Population Pharmacokinetics Research Articles

Population pharmacokinetics of fluconazole for prevention or treatment of invasive candidiasis in Chinese young infants.

The dosing of fluconazole for young infants remains empirical because of the limited pharmacokinetic (PK) data. We aimed to establish a population PK model and assess the systematic exposure-response of commonly used regimens of fluconazole in Chinese infants.We included infants with a postnatal age of less than 120 days and received intravenous fluconazole. Both scheduled and scavenged plasma samples were collected, and fluconzaole concentration was determined by a validated ultra-performance liquid chromatography-tandem mass spectrometry assay. Population PK analysis was conducted using Phoenix NLME, and then Monte Carlo simulation was conducted to predict the probability of target attainment (PTA) of empirically used regimens of both prophylactic and therapeutic purposes.Based on 304 plasma samples from 183 young infants, fluconazole concentration data was best described by a one-compartment model with first-order elimination. Gestational Age (GA), postnatal age (PNA), and body weight (BW) were included in the final model as CL = 0.02*(GA/214)2.77*(PNA/13)0.24*exp(nCL); V = 1.56*(BW/1435)0.90*exp(nV). Model validation revealed the final model had qualified stability and acceptable predictive properties. Monte Carlo simulation indicated that under the same minimum inhibitory concentration (MIC) value and administration regimen, PTA decreased with GA and PNA. The commonly used prophylactic regimens can meet the clinical need, while higher doses might be needed for treatment of invasive candidiasis.This population PK model of fluconazole discriminated the impact of GA and PNA on CL and BW on V. Dosing adjustment was needed according to the GA and PNA of infants to achieve targeted exposures.

Population pharmacokinetics and clinical evaluation of acetaminophen and metabolites after intravenous administration in horses

Population pharmacokinetics and clinical evaluation of acetaminophen and metabolites after intravenous administration in horses

Establishment and validation of a population pharmacokinetic model for apatinib in patients with tumors

ObjectiveThis study aimed to develop a population pharmacokinetic (PPK) model for oral apatinib in Chinese oncology patients and investigate the factors influencing the pharmacokinetics of apatinib.MethodsWe gathered 199 blood concentration monitoring data points from 91 inpatient oncology participants receiving oral apatinib at the Third Affiliated Hospital of Soochow University. Covariates, such as age, gender, body weight, and indices of liver and renal function, were examined to assess their influence on the pharmacokinetic parameters of apatinib. The PPK model was developed using the nonlinear mixed-effects modeling procedure (NONMEM), and model validation was conducted using the bootstrap method and normalized prediction distribution error (NPDE) method.ResultsThe structural model adopted a one-compartment structure with first-order elimination. Notably, aspartate aminotransferase (AST) and the co-administered drug type emerged as primary covariates affecting apatinib clearance (CL/F). The finalized model was expressed as CL/F (L/h) = 56.7 × (AST/26.6)−0.298 × θ, when apatinib was combined with monoclonal antibodies, θ was 1; when combined with paclitaxel, θ was 0.58; when combined with other drugs (e.g., platinum, capecitabine, or the combination of tegafur, gimeracil, and oteracil potassium), θ was 1.60; When used as monotherapy, θ was 1.38. V/F = 674 L, and the absorption rate constant (Ka) was fixed at 0.08 h−1. Bootstrap results affirmed the model’s reliability and stability, while NPDE outcomes attested to the model’s fit.ConclusionOur study successfully established a PPK model for apatinib in oncology patients, revealing that liver function status and co-administered drug types significantly impacted apatinib CL/F. This finding underscored the potential necessity for dose adjustments to optimize efficacy, particularly in patients undergoing different chemotherapy regimens involving apatinib.

Dosing strategy of tacrolimus when co-administered with Wuzhi tablet in renal transplant recipients.

