Steady-state Trough Research Articles

Steady-State Drug Exposure of Repeated IV Bolus Administration for a One Compartment Pharmacokinetic Model with Sigmoidal Hill Elimination.

Drugs exhibiting nonlinear pharmacokinetics hold significant importance in drug research and development. However, evaluating drug exposure accurately is challenging with the current formulae established for linear pharmacokinetics. This article aims to investigate the steady-state drug exposure for a one-compartment pharmacokinetic (PK) model with sigmoidal Hill elimination, focusing on three key topics: the comparison between steady-state drug exposure of repeated intravenous (IV) bolus ( ) and total drug exposure after a single IV bolus ( ); the evolution of steady-state drug concentration with varying dosing frequencies; and the control of drug pharmacokinetics in multiple-dose therapeutic scenarios. For the first topic, we established conditions for the existence of , derived an explicit formula for its calculation, and compared it with . For the second, we identified the trending properties of steady-state average and trough concentrations concerning dosing frequency. For the third, we developed formulae to compute dose and dosing time for both regular and irregular dosing scenarios. As an example, our findings were applied to a real drug model of progesterone used in lactating dairy cows. In conclusion, these results provide a theoretical foundation for designing rational dosage regimens and conducting therapeutic trials.

Comparison of Vancomycin AUC24 Calculation Methods for Neonates and Infants.

For neonates and infants receiving intermittent vancomycin infusions, the area under the concentration-timecurve during 24 h (AUC24) is often estimated with Bayesian forecasting using one or more measured vancomycin concentrations. When practical peak and trough concentrations are measured at steady state, AUC24 can also be calculated with first-order steady-state equations for a one-compartment model (Sawchuk-Zaske method), but previously this method has been applied only for adults. The objective of this studywas to compare AUC24 values obtained with the Sawchuk-Zaske method and two Bayesian models. AUC24 values were estimated retrospectively for 18 neonates and infants with steady-state peak and trough concentrations using traditional compartmental analysis with a one-compartment model (reference method), the Sawchuk-Zaske method, and Bayesian forecasting with two previously published models. In Bayesian forecasting, both original and modified residual error models were used. In the modified models, the residual error was reduced by setting the additive residual error to zero and the proportional error to 15%. AUC24 estimates obtained with the Sawchuk-Zaske method differed -2.7 to 0.9% from the reference method. When both peak and trough concentrations were used in Bayesian forecasting, 61% and 33% of AUC24 estimates obtained with two original models differed less than 15% from the reference method, and these fractions increased to 83% and 72% with the modified models, respectively. When practical peak and trough concentrations are measured at steady state, the simple Sawchuk-Zaske method is very useful for AUC24 estimation in neonates and infants. In Bayesian forecasting, the reduced residual error model can be used to improve the model fit.

The Influence of High Body Mass Index (BMI > 35 kg/m2) on Apixaban Plasma Concentration in Patients with Atrial Fibrillation.

Apixaban, a direct oral anticoagulant is administered for stroke prevention in atrial fibrillation patients. Dosing adjustment is guided by renal function, age, and body weight. However, no data exist on its pharmacokinetics in patients with a body mass index (BMI) ≥ 35 kg/m2. The aim was to investigate the effects of BMI ≥35 kg/m2 on trough plasma concentrations of apixaban in patients with atrial fibrillation. This prospective study compared steady-state trough concentrations of apixaban in patients with a BMI ≥35 kg/m2 and patients with a BMI <35 kg/m2. Sixty patients were included. In patients receiving 5 mg apixaban twice daily, the median trough plasma concentration was 29% lower in patients with a BMI ≥35 kg/m2 than in those with a BMI <35 kg/m2 (148.9 ng/ml, interquartile range [IQR] 94.5-205.6, compared to 209.1 ng/ml, IQR 167-266.8 ng/ml, respectively; P = 0.044). However, median trough concentrations fell within the manufacturer's predicted range for effective steady-state apixaban exposure. A similar trend was observed with 2.5 mg apixaban twice daily, although statistical significance was not reached. Multivariate analysis revealed no correlation between BMI values and trough concentrations. BMI ≥35 kg/m2 patients exhibited lower apixaban trough concentrations, while remaining within the manufacturer's established range for effective steady-state apixaban, suggesting that dose adjustment is unnecessary for this specific patient group.

Automated calculation and reporting of vancomycin area under the concentration-time curve: a simplified single-trough concentration-based equation approach.

