Maintain Plasma Concentrations Research Articles

Zeolites – tabletting ibuprofen with and without zeolites as an excipient

Abstract Introduction Drug delivery via the oral route is a patient and industry-preferred approach. However, maintaining plasma concentrations of the active pharmaceutical ingredient (API) within the therapeutic window can be challenging with immediate-release (IR) tablets. To avoid the plasma peaks and troughs associated with IR tablets, sustained release (SR) formulations have been investigated. Zeolites are microporous aluminosilicate minerals that represent a novel tabletting material with the potential for modifying drug release due to their unique adsorption and ion exchange properties1. Aim This study will investigate the potential for inclusion of zeolites within orally disintegrating tablets (ODTs) and assessment of their ability to modify API release. Methods In-house, 50%w/w ibuprofen (IBU)-loaded ODTs (IHODTs) were prepared from Pearlitol® Flash, magnesium (Mg) stearate and 2 different zeolites (CP814C and CP814E), incorporated at 5%w/w each, using a manual tablet press. Formulations were prepared and mixed for 10 minutes in a cube mixer prior to direct compression (DC) into tablets. Physical characteristics of the tablets were assessed by hardness and friability measurements. Tablet quality was assessed by disintegration and dissolution analysis to British Pharmacopeia (BP) standards2. Release profiles were assessed against various models to determine the effect of zeolites on the release of IBU. Formulations were further examined and characterised using scanning electron microscopy (SEM) and energy-dispersive x-ray (EDX) spectroscopy. An ethics evaluation was completed, and the study was identified as not having any ethical considerations by the University of South Wales. Results The mean weight of blank ODTs was found to be 225.3mg, with a mean thickness of 3.65mm, diameter of 8.10mm, hardness of 43.9±9.2N (mean±SD, n=5) and friability of 0.2±0.2% (mean±SD, n=3). The hardness of IHODTs was found to be 59.98±1.6N, reducing to 54.9±4.3N and 43.4±0.7N (mean±SD, n=3) with the inclusion of CP814C and CP814E, respectively. The friability of IHODTs containing zeolites was 1.76±0.4% and 1.91±0.9N (mean±SD, n=3), for CP814C and CP814E, respectively; conforming to BP specification2. The disintegration time for all in-house tablets, both with and without a zeolite included, was found to be an order of magnitude greater than commercial ODTs (CT) controls, but all remained within the BP specification2. The release of IBU from IHODTs and CTs showed good correlation to the first-order release model (R2 = 0.96 and 0.98, respectively), indicating IR behaviour. Similarly, the release of IBU from IHODTs containing zeolites was shown to correlate best with the first-order release model, R2 = 0.91 for CP814C and R2 = 0.90 for CP814E, respectively. SEM analysis suggested a homogeneous blend of components within IHODTs, whilst EDX analysis indicated the presence of silicon and aluminium from zeolites, and Mg and carbon from Mg stearate and IBU, respectively. Discussion / Conclusion This study investigated the effect of zeolite inclusion on the release properties of ODTs containing IBU. Although the quality of ODTs containing zeolites was not compromised, this study suggests that inclusion of a zeolite by DC only, does not significantly modify the release profile. Future studies are required to ascertain whether zeolites can achieve SR from ODTs using alternative API loading approaches, such as solvent loading1.

OPTIMIZING DRUG DOSING IN CRITICALLY ILL PATIENTS WITH AUGMENTED RENAL CLEARANCE: A COMPREHENSIVE REVIEW AND META-ANALYSIS

Renal clearance plays a pivotal role in eliminating most administered drugs, particularly antibiotics, which is crucial for achieving therapeutic goals by maintaining plasma concentrations within the therapeutic window. Various pre-existing conditions such as renal replacement therapies, kidney or liver impairment, and enhanced excretory organ function can disrupt drug concentrations, leading to treatment failure. Augmented Renal Clearance (ARC) exacerbates this by causing rapid drug elimination, notably in critically ill patients. Consequently, careful monitoring and adjustment of drug dosages tailored to individual patient conditions and comorbidities are imperative to prevent sub-therapeutic outcomes or treatment failures. Our review highlights the necessity of dosage modifications informed by current research to optimize therapeutic outcomes in such cases. We provide a comprehensive table detailing effective antibiotics and their adjustments for ARC.

