Variability In Pharmacokinetic Parameters Research Articles

Assessment of the influence of demographic and anthropometric indicators on the variability of pharmacokinetic parameters

Relevance. Planning the design of bioequivalence clinical studies of generic highly variable drugs requires non-standard approaches – the use of replicative (repeated) or adaptive design. However, both approaches entail an increase in organizational, time, and financial costs. Therefore, it becomes relevant to search for ways to pre-select volunteers with a lower initial level of variability in pharmacokinetic parameters to reduce the number of subjects.Objective. The aim of this study was to determine the potential subjects in clinical trials with a low initial level of variability in pharmacokinetic parameters using methods for assessing initial gender – age and anthropometric and clinical laboratory parameters.Material and methods. Data from clinical studies of the bioequivalence of drugs (valganciclovir, carebastine and raltegravir) with different levels of variability conducted in the period 2020–2022 in Russia were used for analysis. To achieve this goal, a model for grouping pharmacokinetic parameters (PhK) with known demographic and clinical laboratory parameters was developed using discriminant analysis. Discrimination was performed between optimal pharmacokinetics (OPhK) and variable pharmacokinetics (VPhK). Mathematical and statistical analyses of the results were performed using Microsoft Excel 2013 and Statistica 10.0.Results. During the study, the variability of the maximum concentration of the drug in plasma (Cmax), including its logarithmic values, was used as a basis. The levels of intra-individual variability (CVintra), which is the main characteristic of drug variability, in the OPhK group were several times lower than those in the VPhK group for all studied drugs, but for the highly variable drug raltegravir, they differed by almost 10 times.Conclusion. Therefore, the obtained results indicated that using traditional gender – age and anthropometric indicators alone is impossible to separate the OPhK and VPhK groups for the analyzed drugs with high PhK variability.

In-vivo study of Budesonide mini-tablets in enteric coated capsules for the treatment of ulcerative colitis

Budesonide, a corticosteroid, was used as a model drug to study the effects of independent variables like HPMC K4M as a release retarding polymer at 2-6% and Crospovidone as a super disintegrant at 2-5% on in vitro drug release to meet desired Q points of dissolution. Current study used a 32 factorial design (Stat-Ease Design Expert v12) to formulate a mini-tablet in an enteric-coated capsule to treat ulcerative colitis utilising ECDDT and mini-tablets. An in vivo study was conducted in New Zealand rabbits to determine the pharmacokinetic parameters for the optimized formulation (BF4-O). Time vs. plasma concentration plots of the Pure drug and Optimized formulation was observed. Plotted Area under the curve indicates the extent of drug absorption inside the body. Pharmacokinetic analysis of Budesonide pre drug plasma concentration–time data provided the following pharmacokinetic parameters like Cmax value ranging (1.42 ± 2.12 ng/mL), Tmax value (4.0 Hours), AUC value (12.77 ± 0.15 h.ng/mL), Half Life (3.5 Hours) and other pharmacokinetic parameters are depicted. Study demonstrates the variability in pharmacokinetic parameters like Tmax, Cmax, T1/2 (Hours), AUC and Ke. Henceforth, the newly developed Mini-Tablet in Enteric Coated capsule could be utilized clinically for the treatment of Ulcerative Colitis, alternatively with cost-effectiveness.

Microneedle patch with pure drug tips for delivery of liraglutide: pharmacokinetics in rats and minipigs.

