Differences In Pharmacokinetics Research Articles

Physiologically Based Pharmacokinetic Modeling to Unravel the Drug-gene Interactions of Venlafaxine: Based on Activity Score-dependent Metabolism by CYP2D6 and CYP2C19 Polymorphisms.

Venlafaxine (VEN) is a commonly utilized medication for alleviating depression and anxiety disorders. The presence of genetic polymorphisms gives rise to considerable variations in plasma concentrations across different phenotypes. This divergence in phenotypic responses leads to notable differences in both the efficacy and tolerance of the drug. A physiologically based pharmacokinetic (PBPK) model for VEN and its metabolite O-desmethylvenlafaxine (ODV) to predict the impact of CYP2D6 and CYP2C19 gene polymorphisms on VEN pharmacokinetics (PK). The parent-metabolite PBPK models for VEN and ODV were developed using PK-Sim® and MoBi®. Leveraging prior research, derived and implemented CYP2D6 and CYP2C19 activity score (AS)-dependent metabolism to simulate exposure in the drug-gene interactions (DGIs) scenarios. The model's performance was evaluated by comparing predicted and observed values of plasma concentration-time (PCT) curves and PK parameters values. In the base models, 91.1%, 94.8%, and 94.6% of the predicted plasma concentrations for VEN, ODV, and VEN + ODV, respectively, fell within a twofold error range of the corresponding observed concentrations. For DGI scenarios, these values were 81.4% and 85% for VEN and ODV, respectively. Comparing CYP2D6 AS = 2 (normal metabolizers, NM) populations to AS = 0 (poor metabolizers, PM), 0.25, 0.5, 0.75, 1.0 (intermediate metabolizers, IM), 1.25, 1.5 (NM), and 3.0 (ultrarapid metabolizers, UM) populations in CYP2C19 AS = 2.0 group, the predicted DGI AUC0-96h ratios for VEN were 3.65, 3.09, 2.60, 2.18, 1.84, 1.56, 1.34, 0.61, and for ODV, they were 0.17, 0.35, 0.51, 0.64, 0.75, 0.83, 0.90, 1.11, and the results were similar in other CYP2C19 groups. It should be noted that PK differences in CYP2C19 phenotypes were not similar across different CYP2D6 groups. In clinical practice, the impact of genotyping on the in vivo disposition process of VEN should be considered to ensure the safety and efficacy of treatment.

Comparison of in vivo pharmacokinetics of twelve constituents in Qihe Fenqing Yin in normal rats and diabetic rats

This paper aims to study the pharmacokinetic differences of twelve effective constituents(succinic acid, neochlorogenic acid, chlorogenic acid, cryptochlorogenic acid, protocatechuic aldehyde, caffeic acid, 5-O-ferulogeninic acid, p-coumaric acid, nuciferine, quercetin, oleanolic acid, and ursolic acid) in Qihe Fenqing Yin in normal and diabetic rats. The diabetic rat model was established by a high-fat diet combined with intraperitoneal injection of streptozocin. A UHPLC-QTRAP-MS/MS method was established for the simultaneous determination of 12 constituents in the plasma of normal rats and model rats after a single intragastric administration of Qihe Fenqing Yin. The results show that the established analytical method has a good linear relationship with the 12 components, and the specificity, accuracy, precision, and stability meet the requirements. The computational pharmacokinetic parameters are fitted by DAS 3.2.8 software, and the results show that the half-life time(t_(1/2)) of the other nine components in the model group was longer than that in the normal group except for caffeic acid, 5-O-ferulogeninic acid, and oleanolic acid. The area under curve(AUC_(0-t)) of cryptochlorogenic acid, p-coumaric acid, ursolic acid, and oleanolic acid increases compared with the normal group. Meanwhile, mean residence time(MRT) delays. The "double peaks" of quercetin and nuciferine in the normal group are not observed in the model group, suggesting that the pharmacokinetic parameters of the drugs in the disease state are significantly different.