Effect of buprenorphine delivered by target-controlled infusion on the minimum alveolar concentration of isoflurane in cats

ObjectiveTo characterize the effect of buprenorphine on the minimum alveolar concentration of isoflurane (MACiso) in cats. Study designRandomized, crossover experimental study. AnimalsA group of six healthy 2 to 8 years old male neutered cats, body mass 5.0 ± 0.3 kg. MethodsThe MACiso had been determined in each cat in a previous study. Cats were anesthetized with isoflurane in oxygen. Catheters were placed in a medial saphenous vein for drug and fluid administration and in a jugular vein for blood sampling. Buprenorphine was given intravenously using a target-controlled infusion system to reach and maintain plasma concentrations of 0.5, 1, 2, 4, 8, 16, 32 and 64 ng mL-1 and MACiso was determined in duplicate at each concentration using the tail clamp technique. Four target plasma buprenorphine concentrations were administered on each study day, with at least 2 weeks between experiments. Blood was sampled after the second MAC determination at each target for determination of plasma buprenorphine concentration. ResultsA significant effect of buprenorphine on MAC was found; however, pairwise comparisons to MACiso without buprenorphine did not reach statistical significance. Maximum reduction in MACiso in individual cats ranged from 2 to 34% at plasma buprenorphine concentrations ranging from 0.25 to 8.15 ng mL-1. Conclusions and clinical relevanceAlthough buprenorphine significantly affected MACiso in cats, the magnitude of the effect and the plasma concentration at which the largest effect occurred was highly variable among cats, limiting the clinical usefulness of buprenorphine as an agent to reduce MAC in cats.

Ceftobiprole quantification in human serum by HPLC-UV to implement routine TDM in clinical practice

Background and aimsCeftobiprole is a recent 5th generation parenteral cephalosporin with antibacterial activity against a large range Gram+ and Gram− bacteria. Therapeutic drug monitoring (TDM) is an essential tool for maintaining plasma concentrations of antibiotics above the MIC by the end of the dosing interval, thus preventing the resistant strain diffusion. TDM is already recommended for other cephalosporins, and it is a reasonable tool contributing to the safety and efficacy of these drugs. During the treatment of patients in real-life, a number of pharmacokinetic (PK) changes not normally seen in healthy volunteers can occur which can impair the pharmacokinetic/pharmacodynamic target attainment.We aimed to develop simple and rapid HPLC-UV method for determination of ceftobiprole in human serum to implement TDM in clinical practice and support PKs and pharmacokinetic/pharmacodynamic (PK/PD) studies. Materials and methodsSamples preparation of calibration standards, QC, and anonymous patients serum samples was performed by protein precipitation by adding 0.01 ml of sulphosalicylic acid at 30 % to 0.1 ml of each sample. Then samples were vortexed and the centrifuged at 12,000 rpm for 10 min at 4 °C. Fifty microlitres of clear supernatant were diluted 1:1 with mobile phase and transferred into HPLC autosampler held at 8 °C. Chromatographic separation was carried out in a gradient mode at 35 °C on an ultra-Biphenyl column using a Thermo Scientific chromatographic system with a Diode array. Data management was performed with Chromeleon 7.4 software. ResultsThe HPLC-UV method proved to be linear over wide concentration ranges (0.5–50.0 mg/L) and was accurate and reproducible in the absence of matrix effects, allowing for robust, specific, and rapid quantification of ceftobiprole from a low amount of serum (0.1 mL). The mean steady state Ctrough and Cend values measured in the anonymous patients’ samples were 6.26 ± 3.81 mg/L and 22.56 ± 15.69 mg/L, respectively. ConclusionsWe report a broadened simple and fast HPLC with UV detection method for quantification of ceftobiprole in human serum to implement ceftobiprole TDM as clinical routine, and support future (PK/PD) studies in special patients’ population.