Transdermal delivery of peptide drugs is almost impossible with conventional penetration enhancers because of epidermal barrier function. Microneedle (MN) patches can bypass the epidermal barrier and have been developed for trans- and intradermal delivery of peptide drugs and vaccines. However, dissolving MN patches are limited by low drug loading capacities due to their small size and admixture of drug and water-soluble excipients. Furthermore, few in vivo pharmacokinetic studies, especially in large animals such as pigs, have been performed to assess post-application systemic drug exposure. Here, we developed a dissolving MN patch with pure liraglutide at the needle tips. The MN patch could load up to 2.21 ± 0.14mg of liraglutide in a patch size of 0.9 cm2, which was nearly two orders of magnitude higher than that obtained with conventional MN patches of the same size. Raman imaging confirmed that liraglutide was localized at the MN tips. The MN had sufficient mechanical strength to penetrate the epidermis and could deliver up to 0.93 ± 0.04mg of liraglutide into skin with a dosing variability of less than 6.8%. The MN patch delivery enabled faster absorption of liraglutide than that provided by subcutaneous (S.C.) injection, and achieved relative bioavailability of 69.8% and 46.3% compared to S.C. injection in rats and minipigs, respectively. The MN patch also exhibited similar patterns of anti-hyperglycemic effect in diabetic rats and individual variability in pharmacokinetic parameters as S.C. injection. The liraglutide MN application was well tolerated; no skin irritation was observed in minipigs except for mild erythema occurring within 4h after once daily administration for 7days at the same site. Our preclinical study suggests that MN patch with pure drug needle tips might offer a safe and effective alternative to S.C. injection for administration of liraglutide.

Effect of NAT2, GSTM1 and CYP2E1 genetic polymorphisms on plasma concentration of isoniazid and its metabolites in patients with tuberculosis, and the assessment of exposure-response relationships.

Objectives: Isoniazid is a key drug in the chemotherapy of tuberculosis (TB), however, interindividual variability in pharmacokinetic parameters and drug plasma levels may affect drug responses including drug induced hepatotoxicity. The current study investigated the relationships between isoniazid exposure and isoniazid metabolism-related genetic factors in the context of occurrence of drug induced hepatotoxicity and TB treatment outcomes. Methods: Demographic characteristics and clinical information were collected in a prospective TB cohort study in Latvia (N = 34). Time to sputum culture conversion (tSCC) was used as a treatment response marker. Blood plasma concentrations of isoniazid (INH) and its metabolites acetylisoniazid (AcINH) and isonicotinic acid (INA) were determined at three time points (pre-dose (0h), 2h and 6h after drug intake) using liquid chromatography-tandem mass spectrometry. Genetic variations of three key INH-metabolizing enzymes (NAT2, CYP2E1, and GSTM1) were investigated by application PCR- and Next-generation sequencing-based methods. Depending on variables, group comparisons were performed by Student's t-test, one-way ANOVA, Mann-Whitney-Wilcoxon, and Kruskal-Wallis tests. Pearson correlation coefficient was calculated for the pairs of normally distributed variables; model with rank transformations were used for non-normally distributed variables. Time-to-event analysis was performed to analyze the tSCC data. The cumulative probability of tSCC was obtained using Kaplan-Meier estimators. Cox proportional hazards models were fitted to estimate hazard rate ratios of successful tSCC. Results: High TB treatment success rate (94.1%) was achieved despite the variability in INH exposure. Clinical and demographic factors were not associated with either tSCC, hepatotoxicity, or INH pharmacokinetics parameters. Correlations between plasma concentrations of INH and its metabolites were NAT2 phenotype-dependent, while GSTM1 genetic variants did not showed any effects. CYP2E1*6 (T > A) allelic variant was associated with INH pharmacokinetic parameters. Decreased level of AcINH was associated with hepatotoxicity, while decreased values of INA/INH and AcINH/INH were associated with month two sputum culture positivity. Conclusion: Our findings suggest that CYP2E1, but not GSTM1, significantly affects the INH pharmacokinetics along with NAT2. AcINH plasma level could serve as a biomarker for INH-related hepatotoxicity, and the inclusion of INH metabolite screening in TB therapeutic drug monitoring could be beneficial in clinical studies for determination of optimal dosing strategies.