Radiolabeling Diaminosarcophagine with Cyclotron-Produced Cobalt-55 and [55Co]Co-NT-Sarcage as a Proof of Concept in a Murine Xenograft Model.

Cobalt-sarcophagine complexes exhibit high kinetic inertness under various stringent conditions, but there is limited literature on radiolabeling and in vivo positron emission tomography (PET) imaging using no carrier added 55Co. To fill this gap, this study first investigates the radiolabeling of DiAmSar (DSar) with 55Co, followed by stability evaluation in human serum and EDTA, pharmacokinetics in mice, and a direct comparison with [55Co]CoCl2 to assess differences in pharmacokinetics. Furthermore, the radiolabeling process was successfully used to generate the NTSR1-targeted PET agent [55Co]Co-NT-Sarcage (a DSar-functionalized SR142948 derivative) and administered to HT29 tumor xenografted mice. The [55Co]Co-DSar complex can be formed at 37 °C with purity and stability suitable for preclinical in vivo radiopharmaceutical applications, and [55Co]Co-NT-Sarcage demonstrated prominent tumor uptake with a low background signal. In a direct comparison with [64Cu]Cu-NT-Sarcage, [55Co]Co-NT-Sarcage achieved a higher tumor-to-liver ratio but with overall similar biodistribution profile. These results demonstrate that Sar would be a promising chelator for constructing Co-based radiopharmaceuticals including 55Co for PET and 58mCo for therapeutic applications.

Immunogenicity of avelumab in patients with metastatic Merkel cell carcinoma or advanced urothelial carcinoma.

Like other monoclonal antibodies, immune checkpoint inhibitors may be immunogenic in some patients, potentially affecting pharmacokinetics (PKs) and clinical outcomes. In post hoc analyses, we characterized antidrug antibody (ADA) development with avelumab monotherapy in patients with metastatic Merkel cell carcinoma (mMCC) from the JAVELIN Merkel 200 trial (first-line [1L; N = 116] and second-line or later [≥2L; N = 88] cohorts) or with advanced urothelial carcinoma (aUC) from the JAVELIN Bladder 100 (1L maintenance [N = 350]) and JAVELIN Solid Tumor (≥2L [N = 249]) trials. Treatment-emergent ADAs developed in a numerically higher proportion of patients with aUC (1L maintenance, 19.1%; ≥2L, 18.1%) versus mMCC (1L, 8.2%; ≥2L, 8.9%); incidences within tumor types were similar by line of therapy. In PK analyses, numerically lower avelumab trough concentration and higher baseline clearance were observed in treatment-emergent ADA+ versus ADA- subgroups; however, differences were not clinically relevant. Numerical differences in overall survival, progression-free survival, or objective response rate by ADA status were observed; however, no clinically meaningful trends were identified. Proportions of patients with treatment-emergent adverse events (TEAEs; any grade or grade 3/4), serious TEAEs, TEAEs leading to treatment discontinuation, or infusion-related reactions were similar, with overlapping 80% confidence intervals between ADA subgroups. Efficacy and safety observations were similar in subgroups defined by early development of ADA+ status during treatment. In conclusion, no meaningful differences in PKs, efficacy, and safety were observed between subgroups of avelumab-treated patients with different ADA status. Overall, these data suggest that ADAs are not relevant for treatment decisions with avelumab.

Effect of Food Consumption on the Pharmacokinetics, Safety, and Tolerability of Once-Daily Orally Administered Orforglipron (LY3502970), a Non-peptide GLP-1 Receptor Agonist.

