Pharmacokinetic Parameter Values Research Articles

Semaglutide for the treatment of obesity: Results of two open randomized pharmacokinetic studies

Introduction. Obesity is a growing public health issue in Russia, increasing the risk of cardiovascular diseases, type 2 diabetes, and hypertension. Controlling obesity involves lifestyle changes and pharmacotherapy. Semaglutide, an effective obesity treatment, stimulates insulin production and reduces appetite. Developing a generic semaglutide preparation will improve its availability in Russia.Aim. To study the comparative pharmacokinetics, bioequivalence, safety and tolerability of semaglutide products GP40331 and Wegovy using concentrations of 0.68 and 3.2 mg/ml in healthy volunteers under fasting conditions.Materials and methods. Bioequivalence studies, conducted per Good Clinical Practice, were open-label, randomized, and involved healthy male volunteers. Subjects received semaglutide at single doses of 0.25 mg (0.68 mg/ml) and 0.5 mg (3.2 mg/ml) under fasting. Bioequivalence was determined by the 90% CI of the ratios of geometric mean values of the primary pharmacokinetic parameters (AUC0-t, Cmax). Semaglutide concentrations were measured using high-performance liquid chromatography with tandem mass spectrometry.Results. The 90% CI values for the ratios of geometric means of the primary PK parameters of semaglutide were 90.22–110.29 and 86.48–108.98% (0.68 mg/ml) and 90.62–115.71 and 92.86–113.51% (3.2 mg/ml). Comparable safety was proven for both concentrations.Conclusion. GP40331 and Wegovy at 0.68 and 3.2 mg/mL are bioequivalent and equally safe.

Quantitative summary on the human pharmacokinetic properties of cannabidiol to accelerate scientific clinical application of cannabis.

Cannabidiol (CBD) is a non-psychoactive substance that exerts numerous pharmacological benefits, including anti-inflammatory and antioxidant properties. It has received attention as a useful substance for the treatment of intractable pain, seizures, and anxiety, and related clinical trials have continued. However, the CBD pharmacokinetic results between reports are highly variable, making it difficult to clearly identify the pharmacokinetic properties of CBD. The main purpose of this study was to identify CBD clinical pharmacokinetic properties through meta-analysis. In particular, we sought to derive valid, interpretable independent variables and interpret their pharmacokinetic parameter correlations in relation to the large inter-individual and inter-study variability in CBD pharmacokinetics. For this study, CBD-related clinical trial reports were extensively screened and intercomparisons were performed between internal data sets through systematic classification and extraction of pharmacokinetic parameter values. The candidate independent variables associated with interpretation of CBD pharmacokinetic diversity established and explored in this study were as follows: diet, tetrahydrocannabinol (THC) combination, sample matrix type, liver and renal function, exposure route, dosage form, CBD exposure dose, cannabis smoking frequency, multiple exposure. The results of this study showed that CBD pharmacokinetics were influenced (increased plasma exposure by approximately 2-5 times) by diet immediately before or during CBD exposure, and that THC was not expected to have an antagonistic effect on the CBD absorption. The influence of changes in liver function would be significant in CBD pharmacokinetic diversity. Due to decreased liver function, the plasma exposure of CBD increased 2.57-5.15 times compared to healthy adults, and the half-life and clearance showed a 2.58-fold increase and a 5.15-fold decrease, respectively. CBD can be rapidly absorbed into the body (time to reach maximum concentration within 3.18h) by oral, transdermal, and inhalation exposures, and lipid emulsification and nanoformulation of CBD will greatly improve CBD bioavailability (up to approximately 2 times). The pharmacokinetics of CBD generally follow linear kinetic characteristics. The importance of this study is that it suggests key factors that should be considered in terms of pharmacokinetics in further clinical trials and formulations of CBD in the future.

Biocompatible cationic 5-fluorouracil loaded elastic liposomes for ocular delivery: In vitro, ex vivo, and in vivo evaluation

5-fluorouracil (5-FU) is used to treat scleral and episcleral fibroblast proliferations (scarring process) in the eyes. Frequent washing of the conventional solution results in limited drug access to the eyes. Taguchi and central composite design (CCD) oriented optimized mucoadhesive cationic elastic liposomes were prepared and characterized. The optimized F-CEL8 (composed of 85 mg of dipalmitoyl-phosphatidylcholine, 15 mg of sodium cholate, 10 mg of 5-FU, 7 mg of ethanol, and 883 mg of buffer) and its gel were studied for in vitro and ex vivo drug release profiles as compared to the drug solution and the liposomes. In vitro hemolysis and Draize studies corroborated safety concerns. An in vivo pharmacokinetics study was studied in rats. Each mL of F-CEL8 contained dipalmitoyl-phosphatidylcholine (X1), sodium cholate, and ethanol to deliver 10 mg of 5-FU with optimal vesicle size, low polydispersity index (PDI), and high zeta potential (ZP). The %EE value of spherical F-CEL8 was quite high (82.3 ± 7.1 %) as compared to liposomes (∼53 %) due to the large volume of the inner aqueous chamber of vesicles. F-CEL8-gel exhibited relatively high viscosity for slow and sustained release for 24 h as compared to others. The percent permeation of 5-FU from the solution, F-CEL8, F-CEL8-gel, and the liposomes were found to be 28.6 ± 4.6 %, 69.6 ± 7.4 %, 76.89 ± 12.4 %, and 54.8 ± 5.3 %, respectively. All isotonic formulations did not exhibit hemolysis and irritation to the eyes. The gel illustrated the highest values of pharmacokinetics parameters as compared to the solution and the liposomes, which may be attributed to the maximum residence time achieved through electrostatic interaction (the vesicle internalization with the mucosal layer of eyes).