Safety and pharmacokinetics of single ascending doses of TAK‐594/DNL593, a brain‐penetrant progranulin replacement therapy, in healthy volunteers: Interim results from Part A of a Phase 1/2 clinical trial

AbstractBackgroundLoss of function mutations in the granulin (GRN) gene, which encodes the lysosomal protein progranulin (PGRN), account for 5‐10% of frontotemporal dementia (FTD‐GRN). Deficiency of PGRN in neurons and microglia results in lysosomal dysfunction, which in turn leads to neuroinflammation and neurodegeneration. TAK‐594/DNL593 is a novel PGRN replacement therapy that has been engineered to deliver PGRN across the blood brain barrier (BBB) and into lysosomes. In PGRN‐deficient mice, TAK‐594/DNL593 corrected age‐dependent elevations of disease biomarkers that are also observed in patients with FTD‐GRN (Logan et al. 2021).MethodsStudy DNLI‐H‐0001 (NCT05262023) is a Phase 1/2 randomized, placebo‐controlled study to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of TAK‐594/DNL593 in 3‐parts. Part A evaluated single ascending doses of TAK‐594/DNL593 in healthy participants (randomized 6:2 drug to placebo). Part B, currently enrolling, will evaluate multiple doses of TAK‐594/DNL593 for 6 months in participants with FTD‐GRN (randomized 2:1 drug to placebo) and will be followed by Part C, an 18‐month open‐label extension.ResultsPart A enrolled 35 healthy participants. Single doses of intravenously administered TAK‐594/DNL593 were generally safe and well tolerated. There were no discontinuations related to drug. The majority of treatment emergent adverse events (TEAEs) were mild to moderate, and no infusion related reactions were observed. TAK‐594/DNL593 serum exposures increased in a greater than dose‐proportional manner with low to moderate variability in PK parameters. Cerebrospinal fluid (CSF) total PGRN concentration, sampled 24 hours post‐infusion, also increased dose dependently above baseline levels.ConclusionSingle dose safety and PK of TAK‐594/DNL593 in healthy participants support initiation of the multiple dose study in participants with FTD‐GRN. The dose‐dependent increase in CSF PGRN is consistent with delivery of TAK‐594/DNL593 across the BBB and supports the potential of TAK‐594/DNL593 to treat FTD‐GRN.

Examination of the Rate and Extent of Drug Released from Commercial Topical Delivery Systems During Wear: An Example with Lidocaine Topical Systems.

This study aimed to determine the extent and rate of lidocaine released in vivo from two bioequivalent topical delivery systems (TDS) by using complementary assessments: pharmacokinetic analysis in healthy human volunteers, and residual lidocaine in TDS following 12h of wear. The goal was to explore a potentially more clinically meaningful strength presentation than percent active pharmaceutical ingredient loaded in topical systems. A three-arm, open-label, crossover clinical study was conducted in 23 human subjects, with 5% lidocaine topical systems from two manufacturers, and intravenous lidocaine administration. Residual drug and LC-MS/MS analyses were performed on worn TDS and serum samples. The rate and extent of drug released from the TDS during wear were determined through (1) calculations of consumed lidocaine via analysis of residual drug in worn TDS, and (2) a pharmacokinetic approach via derivation of the absolute clearance and serum lidocaine concentration at steady state. Overall the pharmacokinetic approach underestimated the amount transferred to the subject and exhibited greater variability, which may relate to natural inter-subject variability in pharmacokinetic parameters. Further, lidocaine TDS are intended for localized, not systemic, delivery and this may also explain some of the variability seen in the systemic serum concentrations. The residual drug and pharmacokinetic approaches align well for transdermal formulations, but the differences in administration route (topical versus transdermal) all but eliminates the potential use of the pharmacokinetic approach unless additional compartmental modeling is explored.

Personalized Dose of Adjuvant Imatinib in Patients with Gastrointestinal Stromal Tumors: Results from a Population Pharmacokinetic Analysis.