We assessed the effect of the prandial state on the pharmacokinetics, safety, and tolerability of single and multiple doses of orforglipron (LY3502970), an oral, non-peptide glucagon-like peptide1 receptor agonist (GLP-1 RA), in two studies (A and B). StudyA and studyB were phase1, randomized, crossover studies in healthy adults aged 18-65years and 21-70years, respectively. Participants received single (3mg, studyA) or multiple (16mg, studyB) oral doses of orforglipron under fasted and fed conditions. Blood samples were collected pre- and postdose to assess area under the concentration-time curve (AUC), maximum observed drug concentration (Cmax), time of Cmax (tmax), and half-life (t1/2) associated with terminal rate constant. AUC and Cmax were analyzed using a linear mixed-effects model. Treatment differences were presented as ratios of geometric least squares means (GLSM). Treatment-emergent adverse events (TEAEs), adverse events of special interest, and serious adverse events were assessed. StudyA included 12 participants (mean age 45.0years; male 66.7%); studyB included 34 participants (mean age 42.8years; male 88.2%). GLSM AUC and Cmax were lower by 23.7% and 23.2% in studyA, and 17.6% and 20.9% in studyB, in the fed versus fasted states, respectively. In both studies, t1/2 and median tmax were comparable between fed and fasted states. The majority of TEAEs in both studies were gastrointestinal tract-related conditions. No serious adverse events or deaths were reported in either study. The observed pharmacokinetic differences due to the prandial state are unlikely to contribute to clinically meaningful differences in the efficacy of orforglipron. The safety profile was consistent with the known profiles of other GLP-1 RAs. Given the absence of prandial restrictions, orforglipron may emerge as a convenient oral treatment option for patients with type2 diabetes or obesity. ClinicalTrials.gov identifiers, NCT03929744 and NCT05110794.

Gut microbiota and host metabolizing enzymes co‐contribute to pharmacokinetic variability in type 2 diabetes mellitus rats

AbstractThis study aimed to investigate the pharmacokinetic difference of quercetin between normal and type 2 diabetes mellitus (T2DM) rats. Our results showed that the mean residence time and half time were significantly increased, while the peak concentration was significantly reduced in T2DM rats, compared to the control rats. In addition, quercetin remained a high concentration in the liver for a long time with the highest concentration (13.51 ± 4.66 μg/mL) at 4 h after oral administration in T2DM rats. Furthermore, the CYP3A4 messenger RNA (mRNA) levels were downregulated and UGT1A1 mRNA levels in liver were upregulated in T2DM rats. In addition, the relative abundances of Bacteroides, norank, Parabacteroides, and Alistipes were decreased, while the relative abundances of Acrococcus, Frisingicoccus, Romboutsia, and Clostridium_sensu_stricto_1 were increased in the T2DM rats. The metabolism of quercetin in T2DM rats was slower compared to the normal group, which may be related to the lower level of CYP3A4 and the higher level of UGT1A1 in T2DM, as well as the significant enrichment of Acrococcus and other bacteria in the gut of T2DM rats.

Cefdinir vs cephalexin for the treatment of urinary tract infections: A retrospective evaluation.

Cefdinir and cephalexin are cephalosporin antibiotics commonly used in the treatment of urinary tract infections (UTIs). Their efficacy depends on achieving sufficient time with concentrations exceeding the minimum inhibitory concentration (MIC). Despite being frequently prescribed for UTIs, cefdinir has markedly lower urine penetration compared to cephalexin. It is possible that differences in pharmacokinetics could result in dissimilar efficacy between these agents; however, comparative studies of cephalosporins in UTIs are lacking. This was a retrospective comparative study of patients discharged from emergency departments within a community health system with a diagnosis of acute cystitis who were prescribed cefdinir or cephalexin. Treatment failure rates at 7 and 14 days were compared between the 2 agents using a χ2 or Fisher's exact test, as appropriate. There were no differences in overall treatment failure between the cefdinir and cephalexin groups. Treatment failure at 7 days occurred in 11.6% (n = 14) of patients in the cefdinir group and 8.3% (n = 10) of patients in the cephalexin group (P = 0.389). Treatment failure at 14 days was higher for cefdinir at 20.7% (n = 25) than for cephalexin at 11.8% (n = 14), but this difference was not statistically significant (P = 0.053). There were no differences in the rate of treatment failure in subgroup analyses of uncomplicated or complicated UTIs. The results of this study suggest that cefdinir and cephalexin have comparable efficacy for the treatment of lower UTIs. While there was a numerically higher rate of treatment failure with cefdinir, there were no significant differences in treatment failure between the agents.