Evaluation of the pharmacokinetics of an experimental combined form of IFNα and IFNγ for intranasal use

Polypous rhinosinusitis is a chronic inflammatory disease of the nasal mucosa and paranasal sinuses. Recombinant interferon has antiproliferative activity and corrects the deficiency of endogenous regulatory molecules, which allows us to consider this class of immunotropic drugs as a promising component of conservative immunotherapy for polyposis rhinosinusitis. Purpose of the study: To select the optimal composition of the experimental composition of interferons and evaluate their pharmacokinetic parameters in laboratory animals.For laboratory evaluation of the effectiveness of the auxiliary components of the proposed composition in creating a local effect, Wistar rats in the amount of 30 animals were selected, to which the proposed form of the drug (IFN1) was administered once intranasally. The control group included 30 animals that were alternately administered intranasally with a similar dose of IFNα2b and IFNγ dissolved in water for injection (IFN2). Quantitative determination of interferon concentration in blood samples was carried out using the enzyme immunoassay method. To assess the dependence of changes in concentrations in the blood of animals on the time elapsed after their administration, standard pharmacokinetic models were used. Next, the integral from the initial moment of time to infinity was determined, which corresponded to the area under the pharmacokinetic curve and made it possible to calculate a number of pharmacokinetic characteristics.The following indicators were obtained: 1) Area under the pharmacokinetic curve (AUCt) ng/ml/min – IFN1 = 683.0; IFN2 = 1707.7. 2) Absorption constant (Kp) – IFN1 = 0.13096; IFN2 = 0.03836. 3) Suction constant (Kel) – IFN1 = 0.00177; IFN2 = 0.00317. 4) Clearance (Cl) ml/min – IFN1 = 129.35; IFN2 = 51.73.Based on the differences in the values of pharmacokinetic parameters (AUCt) for the IFN1 and IFN2 preparations, it can be concluded that the use of a composition based on chitosan, succinic acid and DMSO leads to a pronounced retention of interferon in the nasal mucosa, which provides a pronounced local therapeutic effect and allows for fewer systemic adverse reactions. This composition is suitable for further clinical studies of the effectiveness of immunotherapy for polyposis rhinosinusitis.

Comparison of Pharmacokinetic Characteristics of Bilosomal Dispersion Versus Pure Solution of Oral Ropinirole Hydrochloride in Rats

Background: Ropinirole hydrochloride is a non-ergoline antiparkinson drug. It is a highly hydrophilic drug and classified as class III according to Biopharmaceutical Classification System with low absolute oral bioavailability of approximately 50% upon oral administration due to significant hepatic first-pass metabolism. Objective: to compare the pharmacokinetic parameters of Ropinirole, when administered orally in the form of a Ropinirole bilosomal dispersion in contrast to an oral Ropinirole solution. Methods: This study involved the use of twelve male Wistar rats, with an average weight of 220±11 g, and these rats were divided into two groups, comprising six rats each. A 1.1mg/kg doses of pure Ropinirole and Ropinirole bilosomes were administered orally through gavage after reconstituting in distilled water. Ropinirole was quantified in the rat's plasma using HPLC, subsequently establishing a spiked calibration curve with plasma samples and utilizing paracetamol as an internal standard. The statistics included mean values (± SD; n = 6) for pharmacokinetic parameters, with statistical significance assessed using a Student's t-test. Results: For the oral bilosomes, the values were 9.4±0.11 μg /ml for Cmax, 3±0.00 h for Tmax, and 55.56±2.12 μg h/ml for AUC0-24. In contrast, for the oral solution, the corresponding values were 7.2±0.14 μg/ml for Cmax, 1.5±0.00 h for Tmax, and 23.70±2.23 μg h/ml for AUC0-24. These parameters were significantly higher (P<0.05) as compared with a pure drug solution. The comparative bioavailability of Ropinirole (AUC0-24 oral solution / AUC0-24 oral bilosomes ) is equal to 42.66%, which indicates the bioavailability of the oral RH solution was less than that of RH bilosomal dispersion. Conclusions: The use of nano vesicular carriers (bilosomes) shows significant potential as an effective delivery system for improving the oral bioavailability of ropinirole hydrochloride