Imatinib is the first-line treatment for patients with gastrointestinal stromal tumors (GIST) after surgery. However, its pharmacokinetic profile varies remarkably between individuals and has not been well characterized in postoperative Chinese patients with GIST. Therefore, this study aimed to develop a population pharmacokinetic (PPK) model and recommend appropriate doses for different patients to achieve the target trough concentration in such a population. A total of 110 surgically treated GIST patients were enrolled, of which 85 were applied to conduct a PPK analysis with a nonlinear mixed-effect model and 25 for external validation of the model. Demographic and biomedical covariates, as well as six single nucleotide polymorphisms were tested to explore the sources of variation in pharmacokinetic parameters of imatinib. Monte Carlo simulations were performed to establish the initial dosing regimens. A one-compartment model was established in postoperative GIST patients. The red blood cell count (RBC) and ABCG2 rs2231142 were observed to have a significant effect on the clearance of imatinib. The typical values estimated by the final model were 9.72 L/h for clearance (CL/F) and 229 L for volume of distribution (V/F). Different from the fixed dose regimen of 400 mg each day, patients carrying rs2231142 heterozygous type and with a lower level of RBC (2.9 × 1012/L), 300 mg imatinib daily is enough to achieve the target trough concentration. When RBC rises to 4.9 × 1012/L, 500 mg daily is recommended. For patients with rs2231142 GG genotype, 500 mg a day is required at RBCs of 3.9 × 1012/L and 4.9 × 1012/L. RBC and rs2231142 contribute to the pharmacokinetic variation of imatinib and personalized dose recommendations based on patient characteristics may be necessary.

MODELING AND SIMULATION PREDICTS ROBUST HAE ATTACK SUPPRESSION WITH EVERY 3 MONTH DOSING OF STAR-0215

<h3>Introduction</h3> Inhibition of plasma kallikrein is a validated mechanism for prevention of hereditary angioedema (HAE) attacks. STAR-0215 is a long-acting monoclonal antibody inhibitor of plasma kallikrein. We sought to generate a mechanistic quantitative systems pharmacology (QSP) model to explore the potential for reduction of HAE attacks with different dosing regimens of STAR-0215. <h3>Methods</h3> A simplified QSP model was established based on published reaction parameters for the plasma kallikrein-kininogen pathway in the vascular space and adjacent to the endothelial surface. The pharmacokinetic (PK) parameters of STAR-0215 were derived from cynomolgus monkey PK studies and scaled to estimate human PK parameters. Variability in PK parameters was simulated using a standard deviation of 50% and a Poisson distribution was applied to randomly determine the timing of trigger events with an average attack frequency of 3 per month. <h3>Results</h3> A long circulating half-life of STAR-0215 in humans (108 days) was predicted from empirically obtained PK parameters in cynomolgus monkeys. The QSP model predicted long-term robust HAE attack suppression following a single subcutaneous administration of STAR-0215 at dose levels of ≥300 mg. The QSP model simulations also showed subcutaneously administered STAR-0215 could provide a potential prolonged HAE attack suppression with a once every 3 months maintenance dose regimen. <h3>Conclusions</h3> STAR-0215 is a novel, potent and selective long-acting monoclonal antibody plasma kallikrein inhibitor for the potential treatment of HAE. Results from the QSP model support STAR-0215 dosing once every 3 months or longer for robust suppression of HAE attacks.

Pharmacokinetic analysis of meropenem therapeutic drug monitoring data (TDM) in critically ill adult patients

Meropenem is a carbapenem antibiotic widely used in treatment of severe infections in ICU. Critically ill patients’ pathophysiological features may cause changes in the pharmacokinetics of meropenem, such as augmented/impaired renal clearance, as well as an increase in the volume of distribution of the drug. Considerable variability in meropenem concentration for the same dosage regimen, severity of the diseases and the escalating antibiotic resistance support the need for an individualization of the dosing in critically ill patients. Estimation of meropenem pharmacokinetic (PK) parameters was performed using the NPAG (non-parametric adaptive grid) program from the Pmetrics package based on peak-trough TDM data. A one-compartment linear PK model with zero-order input and first-order elimination was used to analyze data of the 36 critically ill patients (66 measured meropenem concentrations totally) and to predict pharmacodynamic (PD) parameter values (%T&gt;MIC) based on the time course of free meropenem concentration for empirically prescribed dosage regimens by MIC level. The estimated PK parameters of the meropenem model were in good agreement with those published in the literature earlier. A great interindividual variability for PK parameters from 44.5% up to 167% was revealed. Different regression lines between meropenem clearance and clearance creatinine (CLCr) were registered in patients with CLCr [1] 7 L/h versus &gt; 7 L/h: statistically significant regression (n=30, p=0.015) versus no correlation (n=6, р=0.85), respectively. Bayesian feedback TDM-based meropenem dose personalization is the most practical approach to ensure adequate drug exposure in critically ill patients, especially in patients with augmented renal clearance.