Tacrolimus (TAC) is a first-line immunosuppressant to prevent allograft rejection. Wuzhi tablet is widely used as a TAC-sparing agent in China that could significantly elevate TAC exposure. However, insufficient data support the dose recommendation of TAC when co-administered with Wuzhi. A total of 305 adult renal transplant patients with 2,541 TAC trough concentrations (C0) were enrolled for population pharmacokinetic (PPK) modeling. CYP3A5 polymorphism was genotyped, and corresponding clinical factors were recorded. Nonlinear mixed-effects modeling and Monte Carlo simulation were used for dose recommendation. PK parameters were calculated based on one-compartment model with first-order absorption and elimination. The estimated total clearance (CL/F) and volume of distribution (Vd/F) of TAC were 23.84 L/h and 1,075.96 L, respectively. Wuzhi, CYP3A5 genotype, hematocrit (HCT), and weight were found to have a significant influence on CL/F. CL/F was significantly lower in the individuals who were CYP3A5 non-expressers and received TAC together with Wuzhi. CYP3A5 genotype (expressers or non-expressers), body weight (40-80 kg), and hematocrit (20 - 40%) were selected as the specific clinical scenarios, and the starting dose of TAC ranged from 1.5 to 4.5 mg when co-administered with Wuzhi. We establish a TAC PPK model comprising Wuzhi as a covariate in renal transplant recipients and recommend an initial dose of TAC when co-administered with Wuzhi, which could provide reference for the individualized regimens of TAC.

Exposure Matching-Based Pediatric Dose Selection for Drugs with Renal Excretion - Lessons Learned from Pediatric Development of Direct Oral Anticoagulants.

The pediatric clinical development programs of the direct oral anticoagulants (DOACs) edoxaban, rivaroxaban, and dabigatran have recently been completed, with apixaban close to the finish line. One common pharmacokinetic (PK) characteristic of these four DOACs is that renal excretion contributes 27% or more in their elimination, resulting in age-dependent drug clearance in both pediatric and adult subjects. Several lessons have been learned from adult exposure matching and pediatric dose selection for DOACs. The main goal of this tutorial is to provide an informed perspective on pediatric dose selection for renally excreted drugs, using these four DOACs as case examples. This tutorial is organized into seven steps: (1) consideration of age-related differences in disease and response to treatment; (2) consideration of age-related differences in drug absorption, distribution, metabolism, and excretion; (3) selection of the reference adult population and exposure for pediatric exposure matching; (4) prediction of pediatric clearance and pediatric dose selection based on data from young adults; (5) conduct and design of efficient pediatric PK and pharmacodynamic (PD) studies that inform dose selection; (6) assessment of exposure matching and dose adjustment using population PK simulation; (7) evaluation of the need for dose adjustment in pediatric sub-populations.

Population pharmacokinetic and pharmacodynamic model of evogliptin: Severe uremia increases the bioavailability ofevogliptin.

Uremia, a condition characterized by the retention of uremic toxins due to impaired renal function, may affect drug metabolism mediated by CYP3A4 enzymes. Evogliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor diabetic drug that is primarily metabolized by CYP3A4. This study aimed to construct a population pharmacokinetic (PK) and pharmacodynamic (PD) model for evogliptin in patients with varying degrees of renal disease, including end-stage renal disease on hemodialysis. A total of 688 evogliptin concentration and 598 DPP-4 activity data were available from 46 subjects. PK and PD data analyses were performed using a nonlinear mixed-effects model. The PK of evogliptin was optimally described by a two-compartment model with first-order absorption. The significant covariates in the final model included blood amylase and triglyceride on F1 (relative bioavailability). The simulation findings, together with previously reported PK data, provided evidence of a significant inhibition of the first-pass effect of evogliptin in patients with renal impairment. A direct link sigmoidal Emax model was developed to describe the relationship between evogliptin concentration and DPP-4 inhibition. The PD model predicted significant inhibition of DPP-4 at maximum effect (Emax: 88.9%) and a low EC50 value (1.08 μg/L), indicating the high potency and efficacy of evogliptin. The developed PK/PD model accurately predicted exposure and the resulting DPP-4 activity of evogliptin in renal impairment. The findings of this study suggest that renal impairment and associated biochemical changes may impact the bioavailability of CYP3A4-metabolized drugs.