Investigating pharmacokinetic profiles of Centella asiatica using machine learning and PBPK modelling

ABSTRACT Physiologically based pharmacokinetic (PBPK) modeling serves as a valuable tool for determining the distribution and disposition of substances in the body of an organism. It involves a mathematical representation of the interrelationships among crucial physiological, biochemical, and physicochemical parameters. A lack of the values of pharmacokinetic parameters can be challenging in constructing a PBPK model. Herein, we propose an artificial intelligence framework to evaluate a key pharmacokinetic parameter, the intestinal effective permeability (P eff ). The publicly available P eff dataset was utilized to develop regression machine learning models. The XGBoost model demonstrates the best test accuracy of R-squared (R 2, coefficient of determination) of 0.68. The model is then applied to compute the P eff of asiaticoside and madecassoside, the parent compounds found in Centella asiatica. Subsequently, PBPK modeling was conducted to evaluate the biodistribution of the herbal substances following oral administration in a rat model. The simulation results were evaluated and validated, which agreed with the existing in vivo studies in rats. This in silico pipeline presents a potential approach for investigating the pharmacokinetic parameters and profiles of drugs or herbal substances, which can be used independently or integrated into other modeling systems.

Contrast-enhanced pelvic magnetic resonance imaging (MRI) for the prediction of treatment response in mucinous rectal cancer.

In mucinous rectal cancer, it can be difficult to differentiate between cellular and acellular mucin. The purpose of this study was to evaluate, in patients with mucinous rectal cancer, the value of static enhancement (enh) and pharmacokinetic parameters of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) in predicting pathologic complete response. This retrospective cross-sectional study performed at Memorial Sloan Kettering Cancer Center included 43 patients (24 males and 19 females; mean age, 57 years) with mucinous rectal cancer who underwent MRI at baseline as well as after neoadjuvant chemoradiotherapy but before surgical resection between 2008 and 2019. Two radiologists independently segmented tumors on contrast-enhanced axial 3D T1-weighted images and sagittal DCE magnetic resonance images. On contrast-enhanced axial T1-weighted images, the static parameters enh and relative enhancement (renh) were estimated. On DCE images, the pharmacokinetic parameters Ktrans, kep, relative Ktrans (rKtrans), and relative kep (rkep) were estimated. Associations between all parameters with pathologic complete response were tested using Wilcoxon signed-rank tests. Receiver operating characteristic (ROC) analysis was performed to assess the area under the curve (AUC) for each parameter. Of the 43 patients who were included in the study, 42/43 (98%) had evaluable contrast-enhanced axial T1-weighted images and 35/43 (81%) had evaluable DCE images. Of the patients with evaluable contrast-enhanced axial T1-weighted images, 9/42 (21%) had pathologic complete response and 33/42 (79%) did not have pathologic complete response. For reader 1, enh(pre-neoadjuvant chemotherapy), enh(post-neoadjuvant chemotherapy), and renh were significant predictors of pathologic complete response [P=0.045 (AUC =0.73), 0.039 (AUC =0.74), and 0.0042, respectively]. For reader 2, enh(pre-neoadjuvant chemotherapy) and renh were significant predictors [P=0.021 (AUC =0.77) and 0.002, respectively]. For renh, the AUC was 0.83 for reader 1, and 0.82 for reader 2. Meanwhile, of those patients with evaluable DCE images, 9/35 (26%) had pathologic complete response and 26/35 (74%) did not have pathologic complete response. Ktrans(pre-neoadjuvant chemotherapy), kep(pre-neoadjuvant chemotherapy), and rkep were significant predictors [P=0.016 (AUC =0.73), 0.00057 (AUC =0.81), and 0.0096 (AUC =0.74), respectively]. Static and pharmacokinetic parameters of contrast-enhanced MRI show promise to predict neoadjuvant treatment response. Static enh parameters, which are simpler to assess, showed the strongest prediction.

Assessment of omeprazole and famotidine effects on the pharmacokinetics of tacrolimus in patients following kidney transplant-randomized controlled trial.

