Published Population Pharmacokinetic Research Articles

Model-Aided Adults-to-Children Pharmacokinetic Extrapolation and Empirical Body Size-Based Dosing Exploration for Therapeutic Monoclonal Antibodies-Is Allometry a Reasonable Choice?

The importance of pharmacokinetic (PK) evaluation in pediatric drug development is well recognized, and a pediatric PK study is generally recommended before pivotal trials to ensure the "right" dose in these studies. The PK of therapeutic monoclonal antibodies (mAbs) is primarily affected by body weight, where adults-to-children extrapolation may conform to allometry. Therefore, PK behavior of mAbs in pediatrics, particularly for those with linear PK, is expected to be predictable based on data in adults. To test this hypothesis, we reviewed published population PK reports of marketed mAbs and assessed model-aided PK extrapolation of mAbs to children (2-17 years) through 5 case studies. For each case study, population PK models were developed based on adult data, with allometric exponents of weight on clearance and volume of distribution fixed as standard values (ie, 0.75 for clearance; 1.0 for volume of distribution), approach 1, or coming from adult model estimates, approach 2. Simulated pediatric PK using these 2 approaches was compared with PK observations in pediatric trials to assess the accuracy in model predictions. For pediatrics 6-17 years, model performance was generally comparable with the 2 approaches. For children < 6 years, no definite conclusion could be made, as only 1 case study enrolled children 2-5 years. Our work supports that PK in children 6-17 years is readily predictable for mAbs with linear PK based on adult data and considering weight effect (allometry). Empirical dosing calculations based on PK simulations with allometry are proposed to convert adult doses to equivalent pediatric doses with exposure matching for mAbs in children 2-17 years.

Imipenem Population Pharmacokinetics: Therapeutic Drug Monitoring Data Collected in Critically Ill Patients with or without Extracorporeal Membrane Oxygenation.

Carbapenem pharmacokinetic (PK) profiles are significantly different in critically ill patients because of the drastic variability of the patients' physiological parameters. Published population PK studies have mainly focused on specific diseases, and the majority of these studies had small sample sizes. The aim of this study was to develop a population PK model of imipenem in critically ill patients that estimated the influence of various clinical and biological covariates and the use of extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT). A two-compartment population PK model with creatinine clearance (CLCR), body weight (WT), and ECMO as fixed effects was developed using the nonlinear mixed-effects model (NONMEM). A Monte Carlo simulation was performed to evaluate various dosing schemes and different levels of covariates based on the pharmacokinetic/pharmacodynamic index (ƒ%T>MIC) for the range of clinically relevant MICs. The results showed that there may be insufficient drug use in the clinical routine drug dose regimen, and 750 mg every 6 h (q6h) could achieve a higher treatment success rate. The blood concentrations of imipenem in ECMO patients were lower than those in non-ECMO patients; therefore, dosages may need to be increased. The dosage may need adjustment for patients with a CLCR of ≤70 ml/min, but the dose should be lowered carefully to avoid the insufficient drug exposure. Dose adjustment is not necessary for patients with WT ranging from 50 to 80 kg. Due to the large variation in PK profile of imipenem in critically ill patients, therapeutic drug monitoring (TDM) should be carried out to optimize drug regimens.

In pursuit of the triple crown: mechanism-based pharmacodynamic modelling for the optimization of three-drug combinations against KPC-producing Klebsiella pneumoniae

ObjectivesOptimal combination therapy for Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae (KPC-Kp) is unknown. The present study sought to characterize the pharmacodynamics (PD) of polymyxin B (PMB), meropenem (MEM) and rifampin (RIF) alone and in combination using a hollow fibre infection model (HFIM) coupled with mechanism-based modelling (MBM). MethodsA 10-day HFIM was utilized to simulate human pharmacokinetics (PK) of various PMB, MEM and RIF dosing regimens against a clinical KPC-Kp isolate, with total and resistant subpopulations quantified to capture PD response. A MBM was developed to characterize bacterial subpopulations and synergy between agents. Simulations using the MBM and published population PK models were employed to forecast the bacterial time course and the extent of its variability in infected patients for three-drug regimens. ResultsIn the HFIM, a PMB single-dose (‘burst’) regimen of 5.53 mg/kg combined with MEM 8 g using a 3-hr prolonged infusion every 8 hr and RIF 600 mg every 24 hr resulted in bacterial counts below the quantitative limit within 24 hr and remained undetectable throughout the 10-day experiment. The final MBM consisted of two bacterial subpopulations of differing PMB and MEM joint susceptibility and the ability to form a non-replicating, tolerant subpopulation. Synergistic interactions between PMB, MEM and RIF were well quantified, with the MBM providing adequate capture of the observed data. DiscussionAn in vitro–in silico approach answers questions related to PD optimization as well as overall feasibility of combination therapy against KPC-Kp, offering crucial insights in the absence of clinical trials.