Characterisation of the pharmacokinetic and pharmacodynamic relationship of milvexian in total knee replacement patients

Abstract Background Milvexian, an oral factor XIa inhibitor, is currently being evaluated in patients at risk for thrombotic events due to atrial fibrillation, ischaemic stroke, or acute coronary syndrome. The exposure-response relationship between clinical efficacy and safety endpoints and milvexian pharmacokinetic (PK) metrics was recently submitted as a separate publication. Characterisation of the relationship between the coagulation pharmacodynamic (PD) markers versus milvexian PK metrics at the patient level has yet to be reported. Purpose This analysis characterised the relationship between the coagulation biomarkers, activated partial thromboplastin time (aPTT) and prothrombin time (PT), and milvexian systemic exposure in patients undergoing total knee replacement (TKR) evaluated in the AXIOMATIC-TKR study. Methods A population pharmacokinetic (PopPK) model was previously developed and characterised the PK of milvexian in TKR patients well. The PK/PD relationships between observed aPTT and PT versus PopPK model estimated time-matched milvexian plasma concentrations via nonlinear mixed effects modeling. The relationship between key clinical safety endpoints (e.g., any bleeding or clinically relevant non-major bleeding) and individual PD marker change (e.g., aPTT ratio to baseline) was also explored. Results The aPTT increased with increasing plasma concentration of milvexian over the range of doses evaluated in the study (25mg QD to 200mg BID). An Emax type of model reasonably characterised the PK/PD relationship between the aPTT and model predicted time-matched milvexian plasma concentration, which is consistent with previously observed relationships in healthy volunteers. No change was observed in PT with increased milvexian exposure. No obvious relationship was identified between any (including clinically relevant non-major) bleeding and aPTT ratio to baseline. Conclusions Increased milvexian exposure is directly correlated with aPTT prolongation over the range of doses evaluated in the TKR study. There was no obvious relationship between any (including clinically relevant non-major) bleeding and aPTT ratio. The PK/PD relationship of aPTT without a parallel relationship in PT distinguishes milvexian, a FXIa inhibitor, from previously studied FXa inhibitors. These analyses were a complementary component in dose selection for the milvexian Phase 3 program. Figure 1. PK/PD relationship between aPTT (left) and PT (right) and estimated time-matched plasma concentration (AXIOMATIC-TKR study)

Sulcardine, an investigational multichannel blocker for atrial fibrillation with uniquely intense JTp inhibition to enhance safety

Abstract Background Sulcardine is a multi-ion channel blocker for treating atrial fibrillation (AF) with similar inhibitory potency on peak/late sodium, L-type calcium, and rapidly activating delayed-rectifier potassium (IKr) currents. The therapeutic effect of inhibiting IKr includes QT prolongation (accompanied by a proportional J to T peak [JTp] interval prolongation), which, when excessive, may cause malignant arrhythmias. As previously reported, sulcardine strongly mitigates the JTp increase that may contribute to excessive QT prolongation by inhibiting late sodium and L-type calcium currents, an intrinsic mechanism to protect from excessive IKr block. Purpose We explored the JTp mechanism, pharmacokinetics (PK), electrocardiogram (ECG) changes, safety, and drug-drug interaction (DDI) of a single sulcardine (as HBI-3000) intravenous (IV) infusion in healthy subjects. Methods An open-label Phase 1 study evaluated the PK interaction between sulcardine, dosed as a 350 mg 30-minute infusion of the sulfate salt HBI-3000, and a cytochrome P450 CYP2D6 enzyme inhibitor (paroxetine). Triplicate ECGs were extracted from continuous 12-lead Holter ECG recordings at baseline and 10 time points thereafter. Mean baseline-subtracted and heart rate-corrected QTcF (dQTcF), JTpc (dJTpc), and other ECG changes were calculated at each time point. Left ventricular ejection fraction (LVEF) was assessed at baseline, 30-, and 120-minutes post-infusion start by transthoracic echocardiography (TTE). Results 39 subjects received HBI-3000, 33 in the paired PK population. Expected ECG parameter changes proportional to sulcardine plasma concentrations were observed in the HBI-3000-alone portion of the study, including modest QTcF prolongation (Fig 1, blue slope, confidence band) and JTpc inhibition (Fig 1, red). The usual JTpc increase associated with IKr blockers, even those with mitigating channel block (such as the late sodium current), was not only reduced but actually reversed. We calculated the dQTcF change that would have been observed in the absence of JTpc reduction by sulcardine (Fig 1, green). Sulcardine reduced the QTcF increase that might have occurred by about 21 msec at the highest concentrations, and this mitigating effect was observed at all concentrations. No clinically significant safety findings or arrhythmias were observed. The most frequent TEAEs were nausea and headache (n=2 each [5.1%]). No LVEF changes were clinically significant. Sulcardine had minimal metabolic interactions. Conclusion Acute IV HBI-3000 administration resulted in no clinically significant safety findings, LVEF depression, or DDI with CYP2D6. Sulcardine facilitates QT prolongation, which has a therapeutic benefit in terminating AF, with simultaneous uncoupling and reversing of the JTpc interval increase, a potential mechanism for reducing proarrhythmic risk due to excessive QT prolongation.Figure 1.ECG Intervals vs Sulcardine Conc