Tacrolimus is metabolized in the liver with the participation of the CYP3A4 and CYP3A5 enzymes. Proton pump inhibitors are used in kidney transplant patients to prevent duodenal and gastric ulcer disease due to glucocorticoids. Omeprazole, unlike famotidine, is a substrate and inhibitor of the enzymes CYP2C19, CYP3A4, CYP3A5. The aim of this study was to compare the impact of omeprazole and famotidine on the pharmacokinetics of tacrolimus. A randomized, non-blinded study involving 22 stabilized adult kidney transplant patients was conducted. Patients received the standard triple immunosuppression regimen and omeprazole 20mg (n = 10) or famotidine 20mg (n = 12). The study material consisted of blood samples in which tacrolimus concentrations were determined using the Chemiluminescent Microparticle Immuno Assay method. A single administration of omeprazole increased tacrolimus concentrations at 2h (day 2) = 11.90 ± 1.59ng/mL vs. 2h (day 1 - no omeprazole administration) = 9.40 ± 0.79ng/mL (p = 0.0443). AUC0-6 amounted to 63.07 ± 19.46ng × h/mL (day 2) vs. 54.23 ± 10.48ng × h/mL (day 1), (p = 0.0295). AUC2-6 amounted to 44.32 ± 11.51ng × h/mL (day 2) vs. 38.68 ± 7.70ng × h/mL (day 1), (p = 0.0130). Conversely, no significant changes in values of pharmacokinetic parameters were observed for famotidine. Omeprazole significantly increases blood exposure of tacrolimus. The administration of famotidine instead of omeprazole seems safer for patients following kidney transplantation. Clinical Trial Registration: clinicaltrials.gov, identifier NCT05061303.

Proof of concept of physiologically based pharmacokinetic modelling in paediatric acute lymphoblastic leukaemia.

Physiologically based pharmacokinetic (PBPK) modelling is an alternative modelling technique that is increasingly used in pharmacokinetics. Due to its nature, it can be complementarily employed to population pharmacokinetics, especially when it comes to small population size. Here, we report the proof of concept of its application to accurately describe the pharmacokinetics of a recombinant L-asparaginase in paediatric patients with acute lymphoblastic leukaemia. Data from two randomized, double-blind, phase II/III clinical studies (MC-ASP.4/ALL; MC-ASP.5/ALL) were included to setup and evaluate the final model, respectively. Final population values for basic pharmacokinetic parameters were calculated (clearance: 0.0569 L/h/19.5 kg, volume of distribution: 1.251 L, half-life: 18.5 h, trough concentration: 140.9 IU/L). Pharmacokinetic parameter prediction as well as predictive performance of the model proofed to be comparable to a separately developed population pharmacokinetic model with 13% deviation in predicted median L-asparaginase trough levels. To the best of our knowledge, this is the first whole-body PBPK model of a non-antibody therapeutic protein.

Synthesis, molecular docking, QSTR and in‐silico ADME studies of novel 1,3‐thiazolidine‐amide derivatives as hybrid bioactive heterocycles

AbstractIn this article, we described synthesis of 1,3‐thiazolidine ‐ amide hybrid derivatives by two different methods from (S)‐2‐amino‐3‐(4‐(benzyloxy)phenyl)‐1‐(thiazolidin‐3‐yl)propan‐1‐one (4). In first method, catalytic amidation was carried out under microwave irradiation using Ceric Ammonium Nitrate (CAN) as a green catalyst where as in second conventional method; CDI was used as a significant coupling reagent to optimize reaction condition and yield of product. All new compounds were well characterized by 1H NMR, 13C NMR, IR and ESMS spectral techniques and evaluated in vitro antibacterial and antifungal activity. The molecular docking study revealed that the designed compounds snuggly fit in the active site of 4WMZ protein. In addition, the QSTR study of new compounds were carried out with the help of Toxicity Estimation Software Tool (T.E.S.T). The results showed slight toxic nature of new compounds. In‐silico ADME studies significant values of pharmacokinetic parameters and demonstrated good drug like characteristics based on Lipinski's rule of five.

Bioequivalence and Pharmacokinetics Study of Two Zidovudine/Lamivudine Tablets in Chinese Healthy Volunteers.

Zidovudine/lamivudine tablets are nucleoside reverse transcriptase inhibitors that are used to treat human immunodeficiency virus. The objective of this study was to investigate the bioequivalence and pharmacokinetics (PKs) of test and reference preparations of zidovudine/lamivudine tablets in healthy Chinese subjects. We designed a randomized, open, single-center, single-dose, 2-crossover experiment with a 7-day washout period involving 20 healthy subjects. The subjects were given a single dose of the test or reference preparation after fasting overnight for 10hours. Blood samples were subsequently collected at scheduled time points from 0hour (preadministration) up to 24hours postadministration. The plasma concentrations of zidovudine and lamivudine were determined by a validated ultra-performance liquid chromatography-tandem mass spectrometry method. Analysis of variance (ANOVA) was used to compare differences in the mean values of key PK parameters between the 2 preparations. Bioequivalence was evaluated by 2 one-sided t-tests and 90% confidence intervals (CIs) of the geometric mean ratio (GMR). In total, 19 of the 20 subjects completed the trial. Based on the analysis of PK parameters, the relative bioavailability of zidovudine and lamivudine was 101.1% ± 2.0% and 100.3% ± 1.5%, respectively. ANOVA found no significant difference in primary PK parameters when compared between the 2 formulations, and the 90% CIs of the GMR of the 2 formulations were within the bioequivalence margins of 80%-125%. No serious adverse events occurred. Thus, we confirmed that the 2 preparations were bioequivalent in healthy Chinese volunteers. Our analysis demonstrated that both products showed good tolerance in all subjects.