Stress-free blood sampling in minipigs: A novel method for assessing 24-h cortisol profiles and drug effects on diurnal and ultradian rhythms

We developed a novel, stress-free blood sampling method for minipigs, allowing continuous cortisol monitoring over 24 h. Baseline cortisol levels exhibited both ultradian and diurnal rhythms. During nighttime, smaller ultradian rhythms overlaid a lower baseline cortisol, which increased in sleeping pigs before lights were turned on. Additionally, we developed an analytical tool based on the R package “pracma” to quantify ultradian peak and circadian components of the cortisol profiles.To validate our model, we investigated the effects of Verucerfont, a CRH receptor antagonist, and Venlafaxine, a serotonin-norepinephrine reuptake inhibitor. Verucerfont reduced cortisol levels during the first 9 h without affecting diurnal rhythm. Cortisol peak parameters decreased, with a 31% reduction in overall area under the curve (AUC) and a 38% reduction in ultradian average AUC. Ultradian peaks decreased from 7 to 4.5, with 34% lower amplitude. Venlafaxine maintained plasma concentrations within the targeted human effective range.This method enables us to enhance our understanding of cortisol regulation and provide valuable insights for the impact of investigation drugs on the diurnal and ultradian rhythms of cortisol.

Formulation and Evaluation of Verapamil Hydrochloride Sustain Release Tablet

Verapamil hydrochloride, a calcium channel blocker, is used to treat hypertension, supraventricular arrhythmia and myocardial infarction Verapamil hydrochloride (VPH) sustain release tablets were developed for this study in order to maintain plasma concentrations, enhance bioavailability, and avoid repeated dosing. Materials and procedures Tablets containing a fixed amount of VPH were made using the direct compression method and various combinations and ratios of the polymers hydroxypropyl methyl cellulose (HPMC K15) and ethyl cellulose. The tablets were then tested for thickness, weight variation, hardness, uniformity of the drug content, drug release, and potential ingredient interactions. Regarding thickness, weight variation, hardness, and medication content, all tablets were satisfactory. It may be determined from formulations comprising HPMCK15 and ethyl cellulose that the two polymers functioned well together, controlling the first burst and improving the drug's release throughout the first three hours. A study of in vitro drug release followed the formulation of the 32 factorial planned batches. The formulations F5, F6, and F8 demonstrated better drug release up to 24hours and minimal burst release with more than 80% release in 24hours. They were composed of HPMC K15 60mg, 60 mg, and 75mg, respectively, and ethyl cellulose 30mg, 45mg, and 30mg, respectively. Thus, the F5 formulation with somewhat lower polymer content was chosen as the optimal formulation and they contained HPMC K15 60mg and ethyl cellulose 30mg.

Antitrypanosomal Chloronitrobenzamides.

Human African trypanosomiasis (HAT), a neglected tropical disease caused by Trypanosoma brucei gambiense (Tbg) or Trypanosoma brucei rhodesiense (Tbr), remains a significant public health concern with over 55 million people at risk of infection. Current treatments for HAT face the challenges of poor efficacy, drug resistance, and toxicity. This study presents the synthesis and evaluation of chloronitrobenzamides (CNBs) against Trypanosoma species, identifying previously reported compound 52 as a potent and selective orally bioavailable antitrypanosomal agent. 52 was well tolerated in vivo and demonstrated favorable oral pharmacokinetics, maintaining plasma concentrations surpassing the cellular EC50 for over 24 h and achieving peak brain concentrations exceeding 7 μM in rodents after single oral administration (50 mg/kg). Treatment with 52 significantly extended the lifespan of mice infected with Trypanosoma congolense and T. brucei rhodesiense. These results demonstrate that 52 is a strong antitrypanosomal lead with potential for developing treatments for both human and animal African trypanosomiasis.

P887 Comparative efficacy of JAK inhibitors versus vedolizumab in patients with hypoalbumineamia and Ulcerative colitis