Rifampicin Can Be Given as Flat-Dosing Instead of Weight-Band Dosing.

BackgroundThe weight-band dosing in tuberculosis treatment regimen has been implemented in clinical practice for decades. Patients will receive different number of fixed dose combination tablets according to their weight-band. However, some analysis has shown that weight was not the best covariate to explain variability of rifampicin exposure. Furthermore, the rationale for using weight-band dosing instead of flat-dosing becomes questionable. Therefore, this study aimed to compare the average and the variability of rifampicin exposure after weight-band dosing and flat-dosing.MethodsRifampicin exposure were simulated using previously published population pharmacokinetics model at dose 10–40 mg/kg for weight-band dosing and dose 600–2400 mg for flat-dosing. The median area under the curve (AUC0–24 h) after day 7 and 14 were compared as well as the variability of each dose group between weight-band and flat-dosing.ResultsThe difference of median AUC0–24 h of all dose groups between flat-dosing and weight-band dosing were considered low (< 20%) except for the lowest dose. At the dose of 10 mg/kg (600 mg for flat-dosing), flat-dosing resulted in higher median AUC0–24h compared to the weight-band dosing. A marginal decrease in between-patient variability was predicted for weight-band dosing compared to flat-dosing.ConclusionsWeight-band dosing yields a small and non-clinically relevant decrease in variability of AUC0–24h.

A Dried Blood Spot Analysis for Solithromycin in Adolescents, Children, and Infants: A Short Communication.

Solithromycin is a fourth-generation macrolide antibiotic with potential efficacy in pediatric community-acquired bacterial pneumonia. Pharmacokinetic (PK) studies of solithromycin in pediatric subjects are limited, therefore application of minimally invasive drug sampling techniques, such as dried blood spots (DBS), may enhance the enrollment of children in PK studies. The objectives of this study were to compare solithromycin concentrations in DBS with those in liquid plasma samples (LPS) and to quantify the effects of modeling DBS concentrations on the results of a population PK model. Comparability analysis was performed on matched DBS and LPS solithromycin concentrations collected from two different phase 1 clinical trials of solithromycin treatment in children (clinicaltrials.gov #NCT01966055 and #NCT02268279). Comparability of solithromycin concentrations was evaluated based on DBS:LPS ratio, median percentage prediction error, and median absolute percentage prediction error. The effect of correcting DBS concentrations for both hematocrit and protein binding was investigated. In addition, a previously published population PK model (NONMEM) was leveraged to compare parameter estimates resulting from either DBS or LPS concentrations. A total of 672 paired DBS-LPS concentrations were available from 95 subjects (age: 0-17 years of age). The median (range) LPS and DBS solithromycin concentrations were 0.3 (0.01-12) mcg/mL and 0.32 (0.01-14) mcg/mL, respectively. Median percentage prediction error and median absolute percentage prediction error of raw DBS to LPS solithromycin concentrations were 5.26% and 22.95%, respectively. In addition, the majority of population PK parameter estimates resulting from modeling DBS concentrations were within 15% of those obtained from modeling LPS concentrations. Solithromycin concentrations in DBS were similar to those measured in LPS and did not require correction for hematocrit or protein binding.

Comparison of the Predictive Performance Between Cystatin C and Serum Creatinine by Vancomycin via a Population Pharmacokinetic Models: A Prospective Study in a Chinese Population.

Most of the current published population pharmacokinetic (PopPK) models are based on serum creatinine, but we often encounter an underestimation of its concentration in our clinical work. Therefore, we established a cystatin C-based model of vancomycin. The purpose of this study was to externally verify the PopPK model of vancomycin based on the glomerular filtration rate (GFR) estimated by serum cystatin C in our previous study and to compare the prediction performance of cystatin C (Cys C) and serum creatinine (SCR)-based models. The external data set consists of adults receiving vancomycin treatment at The First Affiliated Hospital of Guangxi Medical University. We summarized and restored published models based on serum creatinine values from the literature and used our external data set for initial screening. Visual and external verifications were used to further select candidate models for comparison. The mean prediction error (ME), mean absolute error (MAE) and root mean squared error (RMSE) were the primary outcomes for the overall comparison. Group comparisons of patients with different glomerular filtration rates (GFRs), ages and body mass index (BMI) levels were obtained by the Bayesian method. A total of 156 patients with 233 samples were collected as an external data set. Sixteen published models were summarized and restored. After screening, four candidate models suitable for the external data set were finally obtained for comparison. The cystatin C-based model has a smaller ME value in the overall comparison. In the group comparison, serum creatinine-based models were underestimated in the prediction for patient groups with age ≥ 60years, abnormal BMI values and GFR < 90ml/min/1.73 m2, for which the cystatin C-based model could solve this problem. After comparison, we suggest that cystatin C is a superior renal function marker to serum creatinine for vancomycin PopPK models.