Evaluation of pharmacokinetic parameters, safety and tolerability of single and multiple doses of Vespireit®: results of phase I clinical trial.

Objective: to evaluate the pharmacokinetic parameters, safety and tolerability of Vespireit® (INN buspirone), prolonged-release tablets, 15 mg (JSC “Valenta Pharm”, Russia), which is being developed as a drug for the treatment of functional vertigo, in healthy volunteers with a single oral dose of 15 and 30 mg on an empty stomach or after meals and multiple doses in a daily dose of 15 mg.Material and methods. JSC “Valenta Pharm” conducted an open-label, three-stage, randomized, two-periods, cross-over comparative clinical trial of Vespireit®. At stages 1 and 2, healthy volunteers were screened and randomized into two equal groups (Group 1 and Group 2), as well as the distribution of participants in Group 3. Then, at stage 1, healthy volunteers (n=24) took Vespireit® once at a dose of 15 mg on an empty stomach or after meals, at stage 2, volunteers (n=24) took Vespireit® once at a dose of 30 mg on an empty stomach or after meals. Stage 3 was conducted in 18 volunteers as a non-randomized, non-comparative study with Vespireit® 15 mg on an empty stomach once daily for 5 days. During the study, blood samples were collected from each subject to determine the concentration of test compounds in blood plasma and subsequently calculate their pharmacokinetic parameters. Quantitative determination of buspirone and its two metabolites, 6-hydroxybuspirone (6OH-bus) and 1-(2-pyrimidinyl)-piperazine (1-PP), was performed by a validated high-performance liquid chromatography method with tandem mass spectrometric detection. During the study, tolerability and safety were also evaluated: adverse events, vital signs, laboratory parameters and electrocardiogram parameters were recorded.Results. When the study drug Vespireit®, prolonged-release tablets, was administered once at a dose of 15 mg to healthy volunteers after a meal, an increase in the relative bioavailability and relative degree of absorption of buspirone was observed compared with the fasting state, which was accompanied by a 1.5- and 2.5-fold increase in the AUC0–t and Cmax of buspirone, respectively. In addition, the Cmax of 6-OH-bus increased 1.4-fold and the Cmax of 1-PP increased 1.2-fold. Meal had no effect on the AUC0–t of 6-OH-bus and 1-PP. When the study drug was administered once at a dose of 30 mg after a meal, an increase in the relative bioavailability and relative degree of absorption of buspirone was observed compared with fasting, which was accompanied by an increase in the AUC0–t and Cmax by 1.5- and 2.1-fold, respectively. A 1.2-fold increase in the Cmax of 6-OH-bus was also observed. Food had no effect on the AUC0–t of 6-OH-bus and on the AUC0–t and Cmax of 1-PP. No accumulation of buspirone and its metabolites was observed with repeated dosing.Conclusion. In the study, the values of pharmacokinetic parameters of the new drug Vespireit® in the prolonged-release tablets dosage form were determined both with single administration on an empty stomach and after meals and with multiple administration. The differences and advantages over buspirone preparations in the form of immediate-release tablets are shown: higher relative bioavailability of buspirone with a reduction in interindividual differences in bioavailability and Cmax, more stable plasma concentration of buspirone with reduced peak values of the active substance and metabolite 1-PP, a 1.2-fold increase in AUC0–∞, a 2-fold increase in T1/2, and a 2-fold increase in the degree of retardation (MRT) for buspirone, a 1.4-fold increase in Cmax and MRT of 6-OH-bus, a decrease in AUC0–∞, AUC0–t, and T1/2 of metabolite 1-PP, and a decrease in the ratio of the concentration of 1-PP to the concentration of buspirone and to 6-OH-bus. A favorable safety profile of Vespireit® was demonstrated.

Empiric dosing strategies to predict lamotrigine concentrations during pregnancy.