Inter-individual variability in pharmacokinetics and clinical features in pediatric patients with severe hemophilia A

IntroductionAs the most commonly used FVIII concentrate in China, the individualized pharmacokinetics (PK) and clinical outcomes of Kovaltry (BAY81-8973) are not fully investigated in this population. Materials and methodsPediatric patients with severe hemophilia A were enrolled in Beijing Children's Hospital. After a three-day washout, they received PK tests after a single-dose infusion of 50 IU/kg. The blood samples were collected with a six-point assay. One-stage-based activated partial thromboplastin time was used for FVIII activity. The PK parameters were generated by WinNonlin software. The bleeding rates were calculated by their routine therapy record. The ultrasound was used to evaluate their both sides of knees, elbows and ankles. ResultSixty-one boys with severe hemophilia A were enrolled and their median age was 5.73 years. Twenty-nine of them were blood group-O. Compared with blood group-O patients, those non-O patients showed longer t1/2 (15.26 vs. 13.03 h, P < 0.001) and reduced CL (3.04 vs. 3.66 mL/kg/h, P < 0.05). Patients with higher VWF:Ag level had longer half-life time (t1/2) (r = 0.60, P < 0.0001) and lower clearance (CL) (r = −0.45, P < 0.001). Patients with higher trough level showed decreased bleeding rates compared with those owning a trough level below 1 IU/dL (P < 0.05). In general, the zero bleeding rates raised with elevation of trough level. However, 20–30% of patients with low trough level (<1 IU/dL) also showed no bleeds and 10–20% of patients with high trough level (>5 IU/dL) still suffer bleeds. An inconsistency of 28% between joint bleeds and ultrasound evaluation was showed. ConclusionThis study revealed the great inter-individual variability in PK parameters, clinical bleeding phenotype and joint vulnerability, which all should be considered in treating hemophilia A.

Novas perspectivas no monitoramento de vancomicina

Vancomycin is an antibiotic mainly used to treat infections caused by gram-positive bacteria. Currently, the monitoring of vancomycin treatment is carried out through the trough of plasma concentration, but the new studies and recommendations suggest the use of the ratio between the area under the plasma concentration curve and the minimum inhibitory concentration of the bacterium (AUC/MIC) for monitoring patients, especially in pediatrics due to the high variability of pharmacokinetic parameters in this population. The AUC/MIC of vancomycin can be determined using Bayesian software or by the trapezoid method with similar results and only practical differences. Comparative studies between monitoring by AUC/MIC and trough levels have shown better results of efficacy and safety in the use of vancomycin in those groups monitored by AUC/MIC and corroborate with the new recommendations.

What Matters in Piglets' Exposure to Antibiotics Administered through Drinking Water?

A number of drugs are given in drinking water in piglet farming, although this way of administering drugs leads to significant and uncontrolled variability in exposures. Three main explanations for this variability have been described in the literature: (1) the drinking behavior of animals, (2) the drug concentration in water, and (3) the inter-individual variability in the pharmacokinetic (PK) parameters. This article assesses the relative importance of these three sources of exposure variability for doxycycline and amoxicillin using pharmacokinetic simulations and by observing watering behavior, and analyzes the consequences of this exposure variability. The water consumption behavior was by far the most important factor as it led to a variation in exposures of up to a factor of 7 between piglets. The second most influential factor was the drug concentration in the drinking water with variations ranging from −43.3% to +48.7% at the beginning and the end of the pipeline. Finally, the between-individual variation in PK parameters depends on the drug, but had a low impact on exposure variability. In the most variable case (doxycycline), the mean ratio between the 10% less exposed and the 10% most exposed piglets varied from 3.7 without PK parameters variability to 6 with PK variability. For both drugs, this study also showed that only a small percentage of the piglets (36%) could be considered as well exposed in case of infection by Actinobacillus pleuropneumoniae or Pasteurella multocida. There may be some existing technical ways to reduce this important variability. However, their cost and ease of implementation merit examination.