Abstract Background The IBD community are seeking ways to personalize medication choices for individual patients. Hypoalbumineamia is a poor prognostic marker in ulcerative colitis (UC) as a surrogate marker of disease activity. Biologic molecules are intermittently dosed using albumin binding to maintain plasma concentration, therefore in low albumin states drug clearance is accelerated. This effect is potentially less significant in regularly dosed, JAK inhibitors (JAKi). Methods All patients at our unit taking a JAKi were included. Patients using vedolizumab were selected for inclusion based on the nearest neighbour with respect to medication start date. Vedolizumab was chosen as a second line advanced therapy used regularly in UC. Demographic and disease characteristics were collected. Blood tests immediately prior to starting medication were collected. Outcome measure was response to treatment based based on drug continuation and clinician documentation of treatment success at 6 months. Results 56 patients were included; 28 receiving a JAKi, 28 patients using vedolizumab. The JAKi group consisted of 8 patients receiving Filgotinib, 12 Tofacitinib and 8 Upadacitinib. Patients receiving JAKi were younger (mean age 44 years, SD 14) compared to vedolizumab (56 years, SD 20). Both were predominantly white (JAKi n=16, Vedolizumab n=22). Chronic liver disease was uncommon in both groups; JAKi n=2 (7.1%) and vedolizumab n=3 (10.7%), none of whom had cirrhosis. More hospital admissions were observed in the year prior to starting treatment in patients who received JAKi (n=16, 57.1%) compared to vedolizumab (n=9, 32%). Hypoalbuminaemia (defined as ≤30g/L) was seen in 5 patients in each group. In patients receiving JAKi 16/23 (69.7%) patients without hypoalbuminaemia responded to treatment at 6 months, compared to 3/5 (60%) with low albumin. (p=0.999). In patients receiving Vedolizumab 18/23 (78.3%) patients responded to treatment at 6 months, compared to 1/5 (20%), (p=0.026). Conclusion In patients with hypoalbumineamia, vedolizumab was less effective compared to normal albumin states. A similar effect was not observed in patients receiving JAKi. Numerically the efficacy of both vedolizumab and JAKi was worse in patients with hypoalbuminaemia, as would be expected given the likely reflection of increased disease severity. This data suggests that those patients requiring advanced therapy with hypalbuminaemia might respond better to a JAKi. Further research is needed to investigate this finding.

Development of dissolving microneedles for intradermal delivery of the long-acting antiretroviral drug bictegravir

Oral administration and intramuscular (IM) injection are commonly recommended options for human immunodeficiency virus (HIV) treatment. However, poor patient compliance due to daily oral dosing, pain at injection sites and the demand for trained healthcare staff for injections limit the success of these administration routes, especially in low-resource settings. To overcome these limitations, for the first time, we propose novel bilayer dissolving microneedles (MNs) for the intradermal delivery of long-acting nanosuspensions of the antiretroviral (ARV) drug bictegravir (BIC) for potential HIV treatment and prevention. The BIC nanosuspensions were prepared using a wet media milling technique on a laboratory scale with a particle size of 358.99 ± 18.53 nm. The drug loading of nanosuspension-loaded MNs and BIC powder-loaded MNs were 1.87 mg/0.5 cm2 and 2.16 mg/0.5 cm2, respectively. Both dissolving MNs exhibited favorable mechanical and insertion ability in the human skin simulant Parafilm® M and excised neonatal porcine skin. Importantly, the pharmacokinetic profiles of Sprague Dawley rats demonstrated that dissolving MNs were able to intradermally deliver 31% of drug loading from nanosuspension-loaded MNs in the form of drug depots. After a single application, both coarse BIC and BIC nanosuspensions achieved sustained release, maintaining plasma concentrations above human therapeutic levels (162 ng/mL) in rats for 4 weeks. These minimally invasive and potentially self-administered MNs could improve patient compliance, providing a promising platform for the delivery of nanoformulated ARVs and resulting in prolonged drug release, particularly for patients in low-resource settings.

Response and Regulation of the Microenvironment Based on Hollow Structured Drug Delivery Systems

AbstractHollow structured materials with easily modifiable surfaces and enclosed interior spaces have emerged as the most promising candidates in drug delivery systems (DDS). With various functional components and inspiring cavities for creative reinvention, the response and regulation of the external and internal microenvironment of hollow structures enable their ideal drug delivery capabilities by improving drug aggregation in targeted sites and maintaining plasma concentrations at the optimal therapeutic ranges. This review begins with an in‐depth explanation of the interactions and release mechanisms of hollow structure‐based DDS, including diffusion, assembly, solvent activation, and chemical control, all of which are of great significance for the design of smart drug carriers. Next, recent advances in external microenvironment‐responsive drug delivery systems are introduced, based on various chemical signals and external field assists. Focusing on the unique view of intra‐carrier variability, the strategies for regulating the internal environment are then highlighted, including pH regulation, temperature regulation, and mechanical force regulation. Finally, this review discusses possible challenges and prospects for hollow structure‐based, particularly hollow multishelled structures intelligence‐responsive drug delivery platforms, providing valuable strategies for the development of the next generation of responsive DDS.