Population Pharmacokinetic Modelling of Norepinephrine in Healthy Volunteers Prior to and During General Anesthesia.

Intraoperation hypotension (IOH) is commonly observed in patients undergoing surgery under general anesthesia, and even a brief episode of IOH can lead to unfavorable outcomes. To reduce the risk, blood pressure is closely measured during general anesthesia, and norepinephrine (NE) is frequently administered if hypotension is detected. Despite its routine application, information on the dose-exposure-response relationship of NE remains limited. Additionally, quantification of the influence of general anesthesia on the pharmacokinetics (PK) of NE is lacking. In this study, we aimed to describe NE PK in healthy volunteers and the influence of general anesthesia on its PK. A single-center, cross-over study was conducted in healthy volunteers. The volunteers received a step-up NE dosing scheme (0.04, 0.08, 0.12, 0.16 and 0.20 mcg-1/kg-1/min-1) first in the awake state and then under general anesthesia. General anesthesia was administered using a propofol/remifentanil Eleveld target-controlled infusion. During general anesthesia, a 30-second electrical stimulus was given as surrogate for surgical incision to the volunteers at each dosage step. Blood samples were drawn before the initial dosing and after each dosing step, and plasma NE, propofol and remifentanil concentrations were subsequently determined. A population PK model was developed using non-linear mixed effects modelling. Simulations were conducted to predict the plasma NE concentration in patients at different measured propofol concentrations. A total of 1219 samples were analyzed from 36 volunteers. A two-compartment model with a first-order elimination best described the data. Weight, age, and session effect (awake vs general anesthesia) were identified as relevant covariates on the clearance (CL) of NE. A 10% decrease in NE CL was observed after general anesthesia induction. This difference between sessions is better explained by the measured concentration of propofol, rather than the anticipated impact of cardiac output. The estimated post-stimulation NE concentration is 0.66 nmol/L-1 (95% CI 0.06-1.20 nmol/L-1) lower than the pre-stimulation NE concentration. Model simulation indicates that patients at a higher measured propofol concentration (e.g., 6 mcg/mL-1) exhibited higher NE concentrations (95% PI 18.10-43.89 nmol/L-1) than patients at a lower measured propofol concentration (e.g., 3 mcg/mL-1) (95% PI 16.81-38.91 nmol L-1). The NE PK is well described with a two-compartment model with a first-order elimination. NE CL exhibiting a 10% decrease under general anesthesia, with this difference being attributed to the measured concentration of propofol. The impact of stimulation on NE PK under general anesthesia is very limited. NL9312.

Population pharmacokinetic modeling study and discovery of covariates for the antidepressant sertraline, a serotonin selective reuptake inhibitor