Population pharmacokinetics and pharmacodynamics of nirmatrelvir in Chinese patients with COVID-19.

The pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of nirmatrelvir (NMV) are unknown in Chinese patients with COVID-19. To understand the PK, as well as PK-PD characteristics of NMV for optimizing the dose in Chinese patients with COVID-19. We enrolled 141 participants who received NMV 300 mg/ritonavir (RTV) 100 mg b.i.d. for 5 days. The NMV concentrations were analyzed using 251 blood samples. PK/PD of NMV was investigated in these COVID-19 patients using a nonlinear mixed-effects model. The patients had a mean age of 82 years (range, 34-97). The absorption rate constant and apparent clearance of NMV in this Chinese cohort were 0.253 h-1 and 6.83L/h, respectively, similar to Caucasian patients. No covariates affected NMV clearance. Predicted peak (Cmax) and trough concentration (Cmin) under 300 mg NMV/100 mg RTV b.i.d. were 4004 and 1498 ng/mL, respectively. Although higher AUC and Cmin were weakly associated with a slight increase in the number of cycle threshold (CT) of viral genes, no significant correlation was found, indicating a weak relationship between drug exposure and efficacy (CT). In all, our findings suggest no ethnic PK differences, a weak and clinically insignificant relationship between drug exposure and efficacy, suitable dosage for Chinese patients (including the elderly) based on PK parameters, and the need for further studies to determine optimal regimens for high-risk patients due to inter-individual variability.

Safety and effectiveness of diazepam nasal spray in male and female patients: Post hoc analysis of data from a phase 3 safety study.

Sex differences in drug pharmacokinetics include variations in the expression of the cytochrome P450 enzymes, which are involved in the metabolism of benzodiazepines. It is unclear whether sex influences outcomes associated with intranasally administered drugs. A post hoc analysis of sex differences was conducted to evaluate the effectiveness and safety of diazepam nasal spray, which included examining changes in the number of days between seizure clusters over time (SEIzure interVAL [SEIVAL]). Diazepam nasal spray is approved for acute treatment of seizure clusters in patients with epilepsy aged ≥6 years. Data from a phase 3 safety study were used to determine the proportion of second doses used within 24 h (ie, a proxy for effectiveness) and SEIVAL. Adverse events were recorded. Of 163 treated patients, 89 were female, and 74 were male. Approximately 16% of both sexes self-administered the study drug. A slightly higher proportion of seizure clusters was treated with a second dose in female (14.7%) than male (9.4%) patients. SEIVAL increased significantly and substantially over a year for all patients. The safety profile was generally similar between the sexes. These results suggest that potential sex differences in benzodiazepine pharmacokinetics do not meaningfully influence outcomes associated with diazepam nasal spray. PLAIN LANGUAGE SUMMARY: Some drugs may have differences in absorption and metabolism between genders that could translate into differences in safety and effectiveness. This safety study looked at diazepam nasal spray for treating seizure clusters in patients at least 6 years old. It found that safety was about the same for females and males. For both groups, most clusters stopped after only 1 dose of the drug, and the time between treated clusters got longer over a year.

Machine Learning-Based Prediction of Escitalopram and Sertraline Side Effects With Pharmacokinetic Data in Children and Adolescents.

