Central nervous system depression and tachycardia were the most common clinical signs. Higher doses and concentrations increased the risk of severe intoxication and were good predictors of intubation, tachycardia, hypotension, QTc prolongation and seizures, but not QRS prolongation, arrhythmia, heart block, hypokalaemia or acidosis. The thresholds for dose and cmax that increased the risk for individual signs and symptoms varied widely. However, doses > 3 g or cmax > 2 mg/L can be considered as alert levels that represent a high risk for severe clinical course of acute quetiapine intoxication.

B-297 Tacrolimus Concentrations in Envarsus vs Prograf Patients: An Evaluation of the Clinical Impact of LC-MS/MS and Immunoassay Methods on Tacrolimus measurement

Abstract Background Tacrolimus is a calcineurin inhibitor used as part of an immunosuppressive regimen in kidney and liver transplant patients to prevent graft-versus-host disease (GvHD) and requires therapeutic drug monitoring due to its narrow therapeutic index. Tacrolimus levels are commonly measured using two different methodologies - immunoassay and liquid chromatography tandem mass spectrometry (LC-MS/MS). A global proficiency study to assess and compare the measurement of trough levels by these two methodologies noted a positive bias with the ARCHITECT immunoassay which is likely due to the presence of tacrolimus metabolites. The aim of our study is to assess the impact of two different formulations of tacrolimus on the accuracy of its analytical measurement. While differences between immunoassay and LC-MS/MS results have been evaluated for immediate-release tacrolimus (Prograf), it has yet to be characterized for extended-release formulations such as Envarsus. The discrepancy between immunoassay and LC-MS/MS has clinical implications, as dosage modifications are based on measured concentrations, analytical variation may cause intervals of subtherapeutic or supratherapeutic exposure, increasing the risk of graft rejection or toxicity. Methods Development of an LC-MS/MS method for the simultaneous quantification of tacrolimus and its major metabolite, desmethyl tacrolimus, was performed in whole blood. Traceable calibrators and quality control material for tacrolimus and specimens supplemented with desmethyl tacrolimus were used to determine accuracy and precision. Tacrolimus concentrations were measured by LC-MS/MS and ARCHITECT immunoassay methods in excess whole blood specimens from patients treated with either Prograf or Envarsus. Measurement biases between LC-MS/MS and immunoassay methodologies were determined for both formulations of tacrolimus. Results External calibration curves for both tacrolimus and desmethyl tacrolimus were linear (R2>0.995), and the analytical measurement range (AMR) for tacrolimus spanned from 1.1 - 31.6 ng/ml. Calibrator and Quality control (QC) biases were within 15% of their target values throughout the AMR and within-run imprecision was less than 10% (n=25) for all calibrators and QCs. Between-run imprecision for Low, Mid, and High QC levels over a period of 2 weeks (n=5 days) was less than 10%. Comparative bias of tacrolimus concentrations between immunoassay and LC-MS/MS was significantly lower (P value=0.0074) for Envarsus (n=20 specimens) relative to Prograf (n=32 specimens). Conclusions The differential bias between immunoassay and LC-MS/MS in the measurement of tacrolimus in patients dosed with immediate-release versus extended-release formulations suggests that their distinct pharmacokinetic profile may impact the accuracy of the measurement. Therefore, applying observed measurement biases from different assays derived from Prograf patients to Envarsus patients and vice versa may result in erroneous estimation of tacrolimus concentrations.

Guiding the starting dose of the once-daily formulation of tacrolimus in "de novo" adult renal transplant patients: a population approach.

