Clearance Research Articles

Population Pharmacokinetics and AUC-Guided Dosing of Tobramycin in the Treatment of Infections Caused by Glucose-Nonfermenting Gram-Negative Bacteria

PurposeTobramycin (TOB) exhibits variable pharmacokinetic properties due to the clinical condition of patients. This study aimed to investigate the AUC-guided dosing of TOB based on population pharmacokinetic analysis in the treatment of infections caused by Pseudomonas aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia. MethodsThis retrospective study was conducted between January 2010 and December 2020 after obtaining approval from our institutional review board. For 53 patients who received therapeutic drug monitoring of TOB, a population pharmacokinetic model was developed with covariates of estimated glomerular filtration rate using serum creatinine (eGFRcre) on clearance (CL) and weight on both CL and Vd in exponential error modeling (CL = 2.84 × [weight/70] × eGFRcre0.568, interindividual variability [IIV] = 31.1%; Vd = 26.3 × [weight/70], IIV = 20.2%; residual variability = 28.8%). FindingsThe final regression model for predicting 30-day mortality was developed with risk factors of AUC during a 24-hour period after the first dose to MIC ratio (odds ratio [OR] = 0.996; 95% CI, 0.968–1.003) and serum albumin (OR = 0.137; 95% CI, 0.022–0.632). The final regression model for predicting acute kidney injury was developed with the risk factors of C-reactive protein (OR = 1.136; 95% CI, 1.040–1.266) and AUC during a 72-hour period after the first dose (OR = 1.004; 95% CI, 1.000–1.001). A dose of 8 or 15 mg/kg was beneficial for achievement of AUC during a 24-hour period after the first dose/MIC >80 and trough concentration <1 µg/mL in patients with preserved kidney function and TOB CL >4.47 L/h/70 kg in the events of MIC of 1 or 2 µg/mL, respectively. We propose that the first dose of 15, 11, 10, 8, and 7 mg/kg for eGFRcre >90, 60 to 89, 45 to 59, 30 to 44, and 15 to 29 mL/min/1.73 m2 be followed by therapeutic drug monitoring at peak and 24 hours after the first dose. ImplicationsThis study suggests that TOB use encourages the replacement of trough- and peak-targeted dosing with AUC-guided dosing.

Prediction of Compound Plasma Concentration-Time Profiles in Mice Using Random Forest.

Pharmacokinetic (PK) parameters such as clearance (CL) and volume of distribution (Vd) have been the subject of previous in silico predictive models. However, having information of the concentration over time profile explicitly can provide additional value like time above MIC or AUC, etc., to understand both the efficacy and safety-related aspects of a compound. In this work, we developed machine learning models for plasma concentration-time profiles after both i.v. and p.o. dosing for a series of 17 in-house projects. For explanatory variables, MACCS Keys chemical descriptors as well as in silico and experimental in vitro PK parameters were used. The predictive accuracy of random forest (RF), message passing neural network, 2-compartment models using estimated CL and Vdss, and an average model (as a control experiment) was investigated using 5-fold cross-validation (5-fold CV) and leave-one-project-out validation (LOPO-V). The predictive accuracy of RF in 5-fold CV for i.v. and p.o. plasma concentration-time profiles was the best among the models studied, with an RMSE for i.v. dosing at 0.08, 1, and 8 h of 0.245, 0.474, and 0.462, respectively, and an RMSE for p.o. dosing at 0.25, 1, and 8 h of 0.500, 0.612, and 0.509, respectively. Furthermore, by investigating the importance of the in vitro PK parameters using the Gini index, we observed that the general prior knowledge in ADME research was reflected well in the respective feature importance of in vitro parameters such as predicted human Vd (hVd) for the initial distribution, mouse intrinsic CL and unbound fraction of mouse plasma for the elimination process, and Caco2 permeability for the absorption process. Also, this model is the first model that can predict twin peaks in the concentration-time profile much better than a baseline compartment model. Because of its combination of sufficient accuracy and speed of prediction, we found the model to be fit-for-purpose for practical lead optimization.

A Systematic Review on Antimicrobial Pharmacokinetic Differences between Asian and Non-Asian Adult Populations.