Individual features of the pharmacokinetics of fludarabin phosphate in the treatment of patients with chronic lymphocytic leukemia

Fludarabine is a purine antimetabolite with a pronounced immunosuppressive effect. The inhibitory effect of fludarabine depends on its concentration in blood plasma. In addition, the phenotypic characteristics of patients affect the pharmacokinetic and pharmacodynamic profile of the drug, which necessitates a personalized approach to the dosage regimen. The chromatography-mass spectrometric method for the quantitative determination of 2-fluorine in blood plasma was developed for studying the individual parameters of pharmacokinetics of the international non-proprietary name (INN) fludarabine in patients with B-cell chronic lymphocytic leukemia during the standard course. Such method for the quantitative determination of 2-fluorine in blood plasma was developed and validated in accordance with international requirements. Significant individual variability of the main pharmacokinetic parameters in patients with B-cell chronic lymphocytic leukemia with a single oral administration of the drug with INN fludarabine at a dose of 40 mg/m2 was established, so the coefficient of variability Cmax was 42 %, Tmax — 92 %, AUC0-t — 45 %, Kel — 23 %, T1/2 — 26 %. It should be noted that there is a high interindividual variability of fludarabine, for example, 24 hours after taking the study drug, the maximum and minimum plasma concentrations of the fludarabine metabolite 2-fluoro-ara-A in different in patients with B-cell chronic lymphocytic leukemia differed 9 times. Individual variability of pharmacokinetic parameters characterizing absorption (Cmax/AUC0-t) and total clearance of the active metabolite of fludarabine is statistically significantly associated with a combination of gender and anthropometric factors.

Influence of the Obesity Phenotype on the Adequacy of Antibiotic Prophylaxis with Cefoxitin for Obese Patients Undergoing Bariatric Surgery: Lessons Learnt and Future Considerations.

A high inter-individual variability in pharmacokinetic parameters inobese patients is observed.The objective of this study was to evaluate the effect of obesity parameters on the pharmacokinetics of cefoxitin administered for antibiotic prophylaxis during bariatric surgery. This a secondary analysis of a pharmacokinetic study involving 174 obese patients scheduled for bariatric surgery and receiving a 4-g dose of cefoxitin. Blood samples were collected at incision and wound closure. The total plasma concentrations were assessed utilising a validated high-performance liquid chromatography-tandem mass spectrometry method. The pharmacokinetic and pharmacodynamic target was defined as an estimated free concentration of cefoxitin at the time of wound closure >8 mg/L. Specific evaluated obesity parameters were fat body mass, fat body mass/height2, lean body mass, lean body mass/height2, visceral adipose tissue and presence of a metabolic syndrome. A total of 174 patients (median age 47 years) with a majority of women (75.3%) and a median BMI of 44 kg/m2 were analysed. The percentage of patients who met the pharmacokinetic and pharmacodynamic target was 85.1%. In the whole population, a tendency to fail to reach the target was observed with a higher lean mass over height2 [OR = 0.79; 95% CI (0.62-1.01); P = 0.060]. In the female subgroup, higher lean mass over height2 [OR = 0.63; 95% CI (0.41-0.97); P = 0.037] and the presence of a metabolic syndrome [OR = 0.17; 95% CI (0.03-0.83); P = 0.030] were associated with failure to reach the pharmacokinetic and pharmacodynamic target. Obese patients with a higher lean mass and a metabolic syndrome could constitute a subgroup at risk for cefoxitin under-dosage.

Exploring the Use of Computer-aided Learning Modules (CAL) to Enhance the Teaching and Learning of Pharmacokinetics to Pharmacy Students