The once-daily extended-release tacrolimus formulation (ER-Tac) has demonstrated similar efficacy and safety to the twice-daily immediate-release formulation (IR-Tac), but few population-based pharmacokinetic models have been developed in de novo kidney transplant patients to optimize doses. Therefore, this study aimed i) at developing a population pharmacokinetic model for ER-Tac in de novo adult kidney transplant patients ii) and identifying genetic factors and time-varying covariates predictive of pharmacokinetic variability to guide tacrolimus dosage during the early post-transplant period. A total of 1,067 blood tacrolimus concentrations from 138 kidney transplant patients were analyzed. A total of 29 out of 138 patients were intensively sampled for 24h on the day 5 post-transplantation; meanwhile, for the remaining patients, concentrations were collected on days 5, 10, and 15 after transplantation. Tacrolimus daily doses and genetic and demographic characteristics were retrieved from the medical files. Biochemistry time-varying covariates were obtained on different days over the pharmacokinetic (PK) study. A simultaneous PK analysis of all concentrations was carried out using the non-linear mixed-effects approach with NONMEM 7.5. A two-compartment model with linear elimination and delayed absorption best described the tacrolimus pharmacokinetics. Between-patient variability was associated with oral blood clearance (CL/F) and the central compartment distribution volume (Vc/F). Tacrolimus concentrations standardized to a hematocrit value of 45% significantly improved the model (p < 0.001). This method outperformed the standard covariate modeling of the hematocrit-blood clearance relationship. The effect of the CYP3A5 genotype was statistically (p < 0.001) and clinically significant on CL/F. The CL/F of patients who were CYP3A5*1 carriers was 51% higher than that of CYP3A5*1 non-carriers. Age also influenced CL/F variability (p < 0.001). Specifically, CL/F declined by 0.0562 units per each increased year from the value estimated in patients who were 60years and younger. The 36% between-patient variability in CL/F was explained by CYP3A5 genotype, age, and hematocrit. Hematocrit standardization to 45% explained the variability of tacrolimus whole-blood concentrations, and this was of utmost importance in order to better interpret whole-blood tacrolimus concentrations during therapeutic drug monitoring. The dose requirements of CYP3A5*/1 carriers in patients aged 60years or younger would be highest, while CYP3A5*/1 non-carriers older than 60years would require the lowest doses.

Pricing dynamics of anti-seizure medications in the U.S.

BackgroundThe median cost of anti-seizure medications (ASM) in the United States (U.S.) nearly doubled per person between 2006 and 2021. This increase, combined with shifts in ASM usage and the impact of the COVID-19 pandemic on drug supply chains amid rising inflation, underscored the urgent need to scrutinize ASM pricing dynamics. This study aimed to analyze the complex dynamics of ASM pricing in the U.S. over the past decade (2013–2023); this included how the entry of generic ASMs influenced the pricing of brand-name counterparts and what impacted price variations across different ASM formulations (e.g., significant inflation, the COVID-19 pandemic). MethodsThis study utilized National Average Drug Acquisition Cost (NADAC) data from November 2013 to July 2023. We adjusted ASM prices for inflation using the Consumer Price Index for Medicinal Drugs - Seasonally Adjusted (CPI-MDS). Statistical analyses included fixed effects regressions and multivariable regression analysis to evaluate the impact of inflation, the number of medication labelers, and the COVID-19 pandemic on ASM prices. ResultsOur study analyzed 23 ASMs approved by the U.S. Food and Drug Administration (FDA), which encompassed 223 oral formulations:112 brand-name and 111 generics. From 2013–2016 to 2020–2023, accounting for standard deviations (SD), the average price of brand-name ASMs increased from $8.71 (SD 5.9) to $15.43 (SD 10.7), while generic ASMs saw a slight decrease from $1.39 (SD 1.8) to $1.26 (SD 1.6). Consequently, the price gap between brand-name and generic ASMs surged from 1452.39 % to 3399.26 %. The proportion of matched brand-name and generic ASMs with a price difference of 1000 %–9999 % increased from 32.88 % (2013–2016) to 41.43 % (2020–2023), while those exceeding 10,000 % rose from 16.44 % to 20 % in the same period. Generic immediate-release (IR) formulations were significantly less expensive than extended-release (ER) or delayed-release (DR) counterparts, with cost differences reaching up to 7751.20 %. The number of medication labelers was inversely related to generic ASM prices, which decreased by 5.45 % (p = 0.001) with each additional generic labeler, while brand-name ASM prices increased by 2.46 % (p < 0.001) with each additional generic labeler. The COVID-19 pandemic led to a 24.4 % increase in brand-name ASM prices and a 23.1 % decrease in generic ASM prices. ConclusionsThe findings reveal an expanding price disparity between brand-name and generic oral ASMs. An inverse relationship was observed between the number of medication labelers and generic ASM prices, with additional labelers driving down generic prices. However, introducing more generic labelers led to a significant increase in brand-name ASM prices. Furthermore, following patent expirations, brand-name ASM prices rose—a trend explained by the "generics paradox," where, contrary to expectations, brand prices do not decrease and may even increase when generics enter the market. These findings underscore the need for targeted interventions in drug pricing policies to manage the rising costs associated with epilepsy treatment. To ensure equitable access to ASMs, stakeholders must understand and address the factors driving these pricing dynamics.