Twice-daily oral administration of a cannabidiol and cannabidiolic acid-rich hemp extract was well tolerated in orange-winged Amazon parrots (Amazona amazonica) and has a favorable pharmacokinetic profile.

To determine the pharmacokinetics of 8 cannabinoids and 5 metabolites after oral administration of single and multiple doses of a cannabidiol (CBD)-cannabidiolic acid (CBDA)-rich hemp extract to orange-winged Amazon parrots (Amazona amazonica) as well as to evaluate the extract's adverse effects. 12 birds. Based on pilot studies, a single-dose study based on 30/32.5 mg/kg of cannabidiol/cannabidiolic acid of a hemp extract was administered orally to 8 fasted parrots, and 10 blood samples were collected over 24 hours after administration. After a 4-week washout period, the hemp extract was administered orally to 7 birds at the previous dose every 12 hours for 7 days, and blood samples were collected at the previous time points. Cannabidiol, Δ9-tetrahydrocannabinol, cannabinol, cannabichromene, cannabigerol, cannabidiolic acid, cannabigerolic acid, Δ9-tetrahydrocannabinolic acid, and 5 specific metabolites were measured by liquid chromatography-tandem/mass-spectrometry, and pharmacokinetic parameters were calculated. Adverse effects and changes in the plasma biochemistry and lipid panels were evaluated. Pharmacokinetic parameters for cannabidiol, cannabidiolic acid, Δ9-tetrahydrocannabinol, Δ9-tetrahydrocannabinolic acid, and the metabolite 11-hydroxy-9-tetrahydrocannabinol were established. For the multiple-dose study, cannabidiol/cannabidiolic acid mean Cmax was 337.4/602.1 ng/mL with a tmax of 30 minutes and a terminal half-life of 8.6/6.29 hours, respectively. No adverse effects were detected during the multidose study. The predominant metabolite was 11-hydroxy-9-tetrahydrocannabinol. Twice daily oral administration of the hemp extract based on 30 mg/kg/32.5 mg/kg of cannabidiol/cannabidiolic acid was well tolerated and maintained plasma concentrations considered to be therapeutic in dogs with osteoarthritis. Findings suggest different cannabinoid metabolism from mammals.

Osmotic pump maintains plasma concentrations of meloxicam for 6 days after orthopedic surgery in pigeons (Columba livia).

To determine the plasma concentration of meloxicam delivered via an osmotic pump in pigeons undergoing orthopedic surgery and if an osmotic pump is a suitable alternative to repeated oral administration of this drug. 16 free-ranging pigeons presented for rehabilitation with a wing fracture. An osmotic pump filled with 0.2 mL of 40 mg/mL meloxicam injectable solution was implanted subcutaneously in the inguinal fold of 9 pigeons under anesthesia for orthopedic surgery. The pumps were removed 7 days postsurgery. Blood samples were collected before pump implantation (time 0) and 3, 24, 72, and 168 hours after pump implantation in 2 pigeons in a pilot study then at 12, 24, 72, and 144 hours in the 7 pigeons of the main study. The blood of 7 other pigeons receiving meloxicam at 2 mg/kg, PO, every 12 hours was also sampled between 2 to 6 hours after the last meloxicam administration. Plasma meloxicam concentrations were measured via high-performance liquid chromatography. The plasma concentration of meloxicam was maintained at significant levels from 12 hours to 6 days after osmotic pump implantation. Median and minimum plasma concentrations in implanted pigeons were maintained at the same or higher level than those measured in pigeons that received meloxicam at a dose known to be analgesic in this species. No adverse effects attributable to either osmotic pump implantation and removal or meloxicam delivery were observed in this study. Plasma concentrations levels of meloxicam in pigeons implanted with osmotic pumps were maintained at a similar concentration or higher than the suggested analgesic meloxicam plasma concentration in this species. Thus, osmotic pumps could represent a suitable alternative to the frequent capture and handling of birds for analgesic drug administration.