Vancomycin, a crucial antibiotic for Gram-positive bacterial infections, requires therapeutic drug monitoring (TDM). Contemporary guidelines advocate for AUC-based monitoring; however, using Bayesian programs for AUC estimation poses challenges. We aimed to develop and evaluate a simplified AUC estimation equation using a steady-state trough concentration (Ctrough) value. Utilizing 1,034 TDM records from 580 general hospitalized patients at a university-affiliated hospital in Ulsan, we created an equation named SSTA that calculates the AUC by applying Ctrough, body weight, and single dose as input variables. External validation included 326 records from 163 patients at a university-affiliated hospital in Seoul (EWUSH) and literature data from 20 patients at a university-affiliated hospital in Bangkok (MUSI). It was compared with other AUC estimation models based on the Ctrough, including a linear regression model (LR), a sophisticated model based on the first-order equation (VancoPK), and a Bayesian model (BSCt). Evaluation metrics, such as median absolute percentage error (MdAPE) and the percentage of observations within ±20% error (P20), were calculated. External validation using the EWUSH data set showed that SSTA, LR, VancoPK, and BSCt had MdAPE values of 6.4, 10.1, 6.6, and 7.5% and P20 values of 87.1, 82.5, 87.7, and 83.4%, respectively. External validation using the MUSI data set showed that SSTA, LR, and VancoPK had MdAPEs of 5.2, 9.4, and 7.2%, and P20 of 95, 90, and 95%, respectively. Owing to its decent AUC prediction performance, simplicity, and convenience for automated calculation and reporting, SSTA could be used as an adjunctive tool for the AUC-based TDM.

A multi-centre, tolerability study of a cannabidiol-enriched Cannabis Herbal Extract for chronic headaches in adolescents: The CAN-CHA protocol

Introduction Cannabis products have been used in the management of headaches in adults and may play a role in pediatric chronic pain. Canadian pediatricians report increasing use of cannabis for the management of chronic headaches, despite no well-controlled studies to inform its dosing, safety, and effectiveness. The aim of our clinical trial is to determine the dosing and safety of a Cannabidiol (CBD)-enriched Cannabis Herbal Extract (CHE) for the treatment of chronic headaches in adolescents. Methods and analysis Youth, parents, and an expert steering committee co-designed this tolerability study. Twenty adolescents (aged 14 to 17 years), with a chronic migraine diagnosis for more than 6 months that has not responded to other therapies will be enrolled into an open label, dose escalation study across three Canadian sites. Study participants will receive escalating doses of a CBD-enriched CHE (MPL-001 with a THC:CBD of 1:25), starting at 0.2–0.4 mg/kg of CBD per day and escalating monthly up to 0.8–1.0 mg/kg of CBD per day. The primary objective of this study is to determine the safety and tolerability of CBD-enriched CHE in adolescents with chronic migraine. Secondary objectives of this study will inform the development of subsequent randomized controlled trials and include investigating the relationship between the dose escalation and change in the frequency of headache, impact and intensity of pain, changes in sleep, mood, function, and quality of life. Exploratory outcomes include investigating steady-state trough plasma levels of bioactive cannabinoids and investigating how pharmacogenetic profiles affect cannabinoid metabolism among adolescents receiving CBD-enriched CHE. Discussion This protocol was co-designed with youth and describes a tolerability clinical trial of CBD-enriched CHE in adolescents with chronic headaches that have not responded to conventional therapies. This study is the first clinical trial on cannabis products in adolescents with chronic headaches and will inform the development of future comparative effectiveness clinical trials. Trial registration CAN-CHA trial is registered with ClinicalTrials.gov with a number of register NCT05337033.

Physiologically-Based Pharmacokinetic Modeling of Total and Unbound Valproic Acid to Evaluate Dosing in Children With and Without Hypoalbuminemia.