Physiologically based in vitro – in vivo correlation of modified release oral formulations with non-linear intestinal absorption: A case study using mirabegron

Establishing an in vitro – in vivo correlation (IVIVC) for oral modified release (MR) formulations would make it possible to substitute an in vitro dissolution test for human bioequivalence (BE) studies when changing the formulation or manufacturing methods. However, the number of IVIVC applications and approvals are reportedly low. One of the main reasons for failure to obtain IVIVCs using conventional methodologies may be the lack of consideration of the dissolution and absorption mechanisms of drugs in the physiological environment. In particular, it is difficult to obtain IVIVC using conventional methodologies for drugs with non-linear absorption processes. Therefore, the aim of the present study was to develop a physiologically based biopharmaceutics model (PBBM) that enables Level A IVIVCs for mirabegron MR formulations with non-linear absorption characteristics.Using human pharmacokinetic (PK) data for immediate-release formulations of mirabegron, the luminal drug concentration-dependent membrane permeation coefficient was calculated through curve fitting. The membrane permeation coefficient data were then applied to the human PK data of the MR formulations to estimate the in vivo dissolution rate by curve fitting. It was assumed that in vivo dissolution could be described using a zero-order rate equation. Furthermore, a Levy plot was generated using the estimated in vivo dissolution rate and the in vitro dissolution rate obtained from the literature. Finally, the dissolution rate of the MR formulations from the Levy plot was applied to the PBBM to predict the oral PK of the mirabegron MR formulations.This PB-IVIVC approach successfully generated linear Levy plots with slopes of almost 1.0 for MR formulations with different dose strengths and dissolution rates. The Cmax values of the MR formulations were accurately predicted using this approach, whereas the prediction errors for AUC exceeded the Level A IVIVC criteria. This can be attributed to the incomplete description of colonic absorption in the current PBBM.

Bioavailability of a novel sustained-release pellet formulation of 5-flucytosine in healthy-fed participants for use in patients with cryptococcal meningitis.

Cryptococcal meningoencephalitis (CM) is an opportunistic fungal infection and a major cause of death among people living with human immunodeficiency virus in sub-Saharan Africa. 5-flucytosine (5-FC) is a unique, brain-permeable antifungal agent used to reduce mortality from CM and to prevent disease in individuals carrying cryptococcal antigen. 5-FC has a short plasma half-life, requiring 6-hourly oral dosing with an immediate-release (IR) formulation, a significant challenge in hospital and outpatient settings, risking a lack of compliance. We recently reported the relative bioavailability in fasting conditions of a sustained release (SR) oral pellet formulation of 5-FC. In this phase I study, we assessed the safety and pharmacokinetic profiles of the new 5-FC SR formulation in a single dose (2 × 3000 mg), relative to 5-FC IR tablets (Ancotil®; 1500 mg b.i.d.) in healthy participants in fed conditions. This randomized, two-period crossover study was conducted in South Africa to confirm the dose of the identified 5-FC SR formulation for a twice-daily 5-FC regimen in patients. Thirty-six healthy participants were included. All treatments were well tolerated and no serious adverse event was reported. Cmax and AUC(0-t) for the SR formulation (49.2 ± 10.49 μg/mL and 640.4 ± 126.4 h.μg/mL, respectively) were significantly higher than for the IR formulation (36.8 ± 7.61 μg/mL and 456.6 ± 72.8 h.μg/mL, respectively). A physiological based pharmacokinetic model (PBPK) predicted that under fasting conditions, 6000 mg SR pellets would show a good overlap with the IR product (3000 mg b.i.d), thus 6000 mg SR 5-FC b.i.d. in fasting conditions is recommended.

Formulation and Evaluation of Immediate Release Tablets of Antimalarial Drug Hydroxychloroquine

The goal of the study was to develop and evaluate an immediate-release antimalarial tablet formulation for the effective management of malaria, an antimalarial drug as an active pharmaceutical ingredient using excipients. Appropriate pharmaceutical products and evaluate their properties in relation to the innovative product. The study was to develop an antimalarial formulation with in-vitro solubility properties equivalent to or better than the improved formulation. Therefore, an orally administered immediate-release tablet with a robust and reproducible formulation technique was developed. According to the study, the number of F3 definitions decreased the most and F8 had the most important medicinal properties. At 20 minutes, F4 appeared to lead the first high decay rate (98. 56%), followed closely by F5 (93.48%). The expansion of F1, F2 and F3 shows high decay rates at this time. Based on this information, one can analyze and compare the decay profiles of unmistakable definitions. Things such as composition, excipients used, and manufacturing geometry can influence degradation behavior, and this information may be necessary to optimize concentrations of substances of interest for drug delivery. It is then concluded that the definition number F5 may be an optimized detail.