While the relevance of inter-ethnic differences to the pharmacokinetic variabilities of antimicrobials has been reported in studies recruiting healthy subjects, differences in antimicrobial pharmacokinetics between Asian and non-Asian patients with severe pathologic conditions require further investigation. For the purpose of describing the potential differences in antimicrobial pharmacokinetics between Asian and non-Asian populations, a systematic review was performed using six journal databases and six theses/dissertation databases (PROSPERO record CRD42018090054). The pharmacokinetic data of healthy volunteers and non-critically ill and critically ill patients were reviewed. Thirty studies on meropenem, imipenem, doripenem, linezolid, and vancomycin were included in the final descriptive summaries. In studies recruiting hospitalised patients, inconsistent differences in the volume of distribution (Vd) and drug clearance (CL) of the studied antimicrobials between Asian and non-Asian patients were observed. Additionally, factors other than ethnicity, such as demographic (e.g., age) or clinical (e.g., sepsis) factors, were suggested to better characterise these pharmacokinetic differences. Inconsistent differences in pharmacokinetic parameters between Asian and non-Asian subjects/patients may suggest that ethnicity is not an important predictor to characterise interindividual pharmacokinetic differences between meropenem, imipenem, doripenem, linezolid, and vancomycin. Therefore, the dosing regimens of these antimicrobials should be adjusted according to patients' demographic or clinical characteristics that can better describe pharmacokinetic differences.

Age associations with tacrolimus and mycophenolic acid pharmacokinetics in stable Black and White kidney transplant recipients: Implications for health inequities.

Tacrolimus (TAC) and mycophenolic acid (MPA) provide maintenance immunosuppression and is dosed empirically in elderly kidney transplant recipients (KTRs) resulting in health inequities. Limited immunosuppressive pharmacokinetics are available comparing adult ages. This secondary analysis compared TAC and MPA pharmacokinetics and adverse effects (AEs) among young, middle-aged, and elderly Black and White KTRs. The 12-h TAC and MPA pharmacokinetics with AE evaluation were conducted in 67 stableKTRs greater than or equal to 6 months post-transplant. TAC regimens were adjusted to target troughs. MPA regimens were adjusted using clinical response. Participants were: young: less than or equal to 40 years; middle age: greater than 40 to 60 years, and elderly greater than 60 years. Noncompartmental pharmacokinetic analysis determined area under the concentration-time curve 0-12 h (AUC0-12h ), clearance (CL), and CL/body mass index (BMI) with 0-h troughs. MPA enterohepatic recirculation (EHR), MPA-AUC6-12h /MPA-AUC0-12h , and MPA glucuronide (MPAG)-AUC0-12h /MPA-AUC0-12h were determined. Univariate analysis of variance (ANOVA) was conducted using SAS version 9.4. No group differences were noted for estimated glomerular filtration rate, MPA, and TAC doses. EHR was reduced in elderly with decreased MPA-AUC6-12h /MPA-AUC0-12h (p=0.049) and increased MPAG-AUC0-12h /MPA-AUC0-12h (p=0.036). MPA troughs (p=0.045) were reduced in the elderly. TAC CL/BMI (p=0.043) was reduced in the elderly. For therapeutic MPA AUC0-12h : 30-60 mg·h/L, 34.3% KTRs achieved this target with 55.2% greater than the therapeutic range. 77.6% KTR were in the TAC AUC0-12h target: 100-190 ng·h/mL and 19.4% were below this range with no age relationship. In 44% young, 26% middle-age and 7.8% elderly subjects achieved target AUC0-12h for both medications (p=0.036). Neurologic AEs were manifested in the elderly (p=0.014). Immunosuppressive pharmacokinetics demonstrated age-related differences with reduced TAC CL/BMI and MPA EHR and increased neurologic AE in the elderly. This immunosuppressive regimen may require age-adjusted individualization to optimize allograft function.

The Disconnect in Intrinsic Clearance Determined in Human Hepatocytes and Liver Microsomes Results from Divergent Cytochrome P450 Activities.