Valproic acid (VPA) demonstrates nonlinear pharmacokinetics (PK) due to a capacity-limited protein binding, which has potential implications on its total and unbound plasma concentrations, especially during hypoalbuminemia. A physiologically based pharmacokinetic (PBPK) model was developed to assess the nonlinear dose-exposure relationship of VPA with special emphasis on pediatric patients with hypoalbuminemia. A PBPK model was first developed and evaluated in adults using PK-Sim® and MoBi® (v.11) and the scaled to children 1 year and older. The capacity-limited protein binding was characterized by second-order kinetics between VPA and albumin with a 2:1 molar ratio. All drug-specific parameters were informed by literature and optimized using published PK data of VPA. PK simulations were performed in virtual populations with normal and low albumin levels. The reported concentration-time profiles of total and unbound VPA were adequately predicted by the PBPK model across the age and dose range (3-120 mg/kg). The model was able to characterize the nonlinear PK, as the concentration-dependent fraction unbound (fu) and the related dose-dependent clearance values were well predicted. Simulated steady-state trough concentrations of total VPA were less than dose-proportional and were within the therapeutic drug monitoring range of 50-100 mg/L for doses between 30 and 45 mg/kg per day in children with normal albumin concentrations. However, virtual children with hypoalbuminemia largely failed to achieve the target exposure. The PBPK model helped assess the nonlinear dose-exposure relationship of VPA and the impact of albumin concentrations on the achievement of target exposure.

Interinstitutional Comparison of Vancomycin Area Under the Concentration-Time Curve Estimation in Korea: Need for Standardized Operational Protocols for Therapeutic Drug Monitoring Consultation.

Vancomycin, a vital antibiotic for treating gram-positive bacterial infections, requires therapeutic drug monitoring (TDM) because of its substantial pharmacokinetic variability. While traditional TDM relies on steady-state trough concentrations, recent guidelines advocate the area under the concentration-time curve (AUC) as the target index. However, detailed protocols for AUC estimation are lacking, leading to potential discrepancies among institutions. We surveyed medical institutions in Korea regarding vancomycin TDM, including AUC estimation. Nineteen participants responded to the TDM case challenge under three patient scenarios. For an ordinary patient in Case 1, the overall CV for AUC values was 0.4% when both trough and peak concentrations were included in the AUC calculation and 1.9% when utilizing only the trough concentration. For Case 2, an older patient with obesity, the corresponding CV was 6.6%. For Case 3 with multiple trough concentrations, the CV was 15.6%, reflecting variations in the selective use of data. Although the agreements in Case 1 were good, significant variability in AUC estimation was noted in cases involving atypical patient characteristics or old TDM data. Our study provides insight into the current status of vancomycin TDM in Korea and underscores the need for standardized operational protocols for AUC estimation.

Pharmacokinetic model-based assessment of factor IX prophylaxis treatment regimens in severe hemophilia B

An important aspect of improving care for people with hemophilia B (HB) is developing optimal treatment strategies. Here we aimed to provide in-silico evidence, comparing the estimated optimal posology of factor IX (FIX) products to support the patient-physician decision-making process. A population pharmacokinetic (popPK) model-based assessment comparing the performance of FIX products (rFIX, rIX-FP, rFIXFc, N9-GP) was developed. PopPK analyses were used to determine a product’s optimal posology to target predefined steady-state FIX activity trough levels in a hypothetical population of 10,000 people with severe HB. Model-derived optimal posologies were compared across several parameters including trough levels, proportion of patients per regimen and consumption, considering 64 hypothetical patient scenarios of different FIX trough level targets and ages. Results indicated a marked difference between FIX products estimated to achieve target trough levels, consumption and dosing frequencies. rIX-FP was associated with higher trough levels than rFIX and rFIXFc, at a lower weekly dose and administration frequency, across all age groups. N9-GP use in adolescents and adults was associated with lower consumption compared with rIX-FP. Insights from this study may be utilized by clinicians to inform decision-making, by considering the model-generated estimated optimal posologies alongside multiple clinical factors and patient preferences.

Influence of C-reactive protein on the pharmacokinetics of voriconazole in relation to the CYP2C19 genotype: a population pharmacokinetics analysis.