Maintaining seizure control with lamotrigine is complicated by altered pharmacokinetics and existence of subpopulations in whom clearance increases or remains constant during pregnancy. Our objective was to characterize the potential for particular dosing scenarios to lead to increased seizure risk or toxicity. Lamotrigine pharmacokinetic parameters obtained from our previous study were applied to a one-compartment model structure with subpopulations (75:25%) exhibiting different clearance changes. A single-patient simulation was conducted with typical pharmacokinetic parameter values from each subpopulation. Population-level simulations (N = 48,000) included six dosing scenarios and considered four preconception doses using the R package mrgsolve (Metrum Research Group). Thresholds for efficacy and toxicity were selected as drug concentration that are 65% lower than preconception concentrations and doubling of preconception concentrations, respectively. Individual simulation results demonstrated that without dose increases, concentrations fell below 0.65 at 6-8 weeks in the high clearance change (HC) subpopulation, depending on preconception clearance. While no simulated dosing regimen allowed all women in both subpopulations to maintain preconception concentrations, some regimens provided a more balanced risk profile than others. Predicted concentrations suggested potential increased seizure risk for 7%-100% of women in the HC group depending on preconception dose and subpopulation. Additionally, in 63% of dosing scenarios for women with low clearance change (LC), there was an increased risk of toxicity (34%-100% of women). A substantial percentage of simulated individuals had concentrations low enough to potentially increase seizure risk or high enough to create toxicity. Early clearance changes indicate possible subpopulation categorization if therapeutic drug monitoring is conducted in the first trimester. An arbitrary "one-size-fits-all" philosophy may not work well for lamotrigine dosing adjustments during pregnancy and reinforces the need for therapeutic drug monitoring until a patient is determined to be in the LC or HC group.

Physiologically-based pharmacokinetic modeling for single and multiple dosing regimens of ceftriaxone in healthy and chronic kidney disease populations: a tool for model-informed precision dosing.

Introduction: Ceftriaxone is one of commonly prescribed beta-lactam antibiotics with several label and off-label clinical indications. A high fraction of administered dose of ceftriaxone is excreted renally in an unchanged form, and it may accumulate significantly in patients with impaired renal functions, which may lead to toxicity. Methods: In this study, we employed a physiologically-based pharmacokinetic (PBPK) modeling, as a tool for precision dosing, to predict the biological exposure of ceftriaxone in a virtually-constructed healthy and chronic kidney disease patient populations, with subsequent dosing optimizations. We started developing the model by integrating the physicochemical properties of the drug with biological system information in a PBPK software platform. A PBPK model in an adult healthy population was developed and evaluated visually and numerically with respect to experimental pharmacokinetic data. The model performance was evaluated based on the fold error criteria of the predicted and reported values for different pharmacokinetic parameters. Then, the model was applied to predict drug exposure in CKD patient populations with various degrees of severity. Results: The developed PBPK model was able to precisely describe the pharmacokinetic behavior of ceftriaxone in adult healthy population and in mild, moderate, and severe CKD patient populations. Decreasing the dose by approximately 25% in mild and 50% in moderate to severe renal disease provided a comparable exposure to the healthy population. Based on the simulation of multiple dosing regimens in severe CKD population, it has been found that accumulation of 2g every 24h is lower than the accumulation of 1g every 12h dosing regimen. Discussion: In this study, the observed concentration time profiles and pharmacokinetic parameters for ceftriaxone were successfully reproduced by the developed PBPK model and it has been shown that PBPK modeling can be used as a tool for precision dosing to suggest treatment regimens in population with renal impairment.

Total, Unbound, Renal, and Hepatic Clearances of Raltegravir and the Formation and Elimination Clearances of Raltegravir Glucuronide in Pregnant Women.

This work aimed to evaluate the total, unbound, renal, and hepatic clearances of raltegravir (RAL) and the formation and elimination clearances of raltegravir glucuronide (RAL GLU) in pregnant women living with HIV. The participants received RAL 400mg twice daily during the third trimester (n=15) of gestation, delivery (n=15), and the postpartum period (n=8). Pharmacokinetic parameter values were calculated on the basis of plasma and urine data using noncompartmental methods. RAL clearances for the third trimester of gestation were as follows: total clearance: geometric mean, 63.63L/h (95% CI, 47.5-85.25); renal clearance: geometric mean, 2.56L/h (95% CI, 1.96-3.34); hepatic clearance: geometric mean, 60.52L/h (95% CI, 44.65-82.04); and unbound clearance: geometric mean, 281.14L/h (95% CI, 203.68-388.05). RAL GLU formation and elimination clearances for the third trimester of gestation were 7.57L/h (95% CI, 4.94-11.6) and 8.71L/h (95% CI, 6.71-11.32), respectively. No differences were observed in RAL GLU pharmacokinetic parameters between the third trimester of gestation and the postpartum period, except for higher formation (7.57 vs 4.03L/h) and elimination (8.71 vs 4.92L/h) clearances during the third trimester. The findings based on plasma and urine data are consistent with an increase in the hepatic uridine 5' diphospho-glucuronosyltransferase isoenzymes activities involved in RAL metabolism during pregnancy, and the formation of RAL GLU is a minor route of RAL elimination. Compared to the postpartum period, in the third trimester of gestation, the similar RAL plasma exposure in pregnant women reinforces the maintenance of an RAL regimen including a 400-mg oral dose twice daily during pregnancy.

Use of Clinical Trial Simulations to Compare the Performance of Different Approaches for Population Analyses of Pediatric Pharmacokinetic Data.