Candidate drugs may exhibit higher unbound intrinsic clearances (CLint,u) in human liver microsomes (HLMs) relative to human hepatocytes (HHs), posing a challenge as to which value is more predictive of in vivo clearance (CL). This work was aimed at better understanding the mechanism(s) underlying this 'HLM:HH disconnect' via examination of previous explanations, including passive permeability limited CL or cofactor exhaustion in hepatocytes. A series of structurally related, passively permeable (Papps > 5 × 10-6 cm/s), 5-azaquinazolines were studied in different liver fractions, and metabolic rates and routes were determined. A subset of these compounds demonstrated a significant HLM:HH (CLint,u ratio 2-26) disconnect. Compounds were metabolized via combinations of liver cytosol aldehyde oxidase (AO), microsomal cytochrome P450 (CYP) and flavin monooxygenase (FMO). For this series, the lack of concordance between CLint,u determined in HLM and HH contrasted with an excellent correlation of AO dependent CLint,u determined in human liver cytosol[Formula: see text], r2 = 0.95, P < 0.0001). The HLM:HH disconnect for both 5-azaquinazolines and midazolam was as a result of significantly higher CYP activity in HLM and lysed HH fortified with exogenous NADPH relative to intact HH. Moreover, for the 5-azaquinazolines, the maintenance of cytosolic AO and NADPH-dependent FMO activity in HH, relative to CYP, supports the conclusion that neither substrate permeability nor intracellular NADPH for hepatocytes were limiting CLint,u Further studies are required to identify the underlying cause of the lower CYP activities in HH relative to HLM and lysed hepatocytes in the presence of exogenous NADPH. SIGNIFICANCE STATEMENT: Candidate drugs may exhibit higher intrinsic clearance in human liver microsomes relative to human hepatocytes, posing a challenge as to which value is predictive of in vivo clearance. This work demonstrates that the difference in activity determined in liver fractions results from divergent cytochrome P450 but not aldehyde oxidase or flavin monooxygenase activity. This is inconsistent with explanations including substrate permeability limitations or cofactor exhaustion and should inform the focus of further studies to understand this cytochrome P450 specific disconnect phenomenon.

Vancomycin Clearance in Obese Adults is not Predictive of Clearance in Obese Adolescents.

Contradictory pharmacokinetic (PK) results have been observed between obese adults and obese adolescents, with absolute clearance (CL) reported to be either unaltered, lower, or higher in obese adolescents compared to obese adults. This study investigates the PK of vancomycin in adolescents and adults who are overweight or obese. Data from 125 overweight and obese adolescents (aged 10-18 years, weight 28.3-188 kg) and 81 overweight and obese adults (aged 29-88 years, weight 66.7-143 kg) were analysed using population PK modelling. In addition to age, sex, renal function estimates, and regular weight descriptors, we evaluated standard weight (WTstandard, defined as weight for length, age, and sex in adolescents and weight for length in adults) and excess weight (WTexcess, defined as total body weight (TBW) minus WTstandard) as covariates in order to distinguish between weight resulting from length versus weight resulting from obesity. Analyzing adolescents and adults together, vancomycin CL was found to increase with TBW and decrease with increasing age (p < 0.001). A covariate analysis investigating adolescents and adults separately found that vancomycin CL increased with WTstandard in adolescents and adults, albeit with different functions, with adolescents having a higher CL per WTstandard than adults. Moreover, in this separate model, adolescent males had 21% higher CL than adolescent females of the same WTstandard, while in adults, CL decreased with increasing age (p < 0.001). There are apparent differences in vancomycin CL in overweight and obese adults versus overweight and obese adolescents, implying that dosing of vancomycin cannot be directly extrapolated between these populations.

Predicting Human Bioavailability of Subcutaneously Administered Fusion Proteins and Monoclonal Antibodies Using Human Intravenous Clearance or Antibody Isoelectric Point

There has been an increasing trend towards subcutaneous (SC) delivery of fusion proteins and monoclonal antibodies (mAbs) in recent years versus intravenous (IV) administration. The prediction of bioavailability is one of the major barriers in clinical translation of SC-administered therapeutic proteins due to a lack of reliable in vitro and preclinical in vivo predictive models. In this study, we explored the relationships between human SC bioavailability and physicochemical or pharmacokinetic properties of 19 Fc- or albumin-fusion proteins and 98 monoclonal antibodies. An inverse linear correlation was observed between human SC bioavailability and intravenous clearance (CL) or isoelectric point (pI). Multivariate regression models were developed using intravenous CL and pI of a training set (N = 59) as independent variables. The predictive models of mAbs were validated with an independent test set (N = 33). Two linear regression models resulted in 24 (73%) and 27 (82%) among 33 predictions within 0.8- to 1.2-fold deviations. Due to the small sample size of dataset, regression model validation was not conducted for fusion proteins. Overall, this study demonstrated that CL- and pI-based multivariate regression models could be used to predict human SC bioavailability of mAbs.