The purpose of this study was to discover effective covariates related to explanation of inter-individual pharmacokinetic (PK) variations through population pharmacokinetic (Pop-PK) modeling for sertraline and to provide insight into establishing scientific regimen. The bioequivalence results of sertraline performed on 24 healthy Korean men and the physiological and biochemical parameters derived from each individual were used as data to develop a Pop-PK model of sertraline for Koreans. And the relevant effectiveness of ∗10 allele polymorphisms of CYP2D6 in sertraline PK polymorphisms was further confirmed through a modeling approach. The Pop-PK profiles of sertraline were explained by the basic structure of sequential 2-absorption with 1-compartment, and in terms of inter-individual PK diversity, the volume of distribution could be significantly correlated with estimated glomerular filtration rate (eGFR) and clearance with total protein levels. CYP2D6∗10 allele was not significant in interpreting sertraline PK diversity. As a result of model simulation, the concentration of sertraline in serum significantly increased as total protein and eGFR levels became higher and lower, respectively. The mean serum concentrations of sertraline at steady-state differed by up to 2.12 times from 10.36 to 22.02 ng/mL depending on changes in total protein and eGFR levels, and the fluctuations between the maximum and minimum concentration values ranged from 2.02 to 29.51 to 4.31–63.78 ng/mL. The factor that significantly influenced change in mean serum concentration of sertraline at steady-state was the total protein level, which was interpreted to be closely related to the change in clearance due to the high serum protein binding of sertraline.

Identification of vancomycin exposure target in neonates: how much is enough?

Vancomycin is commonly used in neonates with the same pharmacokinetics/pharmacodynamics (PK/PD) target as adults. However, no evidence supports this practice, and the association between trough concentrations and treatment outcomes has been widely questioned. This study aimed to identify the optimal PK/PD predictor and assess the correlation between AUC/MIC, trough concentration and the vancomycin efficacy in neonates. This study retrospectively collected neonates who used vancomycin and constructed a population pharmacokinetic (PPK) model to estimate the AUC. Logistic analyses were used to identify the variables related to efficacy. Classification and regression tree analysis was used to explore thresholds. The correlation between trough concentration and AUC/MIC on the first day was analysed using a linear regression model. PPK modelling involved 131 neonates. Postmenstrual age and current weight were included in the covariate analysis. Forty-eight patients were included in the efficacy analysis, 13 of whom were infected with MRSA. The best-performance PK/PD target for efficacy was AUC0-24 h/MIC ≥ 331. The trough concentration was correlated with AUC0-24 h/MIC (r2 = 0.32), but individual differences existed. AUC0-24 h/MIC ranged up to 2.5-fold for a given trough concentration. AUC0-24 h/MIC ≥ 331 was the optimal target of vancomycin efficacy in neonates. The trough concentration was not a reliable predictor of efficacy and AUC0-24 h/MIC. AUC-guided dosage adjustments are more valuable in clinical applications.

Lefamulin dosing optimization using population pharmacokinetic and pharmacokinetic/pharmacodynamic assessment in Chinese patients with community-acquired bacterial pneumonia

PurposeLefamulin is the first pleuromutilin antibiotic approved for the treatment of community-acquired bacterial pneumonia (CABP). However, the pharmacokinetic/pharmacodynamic (PK/PD) characteristics in Chinese CABP patients are not fully understood. This study aimed to evaluate its microbiological efficacy against Streptococcus pneumoniae and Staphylococcus aureus via PK/PD analysis.MethodsThe population PK (PopPK) model, established with foreign data was validated using data from Chinese CABP patients. PK/PD analysis was conducted for the intravenous administration of 150 mg q12 h for 1-h, 1.5-h and extended 2-h infusion. Oral administrations of 600 mg q12 h were assessed, considering original and higher plasma protein binding.ResultsLefamulin displayed similar PK characteristics in both Chinese and Western populations. The PopPK model effectively predicted lefamulin concentrations in Chinese CABP patients. Under the dosage regimen of 150 mg q12 h via intravenous infusion for 1/1.5/2 h, the probability of target attainments reached 98% at the minimum inhibitory concentration for both 90% S. pneumoniae and S. aureus, considering both original and higher protein binding rates. It is advisable to extend the infusion duration from 1/1.5 h–2 h to minimize the risk of adverse effects at the infusion site. Regardless of fasted or fed conditions, the PTAs for 600 mg q12 h lefamulin via oral administration proved comparable to those for intravenous administration.ConclusionThis study proved that intravenous and oral administrations of lefamulin can reach preclinical PK/PD targets of S. pneumoniae and S. aureus. These findings support the optimal use of lefamulin for the safe and effective treatment of Chinese CABP patients.