Voriconazole is a broad-spectrum triazole antifungal agent. A number of studies have revealed that the impact of C-reactive protein (CRP) on voriconazole pharmacokinetics was associated with the CYP2C19 phenotype. However, the combined effects of CYP2C19 genetic polymorphisms and inflammation on voriconazole pharmacokinetics have not been considered in previous population pharmacokinetic (PPK) studies, especially in the Chinese population. This study aimed to analyze the impact of inflammation on the pharmacokinetics of voriconazole in patients with different CYP2C19 genotypes and optimize the dosage of administration. Data were obtained retrospectively from adult patients aged ≥16years who received voriconazole for invasive fungal infections from October 2020 to June 2023. Plasma voriconazole levels were measured via high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS). CYP2C19 genotyping was performed using the fluorescence in situ hybridization method. A PPK model was developed using the nonlinear mixed-effect model (NONMEM). The final model was validated using bootstrap, visual predictive check (VPC), and normalized prediction distribution error (NPDE). The Monte Carlo simulation was applied to evaluate and optimize the dosing regimens. A total of 232 voriconazole steady-state trough concentrations from 167 patients were included. A one-compartment model with first order and elimination adequately described the data. The typical clearance (CL) and the volume of distribution (V) of voriconazole were 3.83L/h and 134L, respectively. The bioavailability was 96.5%. Covariate analysis indicated that the CL of voriconazole was substantially influenced by age, albumin, gender, CRP, and CYP2C19 genetic variations. The V of voriconazole was significantly associated with body weight. An increase in the CRP concentration significantly decreased voriconazole CL in patients with the CYP2C19 normal metabolizer (NM) and intermediate metabolizer (IM), but it had no significant effect on patients with the CYP2C19 poor metabolizer (PM). The Monte Carlo simulation based on CRP levels indicated that patients with high CRP concentrations required a decreased dose to attain the therapeutic trough concentration and avoid adverse drug reactions in NM and IM patients. These results indicate that CRP affects the pharmacokinetics of voriconazole and is associated with the CYP2C19 phenotype. Clinicians dosing voriconazole should consider the patient's CRP level, especially in CYP2C19 NMs and IMs.

Characterization of mavacamten pharmacokinetics in patients with hypertrophic cardiomyopathy to inform dose titration.

Mavacamten is a selective, allosteric, reversible cardiac myosin inhibitor that has been developed for the treatment of adults with symptomatic obstructive hypertrophic cardiomyopathy (HCM). A population pharmacokinetic (PopPK) model was developed to characterize mavacamten pharmacokinetics (PK) and the variation in mavacamten exposure associated with intrinsic and extrinsic factors. Data from 12 clinical studies (phases 1, 2, and 3) were used. Evaluable participants were those who had at least one mavacamten concentration measurement with associated sampling time and dosing information. The base model included key covariates: body weight, cytochrome P450 isozyme 2C19 (CYP2C19) phenotype with respect to PK, and formulation. The final model was generated using stepwise covariate testing and refinement processes. Simulations were performed to evaluate PK: apparent clearance (CL/F); apparent central and peripheral volumes of distribution; and steady-state average, trough, and maximum concentrations. Overall, 9244 measurable PK observations from 497 participants were included. A two-compartment model structure was selected. After stepwise covariate model building and refinement, additional covariates included were: specified mavacamten dose, omeprazole or esomeprazole administration, health/disease status, estimated glomerular filtration rate, fed status, and sex. The final PopPK model accurately characterized mavacamten concentrations. At any given dose, CYP2C19 phenotype was the most influential covariate on exposure parameters (e.g., median CL/F was reduced by 72% in CYP2C19:poor metabolizers compared with the reference participant [CYP2C19:normal metabolizer]). CL/F was also approximately 16% higher in women than in men but lower in participants receiving concomitant omeprazole or esomeprazole (by 33% and 42%, respectively) than in participants not receiving such concomitant therapy.

Association between Extended Meropenem Regimen and Achievement of Aggressive PK/PD in Patients Receiving Continuous Renal Replacement Therapy for Septic AKI.

Aggressive pharmacokinetic (PK)/pharmacodynamic (PD) targets have shown better microbiological eradication rates and a lower propensity to develop resistant strains than conservative targets. We investigated whether meropenem blood levels, including aggressive PK/PD, were acceptable in terms of efficacy and safety using a meropenem regimen of 1 g infusion every 8 h over 3 h in patients undergoing continuous renal replacement therapy (CRRT) for septic acute kidney injury (AKI). Aggressive PK/PD targets were defined as the percentage of time that the free concentration (%fT) > 4 × minimal inhibitory concentration (MIC), the toxicity threshold was defined as a trough concentration >45 mg/L, and the percentage of achievement at each MIC was evaluated. The 100% fT > 4 × MIC for a pathogen with an MIC of 0.5 mg/L was 89%, and that for a pathogen with an MIC of 2 mg/L was 56%. The mean steady-state trough concentration of meropenem was 11.9 ± 9.0 mg/L and the maximum steady-state trough concentration was 29.2 mg/L. Simulations using Bayesian estimation showed the probability of achieving 100% fT > 4 × MIC for up to an MIC of 2 mg/L for the administered administration via continuous infusion at 3 g/24 h. We found that an aggressive PK/PD could be achieved up to an MIC of 0.5 mg/L with a meropenem regimen of 1 g infused every 8 h over 3 h for patients receiving CRRT for septic AKI. In addition, the risk of reaching the toxicity range with this regimen is low. In addition, if the MIC was 1-2 mg/L, the simulation results indicated that aggressive PK/PD can be achieved by continuous infusion at 3 g/24 h without increasing the daily dose.