Physiologically based pharmacokinetic (PBPK) model that describes enhanced FcRn-dependent distribution of monoclonal antibodies (mAbs) by pI-engineering in mice

We previously reported that monoclonal antibodies (mAbs) with a high isoelectric point (pI) value tended to exhibit fast plasma clearance (CL) and large steady-state volume of distribution (Vdss) in mice. However, the positive correlation between pI, CL, and Vdss cannot be described by the reported physiologically based pharmacokinetic (PBPK) models, in which FcRn-mediated transcytosis of mAbs is set to be minimal compared to convection-mediated transport. To address this issue, physiological parameters (lymph flow rate, reflection coefficient, endothelial uptake clearance, and FcRn concentration) were optimized based on the pharmacokinetic profiles of mAbs with various pI values in wild type and FcRn-deficient (beta-2-microglobulin knockout [KO]) mice. Simulations using the PBPK model developed in this study showed a positive correlation between pI, CL and Vdss observed in wild-type mice. Therefore, this model successfully characterized our hypothetical mechanism that an electrostatic positive interaction between mAbs and the endothelial membrane enhances FcRn-mediated transcytosis of mAbs, resulting in large Vdss. We sought to determine the right contribution of the two pathways of antibody distribution to the interstitial space and established a new model that could effectively capture the effect of pI on FcRn-mediated distribution of mAbs in the body.

Does Cytokine-Release Syndrome Induced by CAR T-Cell Treatment Have an Impact on the Pharmacokinetics of Meropenem and Piperacillin/Tazobactam in Patients with Hematological Malignancies? Findings from an Observational Case-Control Study.

Chimeric antigen receptor (CAR) T-cell therapy is a promising approach for some relapse/refractory hematological B-cell malignancies; however, in most patients, cytokine release syndrome (CRS) may occur. CRS is associated with acute kidney injury (AKI) that may affect the pharmacokinetics of some beta-lactams. The aim of this study was to assess whether the pharmacokinetics of meropenem and piperacillin may be affected by CAR T-cell treatment. The study included CAR T-cell treated patients (cases) and oncohematological patients (controls), who were administered 24-h continuous infusion (CI) meropenem or piperacillin/tazobactam, optimized by therapeutic drug monitoring, over a 2-year period. Patient data were retrospectively retrieved and matched on a 1:2 ratio. Beta-lactam clearance (CL) was calculated as CL = daily dose/infusion rate. A total of 38 cases (of whom 14 and 24 were treated with meropenem and piperacillin/tazobactam, respectively) was matched with 76 controls. CRS occurred in 85.7% (12/14) and 95.8% (23/24) of patients treated with meropenem and piperacillin/tazobactam, respectively. CRS-induced AKI was observed in only 1 patient. CL did not differ between cases and controls for both meropenem (11.1 vs. 11.7 L/h, p = 0.835) and piperacillin (14.0 vs. 10.4 L/h, p = 0.074). Our findings suggest that 24-h CI meropenem and piperacillin dosages should not be reduced a priori in CAR T-cell patients experiencing CRS.

Plasma and Cerebrospinal Fluid Concentrations of Micafungin Administered at High Doses in Critically Ill Infants with Systemic Candidiasis: A Pooled Analysis of Two Studies

Background: Neonates may require higher doses of micafungin than adults to reach the therapeutic effect for increased plasma clearance. Only poor and inconclusive data are available still now to support this hypothesis, especially with regard to central nervous system micafungin concentrations. To assess the pharmacokinetics of increased doses (8 to 15 mg/kg/day) of micafungin in preterm and term neonates with invasive candidiasis and to complete previously presented results, we analyzed the pharmacokinetic data on a total of 53 newborns treated with micafungin, whereby 3 of them had Candida meningitis and hydrocephalus. Methods: Fifty-three neonates with systemic candidiasis, three of them with meningitis, were treated for at least 14 days with intravenous micafungin (Mycamine®) at a dosage ranging from 8 to 15 mg/kg/day. Plasma and cerebrospinal fluid (CSF) concentrations of micafungin were measured before the drug administration and at 1, 2, and 8 h after the end of the infusion using high-performance liquid chromatography (HPLC). Systemic exposure was assessed according to AUC0-24, plasma clearance (CL), and half-life measured in 52/53 patients, divided by chronological age. Results and conclusions: The mean micafungin clearance is higher in neonates than in older infants (0.036 L/h/kg before 28 days of life versus 0.028 L/h/kg after 120 days). The drug half-life is shorter in neonates than in older patients (13.5 h before 28 days of life versus 14.4 h after 120 days). With doses ranging between 8 and 15 mg/kg/day, micafungin crosses the blood-brain barrier reaching therapeutic levels in CSF.

Population PK/PD modelling of meropenem in preterm newborns based on therapeutic drug monitoring data.