The adequate characterization of the pharmacokinetics of a drug used in pediatrics is a mainstay of pediatric development programs and is critical for accurate dose selection in pediatrics. Analysis approaches can impact the estimation and characterization of pediatric pharmacokinetic parameters. Simulations were conducted to compare the performance of different approaches for analyzing pediatric pharmacokinetic data in the presence of extensive data from adult studies. Simulated clinical trial datasets were generated encompassing different scenarios that might be encountered in pediatric drug development. For each scenario, 250 clinical trials were simulated and analyzed using each of the following approaches: (1) estimating pediatric parameters using only pediatric data; (2) fixing specific parameters to adult estimates and estimating the remaining pediatric parameters using only pediatric data; (3) estimating pediatric parameters using adult parameters as informative Bayesian priors; (4) estimating pediatric parameters using combined adult and pediatric datasets with exponents for body weight effects estimated using adult and pediatric data; and (5) estimating pediatric parameters using combined adult and pediatric datasets with exponents for body weight effects estimated using pediatric data only. Each analysis approach was evaluated for its success in the estimation of true pediatric pharmacokinetic parameter values. Results demonstrated that analyzing pediatric data using a Bayesian approach generally performed best and had the lowest probability of significant bias in the estimated pediatric pharmacokinetic parameters among different scenarios evaluated. This clinical trial simulation framework can be used to inform the optimal approach for analyses of pediatric data for other pediatric drug development program scenarios beyond the cases evaluated in these analyses.

Clinical Pharmacokinetics and Pharmacodynamics of Voclosporin.

Voclosporin is an approved option for the long-term treatment of lupus nephritis. We aimed to provide a narrative review of the pharmacokinetics and pharmacodynamics of voclosporin. In addition, we derived values for pharmacokinetic and pharmacodynamic parameters by graphical analysis of published diagrams. Compared with cyclosporin, low-dose voclosporin is associated with a lower nephrotoxicity risk and, compared to tacrolimus, with a lower diabetes risk. After repetitive dosing of 23.7 mg twice daily and at target trough concentrations of 10-20 ng/mL, the dominant or effect-indicative half-life is estimated at 7 hours. Compared with the pharmacodynamics of cyclosporin, the potency of voclosporin is stronger, with a lower concentration CE50 of 50 ng/mL already producing the half-maximum immunosuppressive effect. The Hill coefficient can be predicted to be low at H = 1.3, indicating a concentration-dependent effect on the immune system. The corresponding effect bisection time of 10 hours allows for dosing every 12 hours. Accordingly, the trough concentration will be above the threshold concentration that produces 5% of the maximum effect of 5.2 ng/mL for immunosuppression but below both the predicted threshold of 30 ng/mL for nephrotoxicity and the predicted threshold of 40 ng/mL for new-onset diabetes. The pharmacokinetic and pharmacodynamic properties suggest the use of low-dose voclosporin combined with mycophenolate and low-dose glucocorticoids for immunosuppressive maintenance therapy.

Evaluation of model-based bioequivalence approach for single sample pharmacokinetic studies.

In a traditional pharmacokinetic (PK) bioequivalence (BE) study, a two-way crossover study is conducted, PK parameters (namely the area under the time-concentration curve [AUC] and the maximal concentration [ ]) are obtained by noncompartmental analysis (NCA), and the BE analysis is performed using the two one-sided test (TOST) method. For ophthalmic drugs, however, only one sample of aqueous humor, in one eye, per eye can be obtained in each patient, which precludes the traditional BE analysis. To circumvent this issue, the U.S. Food and Drug Administration (FDA) has proposed an approach coupling NCA with either parametric or nonparametric bootstrap (NCA bootstrap). The model-based TOST (MB-TOST) has previously been proposed and evaluated successfully for various settings of sparse PK BE studies. In this paper, we evaluate, via simulations, MB-TOST in the specific setting of single sample PK BE study and compare its performance to NCA bootstrap. We performed BE study simulations using a published PK model and parameter values and evaluated multiple scenarios, including study design (parallel or crossover), sampling times (5 or 10 spread across the dosing interval), and geometric mean ratio (of 0.8, 0.9, 1, and 1.25). Using the simulated structural PK model, MB-TOST performed similarly to NCA bootstrap for AUC. For , the latter tended to be conservative and less powerful. Our research suggests that MB-TOST may be considered as an alternative BE approach for single sample PK studies, provided that the PK model is correctly specified and the test drug has the same structural model as the reference drug.