Optimal dosing regimen of caspofungin in adolescents with allogeneic haematopoietic stem cell transplantation.

The optimal dosing regimen of caspofungin in adolescents undergoing allogeneic haematopoietic stem cell transplantation against Candida spp. is unknown. The study aimed to compare body surface area (BSA)-based and fixed dosing regimens through population pharmacokinetic (PPK) analysis and to optimize dosing regimens likely to achieve therapeutic exposures. Opportunistic sampling was used to collect plasma concentrations through a prospective observational pharmacokinetic study. PPK analysis and Monte Carlo simulations (n = 1000) were performed using NONMEM. A total of 86 samples of 30 adolescents (12-17 years old) were best described by a two-compartment pharmacokinetic model. BSA is the only covariate on clearance and central volume of distribution. For Candida glabrata and Candida albicans, a standard dosing regimen could achieve at least a 90% probability of target attainment for the indicator of AUC0-24/MIC90. Dosing regimen simulations identified a BSA cut-off value of 1.3 m2, where a fixed loading dose (LD) is preferred when BSA ≥ 1.3 m2 and a BSA-based LD is preferred when BSA < 1.3 m2. For maintenance dose (MD), however, the BSA-based dose was proposed, regardless of BSA. The current maximum dosing regimen of LD 70 mg/day and MD 70 mg/day could not result in sufficient antifungal exposure for Candida parapsilosis with MIC90 of 1 mg/L. Furthermore, an LD of 70 mg/day and MD of 60 mg/m2/day rendered 90.4% steady-state trough concentration (Ctrough) over 1 mg/L in the virtual population. Our study proposed optimized dosing regimens of caspofungin based on AUC0-24/MIC90 or Ctrough, which may support further individualized treatment.

Intravenous Golimumab in Children With Polyarticular-Course Juvenile Idiopathic Arthritis: Long-Term Extension of an Open-Label Phase III Study.

To report pharmacokinetics (PK), immunogenicity, clinical effect, and safety of intravenous (IV) golimumab in children with active polyarticular-course juvenile idiopathic arthritis (pcJIA) who participated in A Study to Evaluate the Pharmacokinetics, Efficacy and Safety of Intravenous Golimumab in Pediatric Participants With Active Polyarticular Course Juvenile Idiopathic Arthritis Despite Methotrexate Therapy (GO-VIVA)'s open-label, long-term extension (LTE) through week 252. GO-VIVA participants who continued IV golimumab (80 mg/m2 every 8 weeks) after week 52 were included. PK and safety were assessed through week 244 (last dose) and week 252, respectively, and clinical response through week 116. Clinical outcomes included JIA-American College of Rheumatology (ACR) responses and clinical Juvenile Arthritis Disease Activity Score in 10 joints (cJADAS10). Binary outcomes used nonresponder imputation, and other descriptive analyses used observed data. Of 112/127 (88.2%) participants entering the LTE, 69 completed the week 252 visit. Median steady-state trough golimumab concentrations were generally maintained from week 52 through week 244 (range 0.3-0.6 μg/mL). Antigolimumab antibody rates were consistent through week 52 (39.2% [49/125]) and week 244 (44.8% [56/125]). Week 52 JIA-ACR 30/50/70/90 response rates (75.6% [96/127], 74% [94/127], 65.4% [83/127], and 48.8% [62/127], respectively) were generally maintained through week 116 (72.4% [92/127], 71.7% [91/127], 63.8% [81/127], and 50.4% [64/127], respectively), when the median cJADAS10 was 1.6 and 56.7% (72/127) of participants achieved cJADAS10 ≤ 5 (minimal disease activity). Rates (per 100 patient-years) of serious adverse events and serious infections through week 252 were 7.7 and 3.9, respectively. GO-VIVA LTE participants experienced adequate PK exposure and stable safety and immunogenicity. The majority of participants experienced no more than minimal residual disease activity. Data suggest IV golimumab treatment provided durable clinical response through week 116, with an acceptable risk-benefit profile.

Population pharmacokinetics of Ainuovirine and exposure-response analysis in human immunodeficiency virus-infected individuals.