Impact of Continuous Infusion Meropenem PK/PD Target Attainment on C-Reactive Protein Dynamics in Critically Ill Patients With Documented Gram-Negative Hospital-Acquired or Ventilator-Associated Pneumonia.

Population pharmacokinetic/pharmacodynamic (PK/PD) modelling of antibiotics including C-reactive protein (C-RP) dynamics could be helpful in predicting the efficacy of antimicrobials. We developed a PK/PD model for assessing the impact of continuous infusion (CI) meropenem PK/PD target attainment on C-RP dynamics in critically ill patients with documented Gram-negative hospital- (HAP) or ventilator-acquired pneumonia (VAP). Patients were grouped according to the type of antibiotic treatment received [meropenem monotherapy; meropenem plus empirical anti-MRSA (methicillin-resistant Staphylococcus aureus) therapy; meropenem in combination with another anti-Gram-negative active agent; meropenem plus a targeted anti-MRSA therapy]. A one-compartment population PK model of CI meropenem was developed by including all patients. A full C-RP production inhibition model was developed for fitting the PD data by including only patients receiving meropenem monotherapy or meropenem plus empirical anti-MRSA therapy. Monte Carlo simulations explored the relationship between the type of PK/PD target attainment of CI meropenem, defined as optimal (steady-state plasma concentration [Css] to minimum inhibitory concentration [MIC] ratio = 4-8), quasi-optimal (Css/MIC = 1-4) and sub-optimal (Css/MIC < 1) and the magnitude of C-RP production inhibition over time. A total of 64 patients providing 211 meropenem concentrations were included in the PK analysis, whereas 47 patients providing 328 C-RP data were included in the PD model. Simulations showed that optimal PK/PD target attainment was associated with the highest and most rapid C-RP production inhibition (44% and 56% at days 2 and 4, respectively). Conversely, sub-optimal PK/PD target attainment was shown to be almost ineffective (< 5% at day 4 and < 10% at day 10). Our PK/PD model predicted that attaining optimal PK/PD target with CI meropenem may grant prompt and intense C-RP decrease among critically ill patients receiving targeted monotherapy for Gram-negative HAP/VAP, thus anticipating efficacy.

Population pharmacokinetics of cabotegravir following intramuscular thigh injections in adults with and without HIV.

Cabotegravir intramuscular gluteal injection is approved for HIV treatment (with rilpivirine) and prevention. Thigh muscle is a potential alternative injection site. We aim to characterize cabotegravir pharmacokinetics and its association with demographics following intramuscular thigh injection in comparison with gluteal injection using population pharmacokinetic (PPK) analysis. Fourteen HIV-negative participants received 600 mg single thigh injection in phase 1 study 208832 and 118 participants with HIV received thigh injections 400 mg monthly 4× or 600 mg once-every-2-months 2× after ≥3 years of gluteal injections in phase 3b study ATLAS-2M provided 1,249 cabotegravir concentrations from 366 thigh injections and 1,998 concentrations from 1,618 gluteal injections. The established gluteal PPK model was modified by adding thigh injection compartment and fit to pharmacokinetic data following both gluteal and thigh injections, enabling within-person comparison in ATLAS-2M. Gluteal parameters were fixed. Similar to the gluteal absorption rate constant (KAgluteal), the thigh absorption rate constant (KAthigh) was slower in females than males and in participants with higher BMI. KAthigh was strongly correlated with KAgluteal (correlation coefficient 0.766), best described by the additive linear relationship KAthigh = KAgluteal + 0.0002527 h-1. Terminal half-life of thigh injection was 26% (male) and 39% (female) shorter than gluteal injection. Relative bioavailability of thigh to gluteal was estimated to be 89.9%. The impact of covariates on cabotegravir exposure following thigh injections was ≤35%. In conclusion, cabotegravir absorption following thigh injection was correlated with, faster than, and 10% less bioavailable than gluteal injection, and correlated with sex and BMI. The cabotegravir thigh PPK model can inform dosing strategies and future study design.

An IQ Industry Perspective on Informing Dosing Recommendations in Patients With Renal Impairment.