Background: Preterm neonates rarely participate in clinical trials, this leads to lack of adequate information on pharmacokinetics for most drugs in this population. Meropenem is used in neonates to treat severe infections, and absence of evidence-based rationale for optimal dosing could result in mismanagement. Aim: The objective of the study was to determine the population pharmacokinetic (PK) parameters of meropenem in preterm infants from therapeutic drug monitoring (TDM) data in real clinical settings and to evaluate pharmacodynamics (PD) indices as well as covariates affecting pharmacokinetics. Materials and methods: Demographic, clinical and TDM data of 66 preterm newborns were included in PK/PD analysis. The NPAG program from the Pmetrics was used for modelling based on peak-trough TDM strategy and one-compartment PK model. Totally, 132 samples were assayed by high-performance liquid chromatography. Meropenem empirical dosage regimens (40-120mg/kg/day) were administered by 1-3-h IV infusion 2-3 times a day. Regression analysis was used to evaluate covariates (gestation age (GA), postnatal age (PNA), postconceptual age (PCA), body weight (BW), creatinine clearance, etc.) influenced on PK parameters. Results: The mean ± SD (median) values for constant rate of elimination (Kel) and volume of distribution (V) of meropenem were estimated as 0.31 ± 0.13 (0.3) 1/h and 1.2 ± 0.4 (1.2) L with interindividual variability (CV) of 42 and 33%, respectively. The median values for total clearance (CL) and elimination half-life (T1/2) were calculated as 0.22L/h/kg and 2.33h with CV = 38.0 and 30.9%. Results of the predictive performance demonstrated that the population model by itself gives poor prediction, while the individualized Bayesian posterior models give much improved quality of prediction. The univariate regression analysis revealed that creatinine clearance, BW and PCA influenced significantly T1/2, meropenem V was mostly correlated with BW and PCA. But not all observed PK variability can be explained by these regression models. Conclusion: A model-based approach in conjunction with TDM data could help to personalize meropenem dosage regimen. The estimated population PK model can be used as Bayesian prior information to estimate individual PK parameter values in the preterm newborns and to obtain predictions of desired PK/PD target once the patient's TDM concentration(s) becomes available.

Dose adjustment not required for contezolid in patients with moderate hepatic impairment based on pharmacokinetic/pharmacodynamic analysis.

Objective: Contezolid is an oxazolidinone antimicrobial agent newly approved for treatment of Gram-positive bacterial infections. It is primarily metabolized by the liver. This study aimed to assess whether it is required to adjust the dose of contezolid in patients with moderate hepatic impairment for clinicians to use the drug more rationally. Methods: A single-center, open-label, parallel-group study was conducted to compare the pharmacokinetic (PK) parameters of contezolid and its metabolite M2 between the patients with moderate hepatic impairment and healthy controls with normal liver function after oral administration of 800mg contezolid tablets. Monte Carlo simulation was performed to calculate the probability of target attainment (PTA) and cumulative fraction of response (CFR) of contezolid based on the PK and pharmacodynamic data. Results: Oral treatment with 800mg contezolid tablets was safe and well tolerated in both the patients with moderate hepatic impairment and healthy controls. Moderate hepatic impairment did not result in substantial difference in the area under the concentration-time curve from 0 to 24h (AUC0-24h, 106.79 vs. 97.07hμg/mL) of contezolid even though lower maximum concentration (Cmax, 19.03 vs. 34.49μg/mL) compared with healthy controls. The mean cumulative amount excreted in urine from 0 to 48h (Ae0-48h) and renal clearance (CLR) of contezolid did not show significant difference between the two groups. Moderate hepatic impairment was associated with lower Cmax, slightly lower AUC and Ae0-48h of M2 compared to the healthy controls. fAUC/MIC was the best PK/PD index to predict the clinical efficacy of contezolid. Monte Carlo simulation results indicated that at the proposed fAUC/MIC target value of 2.3, the dosing regimen of oral contezolid 800mg q12h could achieve satisfactory PTA and CFR (both >90%) for the target pathogen (methicillin-resistant S. aureus, MIC ≤4mg/L) in patients with moderate hepatic impairment. Conclusion: Our preliminary data suggest that dose adjustment is not required for contezolid in patients with moderate hepatic impairment. Clinical Trial Registration: https://chinadrugtrials.org.cn, identifier: CTR20171377.