Enhanced Bioavailability and Reduced Variability of Dasatinib and Sorafenib with a Novel Amorphous Solid Dispersion Technology Platform.

Despite clinical advances with protein kinase inhibitors (PKIs), oral administration of many PKIs is associated with highly variable plasma exposure and a narrow therapeutic window. We developed a novel hybrid nanoparticle-amorphous solid dispersion (ASD) technology platform consisting of an amorphous PKI embedded in a polymer matrix. The technology was used to manufacture immediate-release formulations of 2 tyrosine kinase inhibitors (TKIs), dasatinib and sorafenib. Our primary objective was to improve the absorption properties and reduce the pharmacokinetic (PK) variability of each TKI. The PKs of XS004 (dasatinib-ASD, 100mg tablet) and XS005 (sorafenib-ASD, 2×50mg capsules) were compared with their crystalline formulated reference drugs (140mg of dasatinib-reference and 200mg of sorafenib-reference). The in vitro biopharmaceutics of dasatinib-ASD and XS005-granulate showed sustained increased solubility in the pH range 1.2-8.0 compared to their crystalline references. In vivo, XS004 was bioequivalent at a 30% lower dose and showed increased absorption and bioavailability, with 2.1-4.8 times lower intra- and intersubject variability compared to the reference. XS005 had an increased absorption and bioavailability of 45% and 2.2-2.8 times lower variability, respectively, but it was not bioequivalent at the investigated dose level. Taken together, the formulation platform is suited to generate improved PKI formulations with consistent bioavailability and a reduced pH-dependent absorption process.

Evaluation of Published Population Pharmacokinetic Models to Inform Tacrolimus Therapy in Adult Lung Transplant Recipients.

The applicability of currently available tacrolimus population pharmacokinetic models in guiding dosing for lung transplant recipients is unclear. In this study, the predictive performance of relevant tacrolimus population pharmacokinetic models was evaluated for adult lung transplant recipients. Data from 43 lung transplant recipients (1021 tacrolimus concentrations) administered an immediate-release oral formulation of tacrolimus were used to evaluate the predictive performance of 17 published population pharmacokinetic models for tacrolimus. Data were collected from immediately after transplantation up to 90 days after transplantation. Model performance was evaluated using (1) prediction-based assessments (bias and imprecision) of individual predicted tacrolimus concentrations at the fourth dosing based on 1 to 3 previous dosings and (2) simulation-based assessment (prediction-corrected visual predictive check; pcVPC). Both assessments were stratified based on concomitant azole antifungal use. Model performance was clinically acceptable if the bias was within ±20%, imprecision was ≤20%, and the 95% confidence interval of bias crossed zero. In the presence of concomitant antifungal therapy, no model showed acceptable performance in predicting tacrolimus concentrations at the fourth dosing (n = 33), and pcVPC plots displayed poor model fit to the data set. However, this fit slightly improved in the absence of azole antifungal use, where 4 models showed acceptable performance in predicting tacrolimus concentrations at the fourth dosing (n = 33). Although none of the evaluated models were appropriate in guiding tacrolimus dosing in lung transplant recipients receiving concomitant azole antifungal therapy, 4 of these models displayed potential applicability in guiding dosing in recipients not receiving concomitant azole antifungal therapy. However, further model refinement is required before the widespread implementation of such models in clinical practice.

In Vitro In Vivo Extrapolation and Bioequivalence Prediction for Immediate-Release Capsules of Cefadroxil Based on a Physiologically-Based Pharmacokinetic ACAT Model.