Population Pharmacokinetic Analysis of Bisoprolol in Patients With Acute Coronary Syndrome.

To date, many questions about the extent and cause of pharmacokinetic (PK) variability of even the most widely studied and prescribed β1-adrenergic receptor blockers, such as metoprolol and bisoprolol, remain unanswered. Given that there are still no published population pharmacokinetic (PopPK) analyses of bisoprolol in routinely treated patients with acute coronary syndrome (ACS), the aim of this study was to determine its PK variability in 71 Serbian patients with ACS. PopPK analysis was conducted using a nonlinear mixed-effects model (NONMEM), version 7.3.0 (Icon Development Solutions). In each patient, the same formulation of bisoprolol was administered once or twice daily at a total daily dose of 0.625-7.5 mg. We separately assessed the effects of 31 covariates on the PKs of bisoprolol, and our results indicated that only 2 covariates could have possible influence on the variability of the clearance of bisoprolol: the mean daily dose of the drug and smoking habits of patients. These findings suggest that possible autoinduction of drug metabolism by higher total daily doses and induction of cytochrome P450 isoform 3A4 (CYP3A4) by cigarette smoke in liver could be the potential causes of increased total clearance of bisoprolol in patients with ACS.

Pharmacokinetic/pharmacodynamic predictions and clinical outcomes of patients with augmented renal clearance and Pseudomonas aeruginosa bacteremia and/or pneumonia treated with extended infusion cefepime versus extended infusion piperacillin/tazobactam.

Aim:We sought to correlate pharmacokinetic (PK)/pharmacodynamic (PD) predictions of antibacterial efficacy and clinical outcomes in patients with augmented renal clearance (ARC) and Pseudomonas aeruginosa bacteremia or pneumonia treated with extended infusion cefepime or piperacillin/tazobactam.Materials and Methods:Cefepime (2 g every 8 h) and piperacillin/tazobactam (4.5 g every 8 h) were administered over 4 h after a loading dose infused over 30 min, and minimum inhibitory concentration was determined by E-test. Published population PK evaluations in critically ill patients were used, and PD analyses were conducted using estimated patient-specific PK parameters and known minimum inhibitory concentration values for P. aeruginosa. Concentration–time profiles were generated every 6 min using first-dose drug exposure estimates including a loading infusion, and free concentration above the minimum inhibitory concentration (fT> MIC) was estimated. Clinical cure was defined as resolution of signs and symptoms attributable to P. aeruginosa infection without need for escalation of antimicrobial.Results:One hundred and two patients were included (36 cefepime and 66 piperacillin/tazobactam). The two groups of patients had similar age, serum creatinine, weight, and creatinine clearance. The majority of patients required intensive care unit care (63.9% vs. 63.6%) and most had pneumonia (61%). The fT>MIC (93.6 [69.9–100] vs. 57.2 [47.6–72.4], P < 0.001) and clinical cure (91.7% vs. 74.2%, P = 0.039) were significantly higher in cefepime group, whereas mortality (8.3% vs. 22.7%, P = 0.1) and infection-related mortality (0% vs. 2%, P = 0.54) were similar.Conclusions:Patients with ARC and P. aeruginosa pneumonia and/or bacteremia who received extended-infusion cefepime achieved higher fT>MIC and clinical cure than those receiving extended infusion piperacillin/tazobactam.

Population pharmacokinetics of FOLFIRINOX: a review of studies and parameters.