Predictive Factors of Piperacillin Exposure and the Impact on Target Attainment after Continuous Infusion Administration to Critically Ill Patients

Critically ill patients undergo significant pathophysiological changes that affect antibiotic pharmacokinetics. Piperacillin/tazobactam administered by continuous infusion (CI) improves pharmacokinetic/pharmacodynamic (PK/PD) target attainment. This study aimed to characterize piperacillin PK after CI administration of piperacillin/tazobactam in critically ill adult patients with preserved renal function and to determine the empirical optimal dosing regimen. A total of 218 piperacillin concentrations from 106 patients were simultaneously analyzed through the population PK approach. A two-compartment linear model best described the data. Creatinine clearance (CLCR) estimated by CKD-EPI was the covariate, the most predictive factor of piperacillin clearance (CL) interindividual variability. The mean (relative standard error) parameter estimates for the final model were: CL: 12.0 L/h (6.03%); central and peripheral compartment distribution volumes: 20.7 L (8.94%) and 62.4 L (50.80%), respectively; intercompartmental clearance: 4.8 L/h (26.4%). For the PK/PD target of 100% fT>1×MIC, 12 g of piperacillin provide a probability of target attainment > 90% for MIC < 16 mg/L, regardless of CLCR, but higher doses are needed for MIC = 16 mg/L when CLCR > 100 mL/min. For 100% fT>4×MIC, the highest dose (24 g/24 h) was not sufficient to ensure adequate exposure, except for MICs of 1 and 4 mg/L. Our model can be used as a support tool for initial dose guidance and during therapeutic drug monitoring.

The Pharmacokinetics and Target Attainment of Antimicrobial Drugs Throughout Pregnancy: Part III Non-penicillin and Non-cephalosporin Drugs

Understanding the pharmacokinetics (PK) of antimicrobial drugs in pregnant women is crucial to provide effective and safe treatment. This study is part of a series that systematically reviews literature on the PK and analyzes if, based on the changed PK, evidence-based dosing regimens have been developed for adequate target attainment in pregnant women. This part focusses on antimicrobials other than penicillins and cephalosporins. A literature search was conducted in PubMed according to the PRISMA guidelines. Search strategy, study selection, and data extraction were independently performed by two investigators. Studies were labeled as relevant when information on the PK of antimicrobial drugs in pregnant women was available. Extracted parameters included bioavailability for oral drugs, volume of distribution (Vd) and clearance (CL), trough and peak drug concentrations, time of maximum concentration, area under the curve and half-life, probability of target attainment, and minimal inhibitory concentration (MIC). In addition, if developed, evidence-based dosing regimens were also extracted. Of the 62 antimicrobials included in the search strategy, concentrations or PK data during pregnancy of 18 drugs were reported. Twenty-nine studies were included, of which three discussed aminoglycosides, one carbapenem, six quinolones, four glycopeptides, two rifamycines, one sulfonamide, five tuberculostatic drugs, and six others. Eleven out of 29 studies included information on both Vd and CL. For linezolid, gentamicin, tobramycin, and moxifloxacin, altered PK throughout pregnancy, especially in second and third trimester, has been reported. However, no target attainment was studied and no evidence-based dosing developed. On the other hand, the ability to reach adequate targets was assessed for vancomycin, clindamycin, rifampicin, rifapentine, ethambutol, pyrazinamide, and isoniazid. For the first six mentioned drugs, no dosage adaptations during pregnancy seem to be needed. Studies on isoniazid provide contradictory results. This systematic literature review shows that a very limited number of studies have been performed on the PK of antimicrobials drugs-other than cephalosporins and penicillins-in pregnant women.

Population pharmacokinetics and exposure-clinical outcome relationship of remdesivir major metabolite GS-441524 in patients with moderate and severe COVID-19.

Although remdesivir, a prodrug of nucleoside analog (GS-441524), has demonstrated clinical benefits in coronavirus disease 2019 (COVID-19) treatment, its pharmacokinetics (PKs) in patients with COVID-19 remain poorly understood. Therefore, in this study, the PKs of remdesivir and its major metabolite, GS-441524, were evaluated using a population PK (PopPK) approach to understand the PK aspect and exposure-clinical outcome relationship. The serum concentrations of remdesivir and GS-441524 (102 points in 39 patients) were measured using liquid chromatography-tandem mass spectrometry. All patients received 200 mg remdesivir on the first day, followed by 100 mg on 2-5 days, except for one patient who discontinued remdesivir on day 4. The median (range) age, body surface area, and estimated glomerular filtration rate (eGFR) were 70 (42-85), 1.74 m2 (1.36-2.03), and 68 mL/min/1.73 m2 (33-113), respectively. A compartment model with first-order elimination combined with remdesivir and GS-441524 was used for nonlinear mixed-effects model analysis. Remdesivir was rapidly eliminated after infusion, whereas GS-441524 was eliminated relatively slowly (half-time=17.1h). The estimated apparent clearance (CL) and distribution volume of GS-441524 were 11.0L/h (intersubject variability [ISV]%=43.0%) and 271 L (ISV%=58.1%), respectively. The CL of GS-441524 was significantly related to the eGFR (CL × [eGFR/68]0.745 ). The post hoc area under the curve of GS-441524 was unrelated to the recovery rate or aspartate aminotransferase/alanine aminotransferase elevation. Overall, PopPK analysis showed the rapid elimination of remdesivir in the blood, and GS-441524 accumulation depended on eGFR in patients with COVID-19. However, no relevance of exposure-clinical outcome was not suggestive of the dose adjustment of remdesivir.