Physiologically based pharmacokinetic (PBPK) modeling is a mechanistic concept, which helps to judge the effects of biopharmceutical properties of drug product such as in vitro dissolution on its pharmacokinetic and in vivo performance. With the application of virtual bioequivalence (VBE) study, the drug product development using model-based approach can help in evaluating the possibility of extending BCS-based biowaiver. Therefore, the current study was intended to develop PBPK model as well as in vitro in vivo extrapolation (IVIVE) for BCS class III drug i.e. cefadroxil.A PBPK model was created in GastroPlus™ 9.8.3 utilizing clinical data of immediate-release cefadroxil formulations. By the examination of simulated and observed plasma drug concentration profiles, the predictability of the proposed model was assessed for the prediction errors. Furthermore, mechanistic deconvolution was used to create IVIVE, and the plasma drug concentration profiles and pharmacokinetic parameters were predicted for different virtual formulations with variable cefadroxil in vitro release. Virtual bioequivalence study was also executed to assess the bioequivalence of the generic verses the reference drug product (Duricef®).The developed PBPK model satisfactorily predicted Cmax and AUC0-t after cefadroxil single and multiple oral dose administrations, with all individual prediction errors within the limits except in a few cases. Second order polynomial correlation function obtained accurately predict in vivo drug release and plasma concentration profile of cefadroxil test and reference (Duricef®) formulation. The VBE study also proved test formulation bioequivalent to reference formulation and the statistical analysis on pharmacokinetic parameters reported 90% confidence interval for Cmax and AUC0-t in the FDA acceptable limits.The analysis found that a validated and verified PBPK model with a mechanistic background is as a suitable approach to accelerate generic drug development.

Development of immediate-release formulation with reliable absorption of rivaroxaban in various meal regimes.

The bioavailability of rivaroxaban at the higher doses (15 and 20 mg) is considerably reduced when the drug is administered on an empty stomach. This can lead to inadequate anticoagulant effect, and therefore, it is recommended to use the higher doses at fed state. However, proper posology may represent a barrier for some patients. Therefore, the aim of this study was to evaluate innovative rivaroxaban-containing formulations designed to eliminate the food effect to ensure reliable absorption and thus to improve patient adherence with the treatment. Three prototypes (Cocrystal, HPMCP and Kollidon) with rivaroxaban were developed and their bioavailability and food effect in comparison to the reference product was tested in open label, randomized, single oral dose, crossover studies, where test products were administered under fasting and fed conditions and the reference product was administered under fed conditions. Comparable bioavailability for all tested prototypes both under fed and fasting conditions was demonstrated as the 90% confidence intervals of the geometric mean ratios for area under the concentration-time curve remained within the standard acceptance range of 80.00%-125.00%. An innovative immediate release form of rivaroxaban with no food effect on drug bioavailability has been developed, which may represent an important step toward increasing adherence, improving treatment outcome and reducing health care costs.

The impact of tightened prescribing restrictions for PBS-subsidised opioid medicines and the introduction of half-pack sizes, Australia, 2020-21: an interrupted time series analysis.

To evaluate the impact of the tightened Pharmaceutical Benefits Scheme (PBS) prescribing rules for immediate release (IR) and controlled release (CR) opioid medicines (1 June 2020), which also eliminated repeat dispensing without authorisation for codeine/paracetamol and tramadol IR and introduced half-pack size item codes for IR formulations. Population-based interrupted time series analysis of PBS dispensing data claims for a 10% sample of PBS-eligible residents and IQVIA national opioid medicine sales data (PBS-subsidised and private prescriptions), 28 May 2018 - 6 June 2021. Mean amount of PBS-subsidised opioid medicines dispensed per day and mean overall amount sold per day- each expressed as oral morphine equivalent milligrams (OME) - overall, by formulation type (IR, CR), and by specific formulation. During the twelve months following the PBS changes, daily PBS-subsidised opioid medicine dispensing was 81 565 OME lower (95% CI, -106 146 to -56 984 OME) than the mean daily level for 2018-20, a decline of 3.8% after adjusting for the pre-intervention trend; the relative reduction was greater for IR (8.4%) than CR formulations (2.6%). Total daily sales of all, IR formulation, and CR formulation opioid medicines did not change significantly after the PBS changes. Repeat dispensing of prescriptions comprised 7.4% of PBS-subsidised opioid dispensing before 1 June 2020, and 1.3% after the changes. Half-pack sizes comprised 8.4% of PBS-subsidised IR opioid medicine dispensing and 2.8% of all opioid medicines sold in the twelve months after the PBS changes. The introduction of new PBS rules for subsidised opioid medicines was followed by a decline in PBS-subsidised dispensing. Some people may have bypassed the new restrictions by switching to private prescriptions, but our findings suggest that opioid medicine use in Australia declined as a result of the new restrictions.