Ainuovirine (ANV) is a new generation of non-nucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus (HIV) type 1 infection. This study aimed to evaluate the population pharmacokinetic (PopPK) profile and exposure-response relationship of ANV among people living with HIV. Plasma concentration-time data from phase 1 and phase 3 clinical trials of ANV were pooled for developing the PopPK model. Exposure estimates obtained from the final model were used in exposure-response analysis for virologic responses and safety responses. ANV exhibited a nonlinear pharmacokinetic profile, which was best described by a two-compartment model with first-order elimination. There were no significant covariates correlated to the pharmacokinetic parameters of ANV. The PopPK parameter estimate (relative standard error [%]) for clearance adjusted for bioavailability (CL/F) was 6.46 (15.00) L/h, and the clearance of ANV increased after multiple doses. The exposure-response model revealed no significant correlation between the virologic response (HIV-RNA <50 copies/mL) at 48 weeks and the exposure, but the incidence of adverse events increased with the increasing exposure ( P value of steady-state trough concentration and area under the steady-state curve were 0.0177 and 0.0141, respectively). Our PopPK model supported ANV 150 mg once daily as the recommended dose for people living with HIV, requiring no dose adjustment for the studied factors. Optimization of ANV dose may be warranted in clinical practice due to an increasing trend in adverse reactions with increasing exposure. Chinese Clinical Trial Registry https://www.chictr.org.cn (Nos. ChiCTR1800018022 and ChiCTR1800019041).

Clinical pharmacokinetics and pharmacodynamics of empagliflozin in patients with heart failure.

The aim of this work is to compare empagliflozin systemic exposure between patients with heart failure (HF) and patients with type 2 diabetes (T2D). Analysis of covariance (ANCOVA) compared steady state trough concentrations of empagliflozin 10mg in EMPEROR-reduced (patients with HF with reduced ejection fraction [HFrEF]) and EMPA-REG OUTCOME (patients with T2D at high cardiovascular risk) after adjusting for eGFR and body weight. The difference in geometric Mean (gMean) empagliflozin steady state trough concentration of 10mg empagliflozin between EMPEROR-reduced and EMPA-REG OUTCOME was 1.47-fold (95% confidence interval [CI]: 1.33, 1.63). Additionally, ANCOVA for the sub-group of patients with both T2D and HF conditions revealed a difference in gMean steady state trough concentration of 1.53-fold (95% CI: 1.26, 1.85). In both patients with HFrEF and HF with preserved EF (HFpEF), there was no major difference in empagliflozin steady state trough exposure by New York Heart Association (NYHA) classification or by use of angiotensin receptor-neprilysin inhibitor as comedication. A weak positive correlation was observed for NT-proBNP at Week 12 and empagliflozin steady state trough concentration in both patients with HFrEF and HFpEF (Pearson correlation r = 0.19). Plasma concentrations of empagliflozin in patients with HF were higher compared to patients with T2D, but the exposure resulting from the 10mg dose was still below the exposure resulting from the dose of 25 mg approved in patients with T2D. The difference in exposure was attributable to demographic characteristics and HF-induced pathophysiological changes. Overall, the results confirm 10mg as the appropriate empagliflozin dose in patients with HF.

Serum Concentration-Dose Relationship and Modulation Factors in Children and Adolescents Treated with Fluvoxamine.

Fluvoxamine is used in children and adolescents ('youths') for treating obsessive compulsive disorder (OCD) but also off-label for depressive and anxiety disorders. This study aimed to investigate the relationship between fluvoxamine dose and serum concentrations, independent correlates of fluvoxamine concentrations, and a preliminary therapeutic reference range (TRR) for youths with OCD and treatment response. Multicenter naturalistic data of a therapeutic drug monitoring service, as well as prospective data of the 'TDM Vigil study' (EudraCT 2013-004881-33), were analyzed. Patient and treatment characteristics were assessed by standardized measures, including Clinical Global Impressions-Severity (CGI-S) and -Change (CGI-I), with CGI-I of much or very much improved defining treatment response and adverse drug reactions using the Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale. Multivariable regression analysis was used to evaluate the influence of sex, age, body weight, body mass index (BMI), and fluvoxamine dose on fluvoxamine serum concentrations. The study included 70 youths (age = 6.7-19.6 years, OCD = 78%, mean fluvoxamine dose = 140.4 (range = 25-300) mg/d). A weak positive correlation between daily dose and steady-state trough serum concentrations was found (rs = 0.34, p = 0.004), with dose variation explaining 16.2% of serum concentration variability. Multivariable correlates explaining 25.3% of the variance of fluvoxamine concentrations included higher fluvoxamine dose and lower BMI. Considering responders with OCD, the estimated TRR for youths was 55-371 ng/mL, exceeding the TRR for adults with depression of 60-230 ng/mL. These preliminary data contribute to the definition of a TRR in youth with OCD treated with fluvoxamine and identify higher BMI as a moderator of lower fluvoxamine concentrations.