Objectives: To develop an integrated software package to augment the teaching and learning of pharmacokinetics to undergraduate pharmacy students, covering various aspects of pharmacokinetics from basic principles, calculations and their application, including therapeutic drug monitoring (TDM) in clinical practice and bioequivalence calculations for industry, as well as several computer-aided learning modules (CAL). Materials and Methods: JAVA was utilized to allow for a modular design and the ability to build future functionality into the system. A database of patient information with multiple drugs of interest, with plasma concentration values, was constructed to allow students to appreciate the variability of pharmacokinetic parameters in different clinical conditions. Computer-assisted learning (CAL) modules were prepared to assist students in understanding selected pharmacokinetics topics. Software testing, validation, system testing and user satisfaction surveys were conducted to evaluate suitability and accuracy. Results: A comprehensive and modular pharmacokinetics computer program was successfully developed using Java and NetBeans. The program produced accurate and reproducible values for numerous pharmacokinetic parameters, based on a user satisfaction survey, the average usability score of 68.8 indicating good usability status among undergraduate students. Conclusion: The software is the first attempt to produce a comprehensive package with multiple points of calculation including compartmental and non-compartmental analysis, TDM and bioequivalence, as well as learning modules, all integrated into one environment suitable for both pharmacy students and pharmacists. End users were generally satisfied with the software and provided feedback and recommendations to further improvements with the ultimate aim of introducing the system to undergraduates for teaching purposes. Key words: Pharmaceutics, Education, Pharmacokinetics, Pharmacy practice, Drug delivery.

Поиск гендерных различий фармакокинетических параметров розувастатина в исследованиях биоэквивалентности воспроизведенных препаратов

Представлены результаты анализа влияния фактора принадлежности к определенному полу на вариабельность Cmax и AUC розувастатина и на результаты исследований биоэквивалентности. В анализ включены результаты 18 исследований биоэквивалентности розувастатина, в которых приняли участие в сумме 495 здоровых добровольцев (234 мужчины и 261 женщина). С учетом приема 2 лекарственных препаратов каждым субъектом были проанализированы 1980 наборов данных (для параметров Cmax и AUC). Полученные данные демонстрируют, что в исследованиях биоэквивалентности розувастатина отсутствуют статистически значимые гендерные различия вариабельности показателей Cmax и AUC. Связь между фактором половой принадлежности и частотой выявления высокой вариабельности не установлена. В 28 % исследований у мужчин и женщин выявлены различия между фармакокинетическими показателями воспроизведенных и референтных препаратов (более 20 % разница между отношениями геометрических средних T/R параметров Cmax и AUC). Различия были статистически незначимы. Симуляционный анализ результатов исследований биоэквивалентности розувастатина в отдельных популяциях субъектов мужского и женского пола показал, что частота неэквивалентных результатов у мужчин составила 39 %, у женщин — 28 %. Связь между фактором половой принадлежности и частотой выявления неэквивалентных результатов не установлена (χ2 = 0,125; p &gt; 0,05).

Modulation of Drug Release from Natural Polymer Matrices by Response Surface Methodology: in vitro and in vivo Evaluation.

PurposeThe present work aimed at challenging the efficacy of natural gums, karaya and locust bean gum, as matrix-forming polymers for the formulation of sustained-release tablets of diltiazem, a model drug.MethodsCentral design composite was adopted for the formulation and optimization of tablet formulations. The two gums have been selected as independent variables. The dependent factors chosen were the amount of drug released in 1st hour (Y1), amount of drug released after 12 h (Y2), diffusion exponent (Y3), and time for half of the total drug released (T50%) (Y4). Wet granulation approach was used for the formulation of tablets. FT-IR, DSC, in vitro dissolution, swelling-erosion investigations, SEM, and stability studies were carried out.Results and DiscussionIt was evident that the release pattern from the prepared formulations was significantly influenced by the quantity of gum(s) in the tablet. FT-IR and DSC results confirm drug–polymer compatibility. Polynomial equations were used for the prediction of quantitative impact of independent factors at different levels on response variables. After ANOVA analysis, the significant factors were considered for constrained optimization to get the optimized formula. The optimized formula generated by the response surface methodology was evaluated both for in vitro and in vivo properties. The optimized formula and a sustained-release marketed product were subjected to in vivo studies in rabbits and the results of the t-test demonstrated insignificant variation in pharmacokinetic parameters among the two formulations, confirming that the prepared tablet showed sustained-release profile.ConclusionThe results indicated that karaya and locust bean gum can be effectively used to formulate sustained-release tablets.

Caspofungin PK in critically ill patients after the first and fourth doses: suggestions for therapeutic drug monitoring?