Selective serotonin reuptake inhibitors (SSRI) are the first-line pharmacologic treatment for anxiety and depressive disorders in children and adolescents. Many patients experience side effects that are difficult to predict, are associated with significant morbidity, and can lead to treatment discontinuation. Variation in SSRI pharmacokinetics could explain differences in treatment outcomes, but this is often overlooked as a contributing factor to SSRI tolerability. This study evaluated data from 288 escitalopram-treated and 255 sertraline-treated patients ≤ 18 years old to develop machine learning models to predict side effects using electronic health record data and Bayesian estimated pharmacokinetic parameters. Trained on a combined cohort of escitalopram- and sertraline-treated patients, a penalized logistic regression model achieved an area under the receiver operating characteristic curve (AUROC) of 0.77 (95% confidence interval (CI): 0.66-0.88), with 0.69 sensitivity (95% CI: 0.54-0.86), and 0.82 specificity (95% CI: 0.72-0.87). Medication exposure, clearance, and time since the last dose increase were among the top features. Individual escitalopram and sertraline models yielded an AUROC of 0.73 (95% CI: 0.65-0.81) and 0.64 (95% CI: 0.55-0.73), respectively. Post hoc analysis showed sertraline-treated patients with activation side effects had slower clearance (P = 0.01), which attenuated after accounting for age (P = 0.055). These findings raise the possibility that a machine learning approach leveraging pharmacokinetic data can predict escitalopram- and sertraline-related side effects. Clinicians may consider differences in medication pharmacokinetics, especially during dose titration and as opposed to relying on dose, when managing side effects. With further validation, application of this model to predict side effects may enhance SSRI precision dosing strategies in youth.

Pharmacokinetics of Dacarbazine and Unesbulin and CYP1A2-Mediated Drug Interactions in Patients With Leiomyosarcoma.

Unesbulin is being investigated in combination with dacarbazine (DTIC) as a potential therapeutic agent in patients with advanced leiomyosarcoma (LMS). This paper reports the pharmacokinetics (PK) of unesbulin, DTIC, and its unreactive surrogate metabolite 5-aminoimidazole-4-carboxamide (AIC) in 29 patients with advanced LMS. Drug interactions between DTIC (and AIC) and unesbulin were evaluated. DTIC (1000 mg/m2 ) was administered to patients with LMS via 1-hour intravenous (IV) infusion on Day 1 of every 21-day (q21d) cycle. Unesbulin dispersible tablets were administered orally twice weekly (BIW), starting on Day 2 of every cycle, except for Cycle 2 (C2), where unesbulin was dosed either on Day 1 together with DTIC or on Day 2, 1 day after DTIC administration. The PK of DTIC, AIC, and unesbulin in Cycle 1 (C1) and C2 were estimated using noncompartmental analysis. DTIC and AIC were measurable immediately after the start of infusion and reached Cmax immediately or shortly after end of infusion at 1.0 and 1.4 hours (Tmax ), respectively. Coadministration of unesbulin orally at 200 mg or above with DTIC inhibited cytochrome P450 (CYP)1A2-mediated DTIC metabolism, resulting in 66.7% reduction of AIC exposures. Such inhibition could be mitigated when unesbulin was dosed the day following DTIC infusion. Repeated unesbulin dosing demonstrated evidence of clinical CYP1A2 induction and increased AIC Cmax by 69.4% and AUCinf by 57.9%. No meaningful difference in unesbulin PK was observed between C2 and C1. The combination therapy of 1000 mg/m2 IV DTIC q21d and 300 mg unesbulin BIW in a staggered regimen is well tolerated in patients with LMS.

Effects of vitamin C on the pharmacokinetics and pharmacodynamics of nimodipine in rats.

In recent years, researchers have shown a growing interest in the interactions between different pharmaceutical agents. An intriguing instance lies in the possible interaction between nimodipine and vitamin C. To investigate the pharmacokinetic and pharmacodynamic effects of vitamin C on nimodipine in rats, rats were randomly divided into a nimodipine only group and a combination group (nimodipine + vitamin C). The two groups were given intragastric administration and nimodipine blood concentrations were determined using high-performance liquid chromatography-tandem mass spectrum at different time points. Blood pressure and heart rate were measured via carotid artery cannulation. Pharmacokinetic differences were observed between the nimodipine only group and the combination group at the same dose. Compared with the nimodipine only group, the combination group's main pharmacokinetic parameters of peak concentration and area under the curve increased significantly, and the difference was statistically significant (p < 0.05); furthermore, the combination group exhibited a significant reduction in average blood pressure, while no significant effects on heart rate were observed. Vitamin C did not affect the activity of CYP450 in rat liver. The pharmacokinetic characteristics and pharmacodynamics of nimodipine were changed by vitamin C administration in rats.