The IQ CPLG Organ Impairment WG conducted a survey to understand how various IQ member companies develop dosing recommendations for patients with renal impairment. Eighteen IQ member companies participated in the survey. The survey results were summarized by the working group in light of the regulatory renal impairment guidance documents as well as recent publications from the pharmaceutical industry and nephrology community. There were two important learnings from the survey: (i) pharmaceutical companies do not use a consistent methodology to assess renal function in their drug development programs. (ii) there has been significant improvement in predicting how kidney function affects drug pharmacokinetics (PK) and thus dose recommendations. Applying model-based methods such as population PK, physiologically-based PK (PBPK), and virtual controls has enabled earlier prediction of how kidney function influences PK, leading to the participation of more patients with impaired kidney function in Phase 2 and 3 trials.

Pharmacokinetics of Vancomycin in Healthy Korean Volunteers and Monte Carlo Simulations to Explore Optimal Dosage Regimens in Patients with Normal Renal Function.

Background/Objectives: To date, population pharmacokinetic (PK) studies of vancomycin on healthy Korean adults have not been conducted. This study aimed to investigate the PK properties of vancomycin in healthy volunteers and to identify optimal dosing regimens based on the area under the concentration-time curve (AUC) in adult patients with normal renal function. Methods: We conducted a prospective clinical study, analysing PK samples from 12 healthy participants using noncompartmental analysis and non-linear mixed-effects modelling. The population PK parameters derived were employed in Monte Carlo simulations to evaluate the adequacy of the current dosing regimen and to formulate dosing recommendations. Results: The PK profiles were optimally described by a two-compartment model, with body weight and age as significant covariates affecting total clearance. The simulations indicated that to achieve a therapeutic target-defined as an AUC at steady-state over 24 h of 400-600 mg·h/L-daily doses ranging from 60 to 70 mg/kg are necessary in adults with normal renal function. Conclusions: This study underscores the need to actively adjust dosage and administration based on a vancomycin PK model that adequately reflects the demographic characteristics of patients to meet both safety and efficacy standards.

Population Pharmacokinetic Simulations for Dose Optimization of Tenofovir Disoproxil Fumarate in HIV-Infected Patients with Moderate-to-Severe Renal Impairment.

Tenofovir disoproxil fumarate (TDF) requires dosage adjustments from the standard 300 mg once daily to every 48-96 h for moderate-to-severe renal impairment to avoid excessive exposure. However, this extended interval can lead to variable drug exposure and inconvenience. This study aimed to utilize the population pharmacokinetic (PPK) models to optimize TDF dosing regimens for HIV-infected patients with renal impairment. A systematic literature search was conducted across PubMed, Cochrane Library, and Scopus databases to identify relevant PPK studies of TDF in HIV-infected patients. From the included studies, the PPK models and associated parameters were extracted. Monte Carlo simulations (n = 2000) were performed to generate concentration-time profiles and derive PK parameters compared against reference ranges. For moderate renal impairment, the TDF 150 mg once-daily regimen achieved cumulative exposure comparable to the approved 300 mg every-other-day regimen. In severe renal impairment, TDF 75-100 mg administered once daily provided similar cumulative exposure as 300 mg every 72-96 h regimen while maintaining daily exposure comparable to the standard dose in patients with normal renal function. The approved extended dosing intervals of 72-96 h exhibited high drug exposure variability, initially resulting in supratherapeutic levels followed by suboptimal levels preceding the subsequent dose administration. In conclusion, administering smaller once-daily doses of TDF maintains consistent daily drug exposure comparable to the standard dose in patients with normal renal function while reducing variability in drug exposure, potentially mitigating the risk of nephrotoxicity. However, additional clinical studies are required to confirm these findings.

Population pharmacokinetics/pharmacodynamics of minocycline plus rifampicin in patients with complicated skin and skin structure infections caused by MRSA.