Development and Evaluation of Dissolving Microarray Patches for Co-administered and Repeated Intradermal Delivery of Long-acting Rilpivirine and Cabotegravir Nanosuspensions for Paediatric HIV Antiretroviral Therapy

PurposeWhilst significant progress has been made to defeat HIV infection, the efficacy of antiretroviral (ARV) therapy in the paediatric population is often hindered by poor adherence. Currently, two long-acting (LA) intramuscular injectable nanosuspensions of rilpivirine (RPV) and cabotegravir (CAB) are in clinical development for paediatric populations. However, administration requires access to healthcare resources, is painful, and can result in needle-stick injuries to the end user. To overcome these barriers, this proof-of-concept study was developed to evaluate the intradermal delivery of RPV LA and CAB LA via self-disabling dissolving microarray patches (MAPs).MethodsDissolving MAPs of two conformations, a conventional pyramidal and a bilayer design, were formulated, with various nanosuspensions of RPV and CAB incorporated within the respective MAP matrix. MAPs were mechanically robust and were capable of penetrating ex vivo skin with intradermal ARV deposition.ResultsIn a single-dose in vivo study in rats, all ARV MAPs demonstrated sustained release profiles, with therapeutically relevant plasma concentrations of RPV and CAB detected to at least 63 and 28 d, respectively. In a multi-dose in vivo study, repeated MAP applications at 14-d intervals maintained therapeutically relevant plasma concentrations throughout the duration of the study.ConclusionsThese results illustrate the potential of the platform to repeatedly maintain plasma concentrations for RPV and CAB. As such, these MAPs could represent a viable option to improve adherence in the paediatric population, one that is capable of being painlessly administered in the comfort of the patient’s own home on a biweekly or less frequent basis.Graphical abstract

Pharmaceutical characterization and pharmacokinetics of florfenicol-loaded alginate dried beads in rabbits

The pharmacokinetic variables of a new formulation of florfenicol included in dried bean of alginate (FADBs), its acceptance as in food medication, and its relationship with theoretical minimum inhibitory concentration (MIC) values of the main pathogens in rabbits, are presented. FADBs sought to mask the unpleasant taste of florfenicol while enhancing sustained absorption in a day to facilitate and optimise its dosage in this species. The entrapment efficiency was determined to be 94-98% and 73.56±3.26% of drug loading. No reduction in food consumption was detected, nor selectivity when choosing from their usual food. The elimination half-life was 1.23 to 2.4 h slower than the one previously reported in the literature. Possible flip-flop pharmacokinetics is proposed for FADBs in rabbits, thus complying better with the key pharmacokinetics/pharmacodynamics (PK/PD) ratio of t≥MIC. Also, if a MIC2.0 μg/mL is taken as the cut-off point for florfenicol in rabbits, then ad libitum intake of FADBs in their standard diet is sufficient to maintain plasma concentrations of florfenicol above this level during the whole dosing interval of 24 h. Additionally, FADBs are a low-cost and attractive drug delivery system for the oral controlled release of florfenicol in rabbits.

Structural basis for the in vitro efficacy of nirmatrelvir against SARS-CoV-2 variants

The COVID-19 pandemic continues to be a public health threat with emerging variants of SARS-CoV-2. Nirmatrelvir (PF-07321332) is a reversible, covalent inhibitor targeting the main protease (Mpro) of SARS-CoV-2 and the active protease inhibitor in PAXLOVID (nirmatrelvir tablets and ritonavir tablets). However, the efficacy of nirmatrelvir is underdetermined against evolving SARS-CoV-2 variants. Here, we evaluated the in vitro catalytic activity and potency of nirmatrelvir against the Mpro of prevalent variants of concern (VOCs) or variants of interest (VOIs): Alpha (α, B.1.1.7), Beta (β, B.1.351), Delta (δ, B1.617.2), Gamma (γ, P.1), Lambda (λ, B.1.1.1.37/C37), Omicron (ο, B.1.1.529), as well as the original Washington or wildtype strain. These VOCs/VOIs carry prevalent mutations at varying frequencies in the Mpro specifically for α, β, γ (K90R), λ (G15S), and ο (P132H). In vitro biochemical enzymatic assay characterization of the enzyme kinetics of the mutant Mpros demonstrates that they are catalytically comparable to wildtype. We found that nirmatrelvir has similar potency against each mutant Mpro including P132H that is observed in the Omicron variant with a Ki of 0.635 nM as compared to a Ki of 0.933 nM for wildtype. The molecular basis for these observations were provided by solution-phase structural dynamics and structural determination of nirmatrelvir bound to the ο, λ, and β Mpro at 1.63 to 2.09 Å resolution. These in vitro data suggest that PAXLOVID has the potential to maintain plasma concentrations of nirmatrelvir many-fold times higher than the amount required to stop the SARS-CoV-2 VOC/VOI, including Omicron, from replicating in cells.