Ultrasensitive detection of imatinib in human serum using a gold-based paper sensor

Imatinib is the tyrosine kinase inhibitor of choice for the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. However, imatinib has drawbacks such as drug resistance and significant differences in pharmacokinetics within patients. Therefore, a colloidal gold-based immunochromatographic assay (CG-IA) was developed for measuring and monitoring imatinib in human serum. An imatinib derivative containing carboxyl groups was used for the synthesis of the immunogen, and 4-(4-methyl-1-piperazinylmethyl) benzoic acid was selected as the hapten for the heterologous coating antigen. Next, a highly sensitive and specific monoclonal antibody (mAb), 2F7 was screened for the construction of a CG-IA, with an IC50 value of 0.091 ng/mL. For the qualification of imatinib in human serum, the visual limit of detection (vLOD) and cut-off values of the CG-IA were 2 and 20 ng/mL, respectively. For quantitative detection, the calculated LOD value of the CG-IA was 0.068 ng/mL, with a linearity range of 1.004 and 23.087 ng/mL. The recovery rate of spiked serum samples was between 88.24 % and 104.75 %. In addition, the concentration of imatinib in the serum samples from 10 patients was detected by CG-IA and revealed a good correlation with those from LC-MS/MS. These results indicated that the developed gold-based paper sensor could become an effective tool for the rapid monitoring of imatinib in human serum samples.

Is Gender an Important Factor in the Precision Medicine Approach to Levocetirizine?

Currently, there is insufficient information on the variability in levocetirizine pharmacometrics among individuals, a crucial aspect for establishing its clinical use. The gender differences in pharmacokinetics and the extent of variation in pharmacodynamics have not been definitively identified. The primary goal of this study was to investigate gender differences in levocetirizine pharmacokinetics and quantitatively predict and compare how these gender-related pharmacokinetic differences impact pharmacodynamics, using population pharmacokinetic-pharmacodynamic modeling. Bioequivalence results for levocetirizine (only from the control formulation) were obtained from both healthy Korean men and women. Physiological and biochemical parameters for each individual were utilized as pharmacokinetic comparison and modeling data between genders. Pharmacodynamic modeling was performed using reported data on antihistamine responses following levocetirizine exposure. Gender, weight, body surface area, peripheral distribution volume, albumin, central-peripheral inter-compartmental clearance, and the fifth sequential absorption rate constant were explored as effective covariates. A comparison of the model simulation results showed a higher maximum concentration and faster plasma loss in females than in males, resulting in a faster recovery to baseline of the antihistamine effect; however, the absolute differences between genders in the mean values were not large within 10 ng/mL (for plasma concentrations) or % (wheal and flare size changes). Regarding the pharmacokinetics and pharmacodynamics of levocetirizine, the gender effect may not be significant when applying the usual dosage (5 mg/day). This study will be useful for bridging the knowledge gap in scientific precision medicine by introducing previously unconfirmed information regarding gender differences in levocetirizine pharmacometrics.

PBPK Modeling Approach to Predict the Behavior of Drugs Cleared by Metabolism in Pregnant Subjects and Fetuses.

This study aimed to develop a physiologically based pharmacokinetic (PBPK) model that simulates metabolically cleared compounds' pharmacokinetics (PK) in pregnant subjects and fetuses. This model accounts for the differences in tissue sizes, blood flow rates, enzyme expression levels, plasma protein binding, and other physiological factors affecting the drugs' PK in both the pregnant woman and the fetus. The PBPKPlus™ module in GastroPlus® was used to model the PK of metoprolol, midazolam, and metronidazole for both non-pregnant and pregnant groups. For each of the three compounds, the model was first developed and validated against PK data in healthy non-pregnant volunteers and then applied to predict the PK in the pregnant groups. The model accurately described the PK in both the non-pregnant and pregnant groups and explained well the differences in the plasma concentration due to pregnancy. When available, the fetal plasma concentration, placenta, and fetal tissue concentrations were also predicted reasonably well at different stages of pregnancy. The work described the use of a PBPK approach for drug development and demonstrates the ability to predict differences in PK in pregnant subjects and fetal exposure for metabolically cleared compounds.