Interaction of age and CYP2C19 genotypes on voriconazole steady-state trough concentration in Chinese patients.

Both age and CYP2C19 genotypes affect voriconazole plasma concentration; the interaction of age and CYP2C19 genotypes on voriconazole plasma concentration remains unknown. This study aims to investigate the combined effects of age and CYP2C19 genotypes on voriconazole plasma concentration in Chinese patients. A total of 480 patients who received voriconazole treatment were recruited. CYP2C19*2 (rs4244285) and CYP2C19*3 (rs4986893) polymorphisms were genotyped. Patients were divided into the young and the elderly groups by age of 60 years old. Influence of CYP2C19 genotype on steady-state trough concentration (C ss-min ) in overall patients and in age subgroups was analyzed. Voriconazole C ss-min correlated positively with age, and mean voriconazole C ss-min was significantly higher in the elderly group ( P < 0.001). CYP2C19 poor metabolizers showed significantly increased mean voriconazole C ss-min in the young but not the elderly group. The percentage of patients with subtherapeutic voriconazole C ss-min (<1.0 mg/l) was higher in the young group and that of supratherapeutic voriconazole C ss-min (>5.5 mg/l) was higher in the elderly patients. When the average C ss-min in the CYP2C19 normal metabolizer genotype was regarded as a reference, CYP2C19 genotypes showed greater impact on voriconazole C ss-min in the young group, while the influence of age on voriconazole C ss-min exceeded CYP2C19 genotypes in the elderly. CYP2C19 genotypes affects voriconazole exposure is age dependent. Influence of CYP2C19 poor metabolizer genotype on increased voriconazoleexposure is prominent in the young, while age is a more important determinant factor for increased voriconazole exposure in the elderly patients.

CYP1A2 Polymorphism and Drug Co-administration Affect the Blood Levels and Adverse Effects of Pirfenidone

Background: Mutations in metabolic enzymes and co-administration of drugs may affect the blood concentration of pirfenidone effective in pulmonary fibrosis. To provide a basis for the precise clinical use of pirfenidone, the authors analyzed the correlation between steady-state pirfenidone trough concentration and adverse drug reactions (ADRs) and examined the impact of CYP1A2*1C (rs2069514) and *1F (rs762551) variants and co-administration on pirfenidone blood concentrations and ADRs. Methods: Forty-four patients were enrolled. The blood concentration of pirfenidone was determined using high-performance liquid chromatography. CYP1A2*1C and *1F genotypes were determined using direct SNP sequencing. Additional information related to drug associations was collected to screen factors affecting drug metabolism. Results: The highest predictive value of ADRs was observed when the steady-state trough concentration of pirfenidone was 3.18 mcg·mL−1 and the area under the receiver operating characteristic curve was 0.701 (P = 0.024). The pirfenidone concentration-to-dose ratio (C/D) in CYP1A2*1F homozygous AA mutants was lower than that in C carriers (CC+AC) (1.28 ± 0.85 vs. 2.03 ± 1.28 mcg·mL−1; P = 0.036). Adverse drug reaction (ADR) incidence in the homozygous AA mutant group (28.0%) was significantly lower than that in the C carriers (CC+AC) (63.2%; P = 0.020), and ADR incidence in the A carriers (AC+AA) was considerably lower than that in the CC group (85.7%; P = 0.039). The C/D value of the combined lansoprazole/rabeprazole group was lower than that of the noncombination group (P &lt; 0.05). Conclusions: The ADR incidence was positively correlated with pirfenidone blood concentration. The CYP1A2 (rs762551) AA genotype is associated with lower pirfenidone concentrations and fewer ADRs. Lansoprazole/rabeprazole co-administration reduced pirfenidone concentrations. Randomized controlled trials should further explore personalized dosing of pirfenidone and combination therapies.

Development and validation of a deep learning-based model to predict response and survival of T790M mutant non-small cell lung cancer patients in early clinical phase trials using electronic medical record and pharmacokinetic data.