Renal tubular transporter-mediated interactions between mirogabalin and cimetidine in rats

Cimetidine at a clinical dosage decreased the renal clearance (CLr) of mirogabalin in humans by inhibition of renal secretion. Mirogabalin is a substrate of human OAT1/3, OCT2, MATE1 and/or MATE2-K. To clarify the mechanism behind the above interaction, it was investigated whether cimetidine inhibits the process of mirogabalin uptake at the basolateral side or the process of its efflux at the apical side in rat kidney in vivo. Cimetidine was administered to rats by a constant infusion to achieve an unbound plasma concentration of 7.0 μM and examine its effect on the renal disposition of [14C]metformin, [3H]p-aminohippuric acid (PAH), and [14C]mirogabalin. Cimetidine significantly induced the intrarenal accumulation of radioactivity (Kp, kidney) and decreased the renal clearance (CLr) of [14C]mirogabalin. These effects resulted in significantly decreased total clearance (CLt). Kp, kidney, and CLr of [14C]metformin, except CLt, were also affected, but no parameters of [3H]PAH were affected by cimetidine. These findings clarified that an unbound plasma concentration of cimetidine of 7.0 μM inhibited the apical efflux not the basolateral uptake of [14C]mirogabalin in rat kidney, suggesting that mirogabalin/cimetidine interaction was caused by inhibiting the apical efflux transporter, human MATE1 and/or MATE2-K, not the basolateral uptake transporter, human OCT2, in the kidney.

P762 Population Pharmacokinetic Model of Intravenous Infliximab in Korean Patients with Crohn’s Disease

Abstract Background Infliximab (IFX), a monoclonal antibody approved for treating Crohn’s disease (CD), is known to show differing drug clearances in patients according to several clinical factors. However, information on the population pharmacokinetics (PKs) of intravenous (IV) IFX is lacking for Korean patients with CD. Therefore, in this study, we aimed to establish a PK model of IV IFX for this population. Methods We retrospectively analyzed data of CD patients treated with IV IFX at Asan Medical Center, a tertiary university hospital, from April 2019 to March 2022. Serum trough IFX concentration, clinical laboratory values, Crohn’s disease activity index, and demographic data were collected. NONMEM® version 7.5 was used for nonlinear mixed effects modeling. Results Of the one hundred patients included for analysis in this study, 72 were male (72.0%) (Table 1). No patient had detectable antibodies to IFX. [SJ1] A total of 823 serum IFX concentration data were collected and analyzed for fitting according to the minimization of objective function value and weighted residuals. As a result, a one-compartment population PK model with first-order elimination best described the serum trough IFX concentration measurements. Population PK estimates were 0.012 L/h for clearance (CL) (95% confidence interval: 0.012–0.013) and 6.301 L for the volume of distribution (V) (95% confidence interval: 5.932–6.671) (Table 2). Covariate analysis showed that CL and V increased as body weight increased. CL was higher in patients with low serum albumin, high serum C-reactive protein, and older age, with differing coefficients for each covariate (Figure 1). The final covariate model predicted the observed concentration-time profiles of IFX reasonably well (Figure 2). Conclusion We established a population PK model of IV IFX for CD patients in Korea. The final covariate model showed that the CL of IFX was affected by serum albumin and C-reactive protein levels, in addition to body weight and age.

P792 Pharmacokinetics and clinical evaluation of vedolizumab based on real-life routine monitoring data in IBD patients