We describe caspofungin pharmacokinetics (PK) after the first and fourth doses in 20 critically ill septic patients. Monte Carlo simulation was used to analyze the probability of target attainment (PTA) (AUC/MIC > 865) for Candida spp. Caspofungin concentrations were analyzed by HPLC in plasma and urine. A great variability in PK parameters was observed after both doses. Patients were divided in two groups according to their AUC values (AUC ≤ 75 mg h/L cut-off). In the low-AUC group Cmax, Cmin and AUC were lower, while Vd and Cl were higher than in the high-AUC group (p < 0.05, both at day 1 and 4). The mean 24-h urinary recovery of the drug was 8 ± 6.3% (day1) and 9.8 ± 6.3 (day4). Monte Carlo simulation analysis (0.03–1 mg/L MIC-range) showed that PTA was guaranteed only for MICs ≤ 0.03 mg/L in the low-AUC group, and for MICs ≤ 0.06 mg/L in the high-AUC group. No group had a PTA ≥ 90% for 0.125 mg/L MIC (the epidemiological cut-off). Mortality was higher in low-AUC group (p < 0.01). In our ‘real-world’ population, no clinical data can predict which patient will have lower, suboptimal caspofungin exposure, therefore we suggest TDM to optimize caspofungin therapy and reduce the risk of selecting resistances (CEAVC, 32366/2015; OSS.15.114, NCT03798600).

Variation of Pharmacokinetic Parameters for Original Products and Standard Products（Original Products）Used in Clinical Bioequivalence Studies of Generic Products：Montelukast Chewable Tablets as an Example

Variation of Pharmacokinetic Parameters for Original Products and Standard Products（Original Products）Used in Clinical Bioequivalence Studies of Generic Products：Montelukast Chewable Tablets as an Example

Preclinical pharmacokinetic evaluation to facilitate repurposing of tyrosine kinase inhibitors nilotinib and imatinib as antiviral agents

BackgroundSeveral tyrosine kinase inhibitors (TKIs) developed as anti-cancer drugs, also have anti-viral activity due to their ability to disrupt productive replication and dissemination in infected cells. Consequently, such drugs are attractive candidates for “repurposing” as anti-viral agents. However, clinical evaluation of therapeutics against infectious agents associated with high mortality, but low or infrequent incidence, is often unfeasible. The United States Food and Drug Administration formulated the “Animal Rule” to facilitate use of validated animal models for conducting anti-viral efficacy studies.MethodsTo enable such efficacy studies of two clinically approved TKIs, nilotinib, and imatinib, we first conducted comprehensive pharmacokinetic (PK) studies in relevant rodent and non-rodent animal models. PK of these agents following intravenous and oral dosing were evaluated in C57BL/6 mice, prairie dogs, guinea pigs and Cynomolgus monkeys. Plasma samples were analyzed using an LC-MS/MS method. Secondarily, we evaluated the utility of allometry-based inter-species scaling derived from previously published data to predict the PK parameters, systemic clearance (CL) and the steady state volume of distribution (Vss) of these two drugs in prairie dogs, an animal model not tested thus far.ResultsMarked inter-species variability in PK parameters and resulting oral bioavailability was observed. In general, elimination half-lives of these agents in mice and guinea pigs were much shorter (1–3 h) relative to those in larger species such as prairie dogs and monkeys. The longer nilotinib elimination half-life in prairie dogs (i.v., 6.5 h and oral, 7.5 h), facilitated multiple dosing PK and safety assessment. The allometry-based predicted values of the Vss and CL were within 2.0 and 2.5-fold, respectively, of the observed values.ConclusionsOur results suggest that prairie dogs and monkeys may be suitable rodent and non-rodent species to perform further efficacy testing of these TKIs against orthopoxvirus infections. The use of rodent models such as C57BL/6 mice and guinea pigs for assessing pre-clinical anti-viral efficacy of these two TKIs may be limited due to short elimination and/or low oral bioavailability. Allometry-based correlations, derived from existing literature data, may provide initial estimates, which may serve as a useful guide for pre-clinical PK studies in untested animal models.