Epidermal growth factor receptor (EGFR) T790M mutation is the standard predictive biomarker for third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment. While not all T790M-positive patients respond to third-generation EGFR-TKIs and have a good prognosis, it necessitates novel tools to supplement EGFR genotype detection for predicting efficacy and stratifying EGFR-mutant patients with various prognoses. Mixture-of-experts (MoE) is designed to disassemble a large model into many small models. Meanwhile, it is also a model ensembling method that can better capture multiple patterns of intrinsic subgroups of enrolled patients. Therefore, the combination of MoE and Cox algorithm has the potential to predict efficacy and stratify survival in non-small cell lung cancer (NSCLC) patients with EGFR mutations. We utilized the electronic medical record (EMR) and pharmacokinetic parameters of 326 T790M-mutated NSCLC patients, including 283 patients treated with Abivertinib in phase I (n=177, for training) and II (n=106, for validation) clinical trials and an additional validation cohort 2 comprising 43 patients treated with BPI-7711. Furthermore, 18 patients underwent whole-exome sequencing for biological interpretation of CoxMoE. We evaluated the predictive performance for therapeutic response using the area under the curve (AUC) and the Concordance index (C-index) for progression-free survival (PFS). CoxMoE exhibited AUCs of 0.73-0.83 for predicting efficacy defined by best overall response (BoR) and achieved C-index values of 0.64-0.65 for PFS prediction in training and validating cohorts. The PFS of 198 patients with a low risk [median, 6.0 (range, 1.0-23.3) months in the abivertinib treated cohort; median 16.5 (range, 1.4-27.4) months in BPI-7711 treated cohort] of being non-responder increased by 43% [hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.40-0.78; P=0.0013] and 50% (HR, 0; 95% CI, 0-0; P=0.01) compared to those at high-risk [median, 4.2 (range, 1.0-35) months in the abivertinib treated cohort; median, 11.0 (range, 1.4-25.1) months in BPI-7711 treated cohort]. Additionally, activated partial thromboplastin time (APTT), creatinine clearance (Ccr), monocyte, and steady-state plasma trough concentration utilited to construct model were found significantly associated with drug resistance and aggressive tumor pathways. A robust correlation was observed between APTT and Ccr with PFS (log-rank test; P<0.01) and treatment response (Wilcoxon test; P<0.05), respectively. CoxMoE offers a valuable approach for patient selection by forecasting therapeutic response and PFS utilizing laboratory tests and pharmacokinetic parameters in the setting of early-phase clinical trials. Simultaneously, CoxMoE could predict the efficacy of third-generation EGFR-TKI non-invasively for T790M-positive NSCLC patients, thereby complementing existing EGFR genotype detection.

Contribution of genetic polymorphism in ABCB1 to individual variations of imatinib plasma levels in patients with gastrointestinal stromal tumor.

Imatinib mesylate (IM) is a first-line treatment option for the majority of patients diagnosed with gastrointestinal stromal tumors (GISTs). Although the clinical benefit is high, interindividual response is variable. This study thus aimed to assess how genetic polymorphisms can affect the blood levels of IM and treatment outcomes in patients with GIST. A total of 31 single-nucleotide polymorphisms (SNPs) in selected cytochrome P450 (P450), ATP-binding cassette transporter (ABC), solute carrier family (SLC), interleukin-4 receptor (IL4R), and vascular endothelial growth factor (VEGF) genes were genotyped using an SNP mass array platform. A total of 192 consecutive patients with GIST who received 400 mg of IM daily were enrolled into the study, with 1,485 blood samples being analyzed. According to genotypes, IM trough concentrations were tested and compared. Progression-free survival (PFS) and overall survival (OS) were also assessed. With a mean follow-up of 75.99 months, trough concentrations of imatinib were examined at average time points of 7.73 for each patient. Polymorphism in ABCB1 rs1045642 was found to be associated with steady-state IM trough plasma levels (P=0.008). Patients with the C genotype (CT + CC) of rs1045642 exhibited higher IM trough concentrations (1,271.09±306.69 ng/mL) compared to those with the TT genotype (1,106.60±206.05 ng/mL). No statistically significant differences in IM plasma concentration were observed for the other SNPs tested. None of the tested SNPs displayed a significant association with patients' survival in this study. This is the largest cohort study evaluating the associations of SNP and imatinib blood trough levels. The ABCB1 rs1045642 genetic polymorphism may exert an effect on the pharmacokinetics of imatinib. The presence of the C allele in ABCB1 rs1045642 is predictive of a higher plasma concentration of IM.