Nanotechnological innovations in paediatric tuberculosis management: current trends and future prospects

Paediatric Tuberculosis (TB) continues to be a major global cause of morbidity and mortality. Children are more prone to contracting TB, which can spread quickly to extrapulmonary infection sites. Although the pathophysiology of the disease, drug pharmacokinetics, and the therapeutic window in children differ from those of adults, the same drugs used to treat adult TB have long been utilised to treat paediatric TB infections. Since many current formulations such as tablets are unsuitable for children due to difficulty swallowing and risk of choking, adult medications are frequently used by breaking or crushing tablets to obtain a paediatric dose. This can result in inaccurate dosing due to pharmacokinetic differences in children which could subsequently lead to sub-therapeutic or toxic systemic concentrations. In addition, many of the medications used in the treatment of TB and most medicines in general, have a profoundly unpleasant taste to children causing them to reject and spit out medication which contributes to challenges with adherence, ultimately leading to treatment failure. The aforementioned demonstrates a huge need for the development of novel drug delivery formulations that are paediatric-friendly and address the limitations of current dosage forms. This review discusses the currently available oral paediatric formulations, recent developments of novel oral drug delivery systems studied to overcome the current problems associated with the treatment of tuberculosis in paediatrics and provides potential direction for future research through nanotechnology by using a SWOT analysis.

Population Pharmacokinetic and Pharmacodynamic Modeling of Romiplostim Biosimilar GP40141 and Reference Product in Healthy Volunteers to Evaluate Biosimilarity.

GP40141 is a romiplostim biosimilar. A Phase 1 clinical trial was previously conducted in healthy volunteers to evaluate the pharmacodynamics (PD), pharmacokinetics (PK), and safety of GP40141 compared to the reference romiplostim (NCT05652595). Using noncompartmental analysis, the biosimilarity of PD end points was determined according to the classical criterion (0.8-1.25). PK end points were also in good agreement between GP40141 and the reference romiplostim; however, the confidence interval for the area under concentration-time curve from time 0 to the time of last measurement was slightly out of the bioequivalence range (0.91-1.29). Population PK/PD was used in the present study to characterize the individual PK and PD data of 56 healthy subjects in 2 cross-over periods of the Phase 1 clinical trial. Body weight and neutralizing antibodies to romiplostim were found to be important predictors of apparent volume of distribution and linear elimination constant, respectively. Within the framework of the conducted modeling, population estimates of PK/PD parameters were obtained, which were in agreement with literature data for the reference romiplostim. Additionally, values of intersubject variability, previously unreported for romiplostim in a healthy subject population, were derived. Covariate analysis, conducted during model development, as well as visual diagnostics and model-based simulations, demonstrated the absence of significant differences in PK and PD between GP40141 and romiplostim-ref.

Infliximab Monotherapy vs Combination Therapy for Pediatric Crohn's Disease Exhibit Similar Pharmacokinetics.

The use of concomitant azathioprine may improve efficacy and pharmacokinetic (PK) properties of infliximab (IFX) but is also associated with an increased risk of adverse events. Proactive therapeutic drug monitoring (pTDM) of IFX monotherapy is an alternative strategy to improve PK. The aim of this study was to evaluate whether IFX with an immunomodulator (combo) has PK benefits over IFX-pTDM (mono) in pediatric Crohn's disease (CD). This PK analysis included pediatric CD patients who started either IFX combo (TISKids study) or IFX mono with pTDM (REFINE cohort). Combo and mono IFX trough levels (TLs) and antibodies-to-infliximab were assessed at infusion 3, 4, and 5. A population PK model was built to compare IFX PK outcomes (clearance [CL], TLs and cumulative exposure) between combo and mono groups at infusion 4 and 5. Clinical response and steroid-free clinical remission (SFCR) was assessed at infusion 4 and 5. This study included 128 pediatric CD patients (66 mono and 62 combo). At infusion 5, there was no significant difference between mono and combo median TLs 4.1 µg/mL (2.1, 7.8) vs 5.9 µg/mL (3.2, 9.4; P = .14) or median CL 0.26 L/d (0.21, 0.32) vs 0.26 L/d (0.21, 0.33; P = .81). Mono patients had a lower SFCR rate at infusion 5 (53% [31 of 59] vs 80% [32 of 40]; P = .01). Clinical response rates were significantly higher among combo than mono patients at both infusion 4 and 5. This study suggests that there are no PK differences (TLs and CL) between combo and mono therapy in pediatric CD patients who started IFX.