Abstract 2800: Pharmacokinetics, bioavailability, and pharmacodynamics of oral triapine

Abstract Background: Locally advanced cervical cancer accounts for most deaths from disease. Standard of care includes treatment with cisplatin-based chemoradiation with a 70% response rate. The addition of intravenous (IV) triapine to chemoradiation has shown promising clinical activity in phase 1 and 2 studies but comes with a more intensive treatment regimen. An ongoing phase 1 trial has finished the escalation phase, and we report the pharmacokinetics (PK) and pharmacodynamics (PD) of oral (PO) triapine. Methods: This phase 1 study followed a 3+3 design for dose escalation of oral triapine, starting with initial dose of 100 mg five days a week for five weeks combined with external beam pelvic radiation and weekly IV cisplatin. PK was determined by LC-MS/MS, and PD included methemoglobin levels at 4 h post dose. Within patient PK variability after IV and PO dosing and PO bioavailability were calculated. Results: PK data were available for 10 patients at 100 (the MTD) and 150 mg. PO parameter values were Tmax 1.3 h, t1/2 1.4 h, CL/F 104 L/h, and Vz/F 214 L. There was no discernable difference between triapine exposure at 100 vs. 150 mg PO (Cmax 520 (2.5) vs. 344 (1.9) µg/L; AUC 1209 (2.53) vs. 1034 (1.41) µg/L•h), and between patient variability at each dose level was substantial. The correlation of PO Vz/F vs Cl/F was high at R2=0.86, suggesting that the apparent clearance and volume variability is primarily due to variability in the oral bioavailability F. PO within patient variability of Cmax and AUC was also large at 43% and 55%. IV PK was less variable with lower geometric standard deviations across all parameters, including within patients where variability of Cmax and AUC was modest at 10 and 12% coefficient of variation, respectively. Oral bioavailability was estimated at 66%. We found a non-significant trend of smoking almost doubling triapine oral clearance from 68 to 156 L/h (p=0.056). There was no apparent relationship between occurrence of DLT and either IV or PO triapine AUC. Methemoglobin levels directly correlated with triapine exposure expressed as AUC or Cmax. Conclusions: Triapine PK parameter values for PO and IV administration and PO bioavailability values observed in this trial were comparable to previous reports. Correlation of methemoglobin with exposure highlights the importance of optimizing triapine exposure. Additional data may support the exploration of a dose specific to current smokers. Citation Format: Jan H. Beumer, Sarah Behr, Holly Gallion, John Vargo, Frederick Ueland, Haider Mahdi, Brian Orr, Eugenia Girda, Susan Christner, Edward Chu, Charles Kunos, Percy S. Ivy, Sarah Taylor. Pharmacokinetics, bioavailability, and pharmacodynamics of oral triapine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2800.

Pharmacokinetics and RP2D analysis from ETCTN 10388: A phase I trial of triapine and lutetium Lu-177 dotatate in well-differentiated somatostatin receptor–positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs).

648 Background: Radiation is a potent inducer of DNA double-strand breaks, and ribonucleotide reductase (RNR) is the rate-limiting enzyme for conversion of ribonucleoside diphosphate to deoxyribonucleotide diphosphate, and thus repair of DNA in this setting. ETCTN 10388 evaluated safety of combination Lu-177 DOTATATE, a beta-emitting radionuclide in combination with triapine, a ribonucleotide reductase (RNR) inhibitor. Methods: This investigator initiated, NCI sponsored, multicenter phase 1 trial, enrolled a total of 31 patients in the dose escalation [using the Bayesian optimal interval design (BOIN)] and dose expansion cohorts. Oral triapine was administered on days 1-14 and Lu-177 DOTATATE [200 mCi] intravenously on day 1 of every 56-day cycle. A total of 4 cycles were administered. All enrolled patients had blood samples collected for triapine pharmacokinetic (PK) analysis in EDTA tubes prior to and at 0.5, 1, 1.5, 2, 3, 4, 6, and 8 h after oral administration during cycle 1. Results: Five patients were enrolled in triapine Dose Level 1 (100 mg/day), twenty-five to dose level two (150 mg/day), and one patient to dose level three (200 mg/day). PK data were available for 12 patients enrolled in the dose escalation cohort. The geometric mean (SD) AUC0-inf was 1159 (1.22) µg/L•h for the 100mg dose level and 1862 (1.76) µg/L•h for the 150 mg dose level, suggesting that exposure increased with dose, and inter-patient variability was as expected for an oral agent. Triapine PK parameter values observed in this trial, were comparable to previous reports that used a previous formulation [ 1 ]. While exposure was similar, variability appeared smaller with the current oral formulation. Adverse events (AE) were assessed in all 31 patients per CTCAE 5.0. A total of one DLT in dose level 1, seven DLTs (Transient cytopenia; primarily neutropenia and rarely thrombocytopenia) in dose level 2, and one grade 5 DLT (Death probably from progressive cancer and carcinoid heart disease but possibly from trial drugs) in dose level 3 were observed. Detailed AE profile will be presented at the meeting. Conclusions: The RP2D of triapine is 150 mg QD on days 1-14 in combination with Lu-177 DOTATATE on day 1 of every 56-day cycle. Clinical trial information: 04234568 .