Lacosamide extended-release capsules are bioequivalent to lacosamide immediate-release tablets: Pharmacokinetic observations and simulations

ObjectivesAssess the bioequivalence of lacosamide extended-release (XR) capsules and immediate-release (IR) tablets and answer real-world clinical questions regarding the use of lacosamide XR. MethodsAn open-label, randomized, two-treatment, two-sequence, oral comparative bioavailability study was conducted to assess the bioequivalence of two lacosamide formulations. Participants were randomized 1:1 to receive lacosamide XR capsules (400 mg once-daily) or IR tablets (200 mg twice-daily) in 1 of 2 sequences over 7-day periods. Primary outcome was the area under the lacosamide concentration-time curve over 24 h at steady-state (AUC0-τ,ss). Secondary outcomes were maximum (Cmax,ss) and minimum concentrations at steady-state (Cmin,ss). Bioequivalence was established when 90% confidence intervals (CIs) for geometric least square means ratios (GLSMs) were between 80% and 125%. Adverse events (AEs) and other safety outcomes were also assessed. Pharmacokinetic simulations, including adherent and partially adherent dosing scenarios with XR and IR formulations, modeled the clinical use of lacosamide XR. ResultsThirty-five healthy adult males were enrolled in the bioequivalence study. After 7 days of study drug, mean AUC0-τ,ss, Cmax,ss, and Cmin,ss values were similar between XR and IR formulations; all 90% CIs for GLSMs were between 80% and 125%. AEs were mild and no serious AEs or other clinically significant safety findings were observed. Pharmacokinetic simulations suggested that partial adherence affected formulations similarly; and the best strategy for switching formulations was to take the morning lacosamide IR dose followed by the evening lacosamide XR dose, as this resulted in the most consistent lacosamide plasma concentrations. ConclusionsOnce-daily lacosamide XR capsules were bioequivalent to twice-daily lacosamide IR tablets. Pharmacokinetic simulations indicated lacosamide XR and IR formulations were similarly affected by partial adherence, though once-daily dosing with lacosamide XR may offer clinical advantages, and formulations can be easily switched. These results support the use of lacosamide XR capsules as a once-daily alternative to lacosamide IR tablets.

A multi-center interventional study to assess pharmacokinetics, effectiveness, and tolerability of prolonged-release tacrolimus after pediatric kidney transplantation: study protocol for a prospective, open-label, randomized, two-phase, two-sequence, single dose, crossover, phase III b trial.

Tacrolimus, a calcineurin inhibitor (CNI), is currently the first-line immunosuppressive agent in kidney transplantation. The therapeutic index of tacrolimus is narrow due to due to the substantial impact of minor variations in drug concentration or exposure on clinical outcomes (i.e., nephrotoxicity), and it has a highly variable intra- and inter-individual bioavailability. Non-adherence to immunosuppressants is associated with rejection after kidney transplantation, which is the main cause of long-term graft loss. Once-daily formulations have been shown to significantly improve adherence compared to twice-daily dosing. Envarsus®, the once-daily prolonged-release formulation of tacrolimus, offers the same therapeutic efficacy as the conventional twice-daily immediate-release tacrolimus formulation (Prograf®) with improved bioavailability, a more consistent pharmacokinetic profile, and a reduced peak to trough, which may reduce CNI-related toxicity. Envarsus® has been approved as an immunosuppressive therapy in adults following kidney or liver transplantation but has not yet been approved in children. The objective of this study is to evaluate the pharmacokinetic profile, efficacy, and tolerability of Envarsus® in children and adolescents aged ≥ 8 and ≤ 18 years to assess its potential role as an additional option for immunosuppressive therapy in children after kidney transplantation. The study is designed as a randomized, prospective crossover trial. Each patient undergoes two treatment sequences: sequence 1 includes 4 weeks of Envarsus® and sequence 2 includes 4 weeks of Prograf®. Patients are randomized to either group A (sequence 1, followed by sequence 2) or group B (sequence 2, followed by sequence 1). The primary objective is to assess equivalency between total exposure (of tacrolimus area under the curve concentration (AUC0-24)), immediate-release tacrolimus (Prograf®) therapy, and prolonged-release tacrolimus (Envarsus®) using a daily dose conversion factor of 0.7 for prolonged- versus immediate-release tacrolimus. Secondary objectives are the assessment of pharmacodynamics, pharmacogenetics, adherence, gut microbiome analyses, adverse events (including tacrolimus toxicity and biopsy-proven rejections), biopsy-proven rejections, difference in estimated glomerular filtration rate (eGFR), and occurrence of donor-specific antibodies (DSAs). This study will test the hypothesis that once-daily prolonged-release tacrolimus (Envarsus®) is bioequivalent to twice-daily intermediate-release tacrolimus after pediatric kidney transplantation and may reduce toxicity and facilitate medication adherence. This novel concept may optimize immunosuppressive therapy for more stable graft function and increased graft survival by avoiding T-cell mediated and/or antibody-mediated rejection due to improved adherence. In addition, the study will provide data on the pharmacodynamics and pharmacogenetics of prolonged-release tacrolimus in children and adolescents. EUDRA-CT 2019-003710-13 and ClinicalTrial.gov, identifier NCT06057545.