Sex-biased gene expression and gene-regulatory networks of sex-biased adverse event drug targets and drug metabolism genes

BackgroundPrevious pharmacovigilance studies and a retroactive review of cancer clinical trial studies identified that women were more likely to experience drug adverse events (i.e., any unintended effects of medication), and men were more likely to experience adverse events that resulted in hospitalization or death. These sex-biased adverse events (SBAEs) are due to many factors not entirely understood, including differences in body mass, hormones, pharmacokinetics, and liver drug metabolism enzymes and transporters.MethodsWe first identified drugs associated with SBAEs from the FDA Adverse Event Reporting System (FAERS) database. Next, we evaluated sex-specific gene expression of the known drug targets and metabolism enzymes for those SBAE-associated drugs. We also constructed sex-specific tissue gene-regulatory networks to determine if these known drug targets and metabolism enzymes from the SBAE-associated drugs had sex-specific gene-regulatory network properties and predicted regulatory relationships.ResultsWe identified liver-specific gene-regulatory differences for drug metabolism genes between males and females, which could explain observed sex differences in pharmacokinetics and pharmacodynamics. In addition, we found that ~ 85% of SBAE-associated drug targets had sex-biased gene expression or were core genes of sex- and tissue-specific network communities, significantly higher than randomly selected drug targets. Lastly, we provide the sex-biased drug-adverse event pairs, drug targets, and drug metabolism enzymes as a resource for the research community.ConclusionsOverall, we provide evidence that many SBAEs are associated with drug targets and drug metabolism genes that are differentially expressed and regulated between males and females. These SBAE-associated drug metabolism enzymes and drug targets may be useful for future studies seeking to explain or predict SBAEs.

Exploration of pharmacokinetic differences between East Asians and Caucasians: insights from pharmacokinetic studies in healthy subjects.

Interethnic differences in the pharmacokinetics of drugs result from a complex interplay of environmental, genetic, and demographic factors. Identifying ethnic differences in pharmacokinetics is challenging due to the multifaceted contributions of the underlying factors. To address these challenges, this paper reviews 9 pharmacokinetic studies meeting the following criteria: (A) Conducted at Seoul National University Hospital from 2013 to 2022 as a single-center study. (B) Pharmacokinetic studies involving both East Asians (Korean, Japanese, or Chinese) and Caucasians. (C) Study drugs were administered orally. (D) Raw data was provided for reanalysis. This retrospective analysis aimed to investigate the existence of ethnic differences in drug exposure and understand the possible factors contributing to these variabilities. Pharmacokinetic, demographic, and clinical laboratory test data were analyzed to assess potential pharmacokinetic differences between East Asians and Caucasians. This assessment involved calculating the geometric mean ratio of dose-normalized area under the time-concentration curve (AUC) and dose- and weight-normalized AUC, along with their 90% confidence intervals. Additionally, pharmacological information, including metabolic pathways, was gathered from the investigational brochure or the respective country's drug label. Among 9 studies, 4 studies demonstrated approximately 1.3 to 1.8 times higher drug exposure in East Asians compared to Caucasians. These drugs were primarily eliminated through hepatic metabolism, with less than 5% excreted unchanged in the urine. Two drugs were metabolized by hepatic cytochrome P450 3A4, one by glutathione S-transferase, and specific metabolic pathways for another drug were not identified. Further research is needed to assess the causes of ethnic variability in these drugs.