Preparation, characterization, and in vivo evaluation of levonorgestrel-loaded thermostable microneedles.

To facilitate the storage and use of poly (lactic-co-glycolic acid) (PLGA)-based microneedles (MNs) in hot seasons and regions, thermally stable MNs loaded with levonorgestrel (LNG) were developed. Due to its good biocompatibility and high glass transition temperature (Tg), Hydroxypropyl methylcellulose (HPMC) was added to the PLGA-based MNs to increase thermal stability. MNs with HPMC exhibited excellent thermal stability at high temperatures. After the MNs has been applied to the skin for 10min, the backing layer of the MNs was dissolved by contact with the interstitial fluid of skin, which resulted in the separation of the MN tips from the backing layer. The MN tips were implanted intradermally and sustained-release LNG. Biodegradable polymers were used to encapsulate the LNG, providing long-acting contraception. The in vitro release rate of LNG from the MNs reached 72.78%-83.76% within 21days. In rats, the MNs maintained plasma concentrations of LNG above the human contraceptive level for 8-12days. In mice, the time required for complete degradation of the MN tips was 12-16days. MNs have excellent medication adherence due to the advantages of painlessness, minimally invasive, and self-administered. MNs can make long-acting contraceptives more readily available to humans.

Pharmacokinetics of oral and compounded intravenous gabapentin in Duroc swine (Sus Scrofa).

The objective of this study was to determine the pharmacokinetics (PK) of oral (OS; 20mg/kg) and compounded intravenous (IV; 5.5mg/kg) gabapentin in 6 healthy, adult, Duroc pigs. Subjects were randomized to receive IV and OS gabapentin in a cross-over design, with at least 14days of wash-out period between the two rounds of drug administrations. Blood samples were obtained before gabapentin administration and at various times up to 24h, and harvested plasma was stored at -80°C until analysis. Concentration of gabapentin was quantified using a previously validated liquid chromatography/tandem mass spectrometry method, and compartment models were fitted to time-concentration data using non-linear mixed effect (population) analysis. A two-compartment model best fitted the data following IV administration. Typical values for volume of the central compartment and clearance and calculated volume of distribution at steady-state and terminal half-life were 170ml/kg, 1.2ml/(kg*min), and 594ml/kg and 360min, respectively. For the oral route, absorption half-life, estimated maximal plasma concentration and time to reach maximal plasma concentration were 58min, 9155ng/ml, and 194min, respectively. Estimated oral bioavailability was 47%. Short-lived sedation (approximately 15min) with sternal or lateral recumbency after IV administration was observed in all subjects without adverse clinical effects. Simulation based on the results of this study suggests that a first oral gabapentin dose of 15mg/kg and subsequent doses of 8.5mg/kg every 8h would achieve and maintain plasma concentrations between 5 and 8μg/ml in pigs.

Population Pharmacokinetic Modeling of Vancomycin in Thai Patients With Heterogeneous and Unstable Renal Function.