Do dietary interventions exert clinically important effects on the bioavailability of β-lactam antibiotics? A systematic review with meta-analyses.

Managing drug-food interactions may help to achieve the optimal action and safety profile of β-lactam antibiotics. We conducted a systematic review with meta-analyses in adherence to PRISMA guidelines for 32 β-lactams. We included 166 studies assessing the impact of food, beverages, antacids or mineral supplements on the pharmacokinetic (PK) parameters or PK/pharmacodynamic (PK/PD) indices. Eighteen of 25 β-lactams for which data on food impact were available had clinically important interactions. We observed the highest negative influence of food (AUC or Cmax decreased by >40%) for ampicillin, cefaclor (immediate-release formulations), cefroxadine, cefradine, cloxacillin, oxacillin, penicillin V (liquid formulations and tablets) and sultamicillin, whereas the highest positive influence (AUC or Cmax increased by >45%) for cefditoren pivoxil, cefuroxime and tebipenem pivoxil (extended-release tablets). Significantly lower bioavailability in the presence of antacids or mineral supplements occurred for 4 of 13 analysed β-lactams, with the highest negative impact for cefdinir (with iron salts) and moderate for cefpodoxime proxetil (with antacids). Data on beverage impact were limited to 11 antibiotics. With milk, the extent of absorption was decreased by >40% for cefalexin, cefradine, penicillin G and penicillin V, whereas it was moderately increased for cefuroxime. No significant interaction occurred with cranberry juice for two tested drugs (amoxicillin and cefaclor). Factors such as physicochemical features of antibiotics, drug formulation, type of intervention, and patient's health state may influence interactions. Due to the poor actuality and diverse methodology of included studies and unproportionate data availability for individual drugs, we judged the quality of evidence as low.

Inhibition of Receptor-Interacting Protein Kinase1 in Chronic Plaque Psoriasis: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study.

Receptor-interacting protein kinase1 (RIPK1), a key mediator of inflammation through necroptosis and proinflammatory cytokine production, may play a role in the pathogenesis of immune-mediated inflammatory diseases such as chronic plaque psoriasis. An experimental medicine study of RIPK1 inhibition with GSK2982772 immediate-release formulation at doses up to 60mg three times daily in mild to moderate plaque psoriasis indicated that efficacy may be improved with higher trough concentrations of GSK2982772. This multicenter, randomized, double-blind, placebo-controlled, repeat-dose study (NCT04316585) assessed the efficacy, safety, pharmacokinetics, and pharmacodynamics of 960mg GSK2982772 (once-daily modified-release formulation) in patients with moderate to severe plaque psoriasis. Twenty-nine patients were randomized 2:1 to GSK2982772 (N = 19) or placebo (N = 10) for 12weeks. GSK2982772 was well tolerated with trough concentrations greater than tenfold higher than the previous phase1 study with immediate release. Despite near complete RIPK1 target engagement in blood and modest reduction in circulating inflammatory cytokines, the proportion of patients achieving 75% improvement from baseline in Psoriasis Area Severity Index score at week12 was similar between GSK2982772 and placebo (posterior median 1.8% vs 4.9%, respectively), with an estimated median treatment difference of - 2.3%. This analysis incorporated historical placebo data through the use of an informative prior distribution on the placebo arm. Week4 changes in skin biopsy gene expression suggested sufficient local drug exposure to elicit a pharmacodynamic response. Administration of the RIPK1 inhibitor GSK2982772 to patients with moderate to severe plaque psoriasis did not translate into meaningful clinical improvements.

Pharmacokinetics of Tacrolimus in Pregnant Solid-Organ Transplant Recipients: A Retrospective Study.