The population pharmacokinetics/pharmacodynamics (PK/PD) of minocycline, rifampicin and linezolid in patients with complicated skin and soft tissue infections (cSSTIs) caused by MRSA are described. Samples were collected in a Phase 4 study of oral minocycline plus rifampicin versus linezolid showing minocycline plus rifampicin to be non-inferior to linezolid. Antibiotics were assayed by HPLC or LC-MS, and a population PK model was developed using Pmetrics. The association between PK/PD indices and patient outcomes was explored. A three-compartment model (with an absorption compartment) with first-order input and elimination best described the data for the three drugs. No covariates were included in the final model. The population median values (95% credibility limits) of the clearance and volume of distribution were 7.412 L/h (5.121-8.361) and 14.155 L (6.799-33.901) for minocycline, 5.683 L/h (3.703-7.726) and 7.736 L (6.031-8.948) for rifampicin, and 1.970 L/h (1.326-2.499) and 20.169 L (12.857-32.629) for linezolid, respectively. Maximum a posteriori probability-Bayesian estimation plots of observed versus predicted had a slope of 0.999 r20.967 for minocycline, slope 0.998 r20.769 for rifampicin and slope 0.998 r20.895 for linezolid. PK/PD indices were not related to clinical outcome. Taking a translational minocycline fAUC24h/MIC target of >0.5 for minocycline in the presence of rifampicin, 96% (49/51) of patients reached the target. Population PK models of minocycline, rifampicin and linezolid were developed in patients with MRSA cSSTI and almost all patients reached the predefined PD index targets. As a result, neither AUC, MIC nor the AUC/MIC ratio could be related to clinical outcome.

Systematic Review of Ex Vivo and In Vivo Pharmacokinetic Studies of Drugs Commonly Used During Extracorporeal Membrane Oxygenation

Extracorporeal membrane oxygenation (ECMO) is a lifesaving treatment for critically ill patients in cardiac or respiratory failure refractory to conventional treatment. Patients on an ECMO circuit (pump, oxygenator, tubing) require numerous medications including sedatives, analgesics, cardioactive medications, and anticonvulsants. Currently, there are few dosing guidelines to optimize pharmacotherapy in this situation. A systematic review was conducted to describe pharmacokinetics (PK) of medications commonly used during ECMO. MEDLINE, Embase, Cochrane, BIOSIS, PubMed, and Web of Science databases were searched. All articles presenting ex vivo, animal, and human data on the PK of the subject medications in the ECMO circuit were included. Three authors independently examined citation titles and abstracts. Four authors extracted relevant details from included studies into standardized data extraction forms. Methodological quality was assessed using the ClinPK guidelines and the Joanna Briggs Institute Checklist. Forty-four studies examining 30 medications were included, 26 ex vivo studies (mostly adult circuits) and 18 observational studies (mainly neonatal patients). Pharmacokinetics varied depending on the medication’s characteristics, study type, and population. Study quality was variable, limiting the possibility of deriving hard dosing guidelines from this available literature. Further population PK studies are needed to adequately determine dosing guidelines in adults and children requiring ECMO.

Population Pharmacokinetic and Pharmacodynamic of Atorvastatin in Chinese Lung Transplant Recipients.

Atorvastatin is a widely prescribed cholesterol-lowering drug that inhibits 3-hydroxy-3-methylglutaryl coenzyme A reductase to reduce lipid levels. This study aimed to establish a population pharmacokinetic and pharmacodynamic model for atorvastatin in Chinese lung transplant recipients (LTRs), particularly those using voriconazole (VOR) and with different genotypes. It evaluated precise dosing regimens and analyzed the correlation between atorvastatin exposure and clinical outcomes. A nonlinear mixed-effects model was used for the population pharmacokinetic/pharmacodynamic (PK/PD) analysis. A one-compartment population PK model was developed, incorporating VOR, SLCO2A1 rs76906503, and SLC22A8 rs2187383 to assess apparent clearance and volume of distribution. LDL-C was modeled as a biomarker to evaluate atorvastatin efficacy. A Monte Carlo simulation was conducted to assess various dosing schemes and the effects of different covariates on achieving the target LDL concentration. The correlation between atorvastatin exposure and clinical outcomes was also evaluated. Results indicated that the average probability of target attainment for optimal dosing regimens across various covariate results exceeded 45.8%. Dosages of 10, 20, and 40 mg were deemed suitable for LTRs. A lower dose was recommended for LTRs taking VOR or with mutant-type genotypes to avoid overexposure and adverse reactions. The population PK/PD model offers valuable guidance for evaluating atorvastatin dosing regimens in clinical settings, particularly for LTRs using VOR and those with different genotypes.