Vancomycin is widely used to treat gram-positive bacterial infections. However, given significant interpatient variability in its pharmacokinetics, maintaining plasma concentrations is difficult within its characteristically narrow therapeutic window. This is especially challenging in patients with unstable renal function. Thus, the aim of this study was to develop a population pharmacokinetic model for vancomycin that is suitable for Thai patients with variable renal functions, including those with unstable renal function. Data from 213 patients, including 564 blood samples, were retrospectively collected; approximately 70% patients exhibited unstable renal function during vancomycin treatment. The model building group was randomly assigned 108 patients and the remaining 33 patients comprised the validation group. A population pharmacokinetic model was developed that incorporated drug clearance (CL) as a function of time-varying creatine clearance (CrCL). The predictive ability of the resulting population model was evaluated using the validation data set, including its ability to forecast serum concentrations within a Bayesian feedback algorithm. A 2-compartment model with drug CL values that changed with time-varying CrCL adequately described vancomycin pharmacokinetics in the evaluated heterogeneous patient population with unstable renal function. Vancomycin CL was related to time-varying CrCL as follows: CL (t) = 0.11 + 0.021 × CrCL (t) (CrCL <120 mL/min. Using the population model, Bayesian estimation with at least one measured serum concentration resulted in a forecasting error of small bias (-2.4%) and adequate precision (31.5%). In hospitals with a high incidence of unstable renal function, incorporating time-varying CrCL with Bayesian estimation and at least one measured drug concentration, along with frequent CrCL monitoring, improves the predictive performance of therapeutic drug monitoring of vancomycin.

Pharmacokinetic Profiles of Gabapentin after Oral and Subcutaneous Administration in Black-tailed Prairie Dogs (Cynomys ludovicianus).

In veterinary and human medicine, gabapentin (a chemical analog of γ-aminobutyric acid) is commonly prescribed to treat postoperative and chronic neuropathic pain. This study explored the pharmacokinetics of oral and subcutaneous administration of gabapentin at high (80 mg/kg) and low (30 mg/kg) doses as a potential analgesic in black-tailed prairie dogs (Cynomys ludovicianus; n = 24). The doses (30 and 80 mg/kg) and half maximal effective concentration (1.4 to 16.7 ng/mL) for this study were extrapolated from pharmacokinetic efficacy studies in rats, rabbits, and cats. Gabapentin in plasma was measured by using an immunoassay, and data were evaluated using noncompartmental analysis. The peak plasma concentrations (mean ±1 SD) were 42.6 ±14.8 and 115.5 ±15.2 ng/mL, respectively, after 30 and 80 mg/kg SC and 14.5 ±3.5 and 20.7 ±6.1 ng/mL after the low and high oral dosages, respectively. All peak plasma concentrations of gabapentin occurred within 5 h of administration. Disappearance half-lives for the low and high oral doses were 7.4 ± 6.0 h and 5.0 ± 0.8 h, respectively. The results of this study demonstrate that oral administration of gabapentin at low (30 mg/kg) doses likely would achieve and maintain plasma concentrations at half maximum effective concentration for 12 h, making it a viable option for an every 12-h treatment.

Maturation of midazolam clearance in critically ill children with severe bronchiolitis: A population pharmacokinetic analysis

PurposeThe aim of the present study was to develop a population pharmacokinetic model of midazolam, and to evaluate the influence of maturation process and other variability factors in critically ill children with severe acute bronchiolitis, who received a long-term intravenous infusion of midazolam. MethodsIn the study were included 49 critically ill children of both genders (from 0 to 130 weeks of age) with severe acute bronchiolitis hospitalised in intensive care units. Nonlinear mixed effects modelling approach was applied for data analyses and simulations. ResultsThe final model is a two-compartment model that includes the effects of body weight using allometric scaling with fixed exponents and maturation of clearance. For a typical subject, scaled to the adult body weight of 70 kg, population pharmacokinetic values were estimated at 8.52 L/h for clearance (when maturation function was 1), 25.5 L/h for intercompartmental clearance, and 5.71 L and 39.8 L for the volume of the central and peripheral compartment, respectively. Based on the final model, maturation reaches 50% of the adult clearance in 45.9 weeks of postmenstrual age. The influence of gender, ABCB1 genotype and biochemical parameters on midazolam clearance was not detected. Results of simulations indicate the need for reduced dosing in certain groups of patients in order to maintain plasma concentrations of midazolam within recommended values. ConclusionsThe developed population pharmacokinetic model can contribute to the dosing optimisation of midazolam, especially in critically ill children as it includes the influence of size and maturation of clearance, which are important parameters for achieving the desired plasma concentrations of midazolam.