Data on the pharmacokinetics of tacrolimus during pregnancy are limited. Therefore, the aim of this retrospective study was to characterize the whole-blood pharmacokinetics of tacrolimus throughout pregnancy. In this single-center retrospective cohort study, whole-blood tacrolimus trough concentrations corrected for the dose (concentration-to-dose [C/D] ratios) were compared before, monthly during, and after pregnancy in kidney, liver, and lung transplant recipients who became pregnant and gave birth between 2000 and 2022. Descriptive statistics and linear mixed models were used to characterize changes in tacrolimus C/D ratios before, during, and after pregnancy. The total study population included 46 pregnancies (31 pregnant women). Nineteen, 21, and 6 pregnancies were following kidney, liver, and lung transplantation, respectively. Immediate-release or extended-release formulations were used in 54.5% and 45.5% of the women, respectively. Tacrolimus C/D ratios significantly (P<.001) decreased (-48%) compared to the prepregnancy state at 7 months of pregnancy. These ratios recovered within 3 months postpartum (P = .002). C/D ratios tended to be lower during treatment with an extended-release formulation than with an immediate-release formulation (P = .071). Transplantation type did not significantly affect C/D ratios during pregnancy (P = .873). In conclusion, we found that tacrolimus whole-blood pharmacokinetics change throughout pregnancy, with the lowest C/D ratios (48% decrease) in the 7th month of pregnancy. In general, the decrease in C/D ratios seems to stabilize from month 4 onward compared to prepregnancy.

Reduced Plasma Levodopa Fluctuations with More Frequent Administration of a Novel Carbidopa/Levodopa Functionally Scored Tablet.

Levodopa/carbidopa remains the gold standard for treating Parkinsondisease (PD), but chronic pulsatile administration contributes to motor complications. This Phase 1 study used a new immediate-release (IR) formulation of carbidopa/levodopa 25/100mg that is functionally scored for easy and precise splitting to evaluate the effects on levodopa plasma variability when smaller doses are taken more frequently. These functionally scored tablets were shown to be bioequivalent to carbidopa/levodopa 25-/100-mg IR generic reference tablets. Twenty-two healthy volunteers received a whole tablet every 4 hours versus half of the tablet every 2 hours. Plasma levodopa fluctuations were significantly reduced with half-tablets dosed every 2 hours, with a 44% reduction in peaks (P< .0001). While drug exposure did not differ, parameters that underlie motor response variations, including mean peak-to-trough difference and variance, were 51% and 56% less, respectively, with more frequent dosing (both P ≤ .0024). Safety and tolerability of both regimens were similar. In conclusion, more frequent administration of half-tablets of the new functionally scored IR formulation safely provided more constant levodopa levels than whole tablets dosed less often. This tablet technology could facilitate the benefits of more physiologic dopamine replenishment in patients with PD, particularly those with reduced manual dexterity.

Bioavailability of Orally Administered Drugs After Bariatric Surgery.

Oral drug absorption after bariatric surgery is likely to be altered, but the impact of different bariatric surgery procedures on individual drugs is not uniform. The aim of this article is to describe factors influencing the bioavailability of orally administered drugs after bariatric surgery and to provide readers with practical recommendations for drug dosing. We also discuss the medications that may be harmful after bariatric surgery. The fundamental factors for enteral drug absorption are the production of gastric acid; the preserved length of the intestine, i.e., the size of the absorption surface and/or the preserved enterohepatic circulation; and the length of common loop where food and drugs are mixed with digestive enzymes and bile acids. Bypassing of metabolizing enzymes or efflux pumps and changes in intestinal motility can also play an important role. Significant changes of drug absorption early after the anatomic alteration may also be gradually ameliorated due to gradual intestinal adaptation. The most affected drugs are those with low or variable bioavailability and those undergoing enterohepatic circulation. Attention should also be paid to oral drug formulations, especially in the early postoperative period, when immediate-release and liquid formulations are preferred. The changes in oral bioavailability are especially clinically meaningful in patients treated with drugs possessing narrow therapeutic index (e.g., oral anticoagulants, levothyroxine, and anticonvulsants) or in acute conditions (e.g., anti-infectives); nevertheless, it may also influence the therapeutic value of chronic therapy (e.g., antidepressants. antihypertensives, antiplatelets, statins, PPIs, contraceptives, and analgesics); therapeutic effect of chronic therapy is further influenced by pharmacokinetic alterations resulting from weight loss. Therapeutic drug monitoring, periodical clinical evaluation, and adequate dose adjustments are necessary. Due to safety reasons, patients should avoid oral bisphosphonates, regular use of non-steroidal anti-inflammatory drugs, and, if possible, corticosteroids after bariatric surgery.