Abstract Background Vedolizumab (VDZ) is recommended for induction of remissionin patients with inflammatory bowel disease (IBD). Therapeutic drug monitoring (TDM) based on pharmacokinetic measurements of VDZ trough plasma concentrations adds-up on routine patients’ clinical follow-up. Great interpatient variability in VDZ serum concentrations is observed. Our aim was to investigate factors contributing to variations in VDZ levels by developing population pharmacokinetic model based on sparse TDM data, and understand its importance in reaching adequate response. Methods Retrospective data from IBD patients undergoing treatment with VDZ were reviewed, and patients with measured VDZ serum concentration were included in analysis. In addition, demographic, therapy and clinical characteristics were collected; including various inflammatory biomarkers such as platelets, leucocytes, C-reactive protein, sedimentation rate, fecal calprotectin, etc., and calculated Mayo, SES scores, where appropriate. VDZ dose of 300 mg was administered as 30-minutes infusion at week: 0, 2 and 6 during induction, with a 4-, 6- or 8-week dosing interval during maintenance phase. Population modeling approach was applied to characterize pharmacokinetic profile of VDZ. In addition, logistic analysis was implemented to test correlation among VDZ concentration, disease biomarkers, and appropriate clinical scores. Results In total, 115 VDZ trough concentrations obtained from 107 patients were analysed. Patients’ characteristics are given in Table 1. VDZ concentrations were described by two-compartment model. Estimated typical value of VDZ clearance (CL) was 0.226 L/day, without any difference among ulcerative colitis (UC) and Crohn’s disease (CD) patients. We identified that previous treatment with anti-TNF biologics increases CL by on average 24.8%. In addition, our preliminary analyses indicate higher probability of thrombocytosis with lower VDZ levels. Median VDZ concentration in patients whose platelets were above and below 350 (109/L) were 15.33 and 20.29 microg/mL, respectively (Figure 1). Conclusion Our preliminary results suggest that platelets account as inflammation burden marker and previous antiTNF treatment may be predictive factors for proactive VDZ optimization.

Population pharmacokinetic model and dosing optimization of vancomycin in hematologic malignancies with neutropenia and augmented renal clearance

AimData on the pharmacokinetics (PK) and area under the curve (AUC)-based dosing strategy of vancomycin (VCM) in hematologic malignancies are limited. According to our preliminary narrative review, only a few population PK analyses in hematologic malignancies have been performed. Therefore, we aimed to develop a population PK model, investigate the factors influencing VCM PK, and propose an optimal dosing regimen for hematologic malignancies. MethodsA retrospective study was conducted in patients with underlying hematologic malignancies treated with VCM. A total of 148 patients were enrolled for population PK modeling. Simulation analyses were performed to identify dosing regimens achieving a target exposure of AUC0-24 of 400–600 mg h/L at the steady-state. ResultsThe VCM PK data were best described with a one-compartment model. Significant covariates included creatinine clearance (Ccr), diagnosis of acute myeloid leukemia (AML) and neutropenia on VCM clearance (CL), and body weight (WT) on the volume of distribution (Vd). The typical values of CL and Vd were 3.09 L/h (normalized to Ccr value of 90 mL/min) and 122 L/70 kg, respectively. Concerning the effect on VCM dosing, AML patients required 15% higher doses than non-AML patients, independently of renal function. In contrast, for neutropenic patients, only those with augmented renal clearance (ARC, Ccr value ≥ 130 mL/min) required a 10% dose increase compared to non-neutropenic patients. ConclusionAML patients with neutropenia and ARC represent a critical population with a higher risk of VCM underexposure. Thus, individualized dosing adjustment and therapeutic drug monitoring are strongly recommended.

Pharmacokinetics of Novel Furoxan/Coumarin Hybrids in Rats Using LC-MS/MS Method and Physiologically Based Pharmacokinetic Model.

Novel furoxan/coumarin hybrids were synthesized, and pharmacologic studies showed that the compounds displayed potent antiproliferation activities via downregulating both the phosphatidylinositide 3-kinase (PI3K) pathway and the mitogen-activated protein kinase (MAPK) pathway. To investigate the preclinical pharmacokinetic (PK) properties of three candidate compounds (CY-14S-4A83, CY-16S-4A43, and CY-16S-4A93), liquid chromatography, in tandem with the mass spectrometry LC-MS/MS method, was developed and validated for the simultaneous determination of these compounds. The absorption, distribution, metabolism, and excretion (ADME) properties were investigated in in vitro studies and in rats. Meanwhile, physiologically based pharmacokinetic (PBPK) models were constructed using only in vitro data to obtain detailed PK information. Good linearity was observed over the concentration range of 0.01−1.0 μg/mL. The free drug fraction (fu) values of the compounds were less than 3%, and the clearance (CL) values were 414.5 ± 145.7 mL/h/kg, 2624.6 ± 648.4 mL/h/kg, and 500.6 ± 195.2 mL/h/kg, respectively. The predicted peak plasma concentration (Cmax) and the area under the concentration-time curve (AUC) were overestimated for the CY-16S-4A43 PBPK model compared with the experimental ones (fold error > 2), suggesting that tissue accumulation and additional elimination pathways may exist. In conclusion, the LC-MS/MS method was successively applied in the preclinical PK studies, and the detailed information from PBPK modeling may improve decision-making in subsequent new drug development.