FOLFIRINOX regimen is commonly used in colorectal and more recently pancreatic cancer. However, FOLFIRINOX induces significant and dose-limiting toxic effects leading to empirical dose reduction and sometimes treatment discontinuation. Model-based FOLFIRINOX regimen optimization might help improving patients' outcome. As a first step, the current review aims at bringing together all published population pharmacokinetics models for FOLFIRINOX anticancer drugs. A literature search was conducted in the PubMed database from inception to February 2018, using the following terms: population pharmacokinetic(s), irinotecan, oxaliplatin, fluorouracil, FOLFIRI, FOLFOX, FOLFIRINOX. Only articles displaying nonlinear mixed effect models were included. Study description, pharmacokinetic parameter values and influential covariates are reported. For each model, the typical pharmacokinetic profile was simulated for the standard FOLFIRINOX protocol. The FOLFIRINOX compounds have been studied only separately so far. A total of six articles were retained for 5-fluorouracil, 6 for oxaliplatin and 5 for irinotecan (also including metabolites). Either one- or two-compartment models have been described for 5-fluorouracil, while two- or three-compartment models were reported for oxaliplatin and irinotecan pharmacokinetics. Non-linear elimination was sometimes reported for 5-fluorouracil. Sex and body size were found as influential covariates for all molecules in some publications. Despite some differences in model structures and parameter values, the simulated profiles and subsequent exposure were consistent between studies. The current review allows for a global understanding of FOLFIRINOX pharmacokinetics, and will provide a basis for further development of pharmacokinetics-pharmacodynamics-toxicity models for model-driven FOLFIRINOX protocol optimization to reach the best benefit-to-risk ratio.

Rivaroxaban plasma levels in patients admitted for bleeding events: insights from a prospective study

BackgroundSerious bleeding events have been frequently described in patients taking direct oral anticoagulants (DOAC). In secondary analyses of phase 3 trials, DOAC plasma concentrations were shown to correlate with bleeding outcomes. This study aimed to describe rivaroxaban plasma levels in patients admitted to the emergency department (ED) for bleeding events. For each patient, risk factors for experiencing bleeding events were also investigated.MethodsThis analysis was part of an observational study conducted in the ED of two teaching hospitals. Plasma samples from 10 rivaroxaban-treated patients admitted for bleeding events were collected. Rivaroxaban plasma concentrations were determined by calibrated chromogenic anti-Xa assay. The measured rivaroxaban levels were then extrapolated at trough using a published population pharmacokinetic (PopPK) model, and compared to on-therapy ranges observed in large clinical trials. For each patient, clinical, medication and ABCB1 genotype data were collected.ResultsRivaroxaban measurements varied from 5 to 358 ng/ml, with a post-intake delay ranging from 9 to 38 h. At trough, estimated plasma concentrations were between 12 and 251 ng/ml (median value 94 ng/ml). Four patients had higher-than-expected rivaroxaban levels. Inadequate dose regimen, excessive alcohol consumption and lack of treatment reassessment were observed in several patients. Half of patients were taking ≥1 drug with potential pharmacokinetics interactions (e.g. amiodarone, diltiazem), while half of patients were taking ≥1 drug increasing the risk of bleeding. All 3 patients with available genotyping data and higher-than-expected rivaroxaban levels were heterozygous or homozygous mutated for the ABCB1 1236C > T, 2677G > T, 3435 C > T and rs4148738 single nucleotide polymorphisms (SNP).ConclusionsRivaroxaban patients admitted to the ED for bleeding events showed highly variable plasma concentrations. This analysis underlines the usefulness of rapid DOAC measurement and the value of PopPK models to estimate concentrations at trough in a context where the post-intake delay is unmanageable. Close patient follow-up, including renal function assessment and drug interactions review, is essential for bleeding risk minimization.

Achievement of Therapeutic Vancomycin Exposure With Continuous Infusion in Critically Ill Children.

Describe and assess a continuous infusion dosing scheme of vancomycin therapy in critically ill children. Retrospective single-center study, January to June 2015. PICU located within a French tertiary academic pediatric hospital. All children admitted in the PICU from January 2015 to June 2015, receiving continuous infusion of vancomycin therapy. None. Clinical and biological data, vancomycin dosing information, and plasma concentrations were recorded. Using a previously published population pharmacokinetics model, pharmacokinetic parameters were derived for each patient and vancomycin concentrations described after the loading dose. Areas under the curve were estimated for each patient, and an initial covariate-adjusted dose was calculated for every patient. A total of 87 vancomycin concentrations were analyzed from 28 patients between 1 month and 17 years old. The median (range) loading dose was 14.8 (12-16) mg/kg followed by a continuous infusion of vancomycin of 44 (35-61) mg/kg/d. On their first sample, 12 patients (43%) had a concentration between 15 and 30 mg/L. On day 1, the median (range) estimated area under the curve was 349 (201-1,001) mg/L × hr, and seven patients (25%) had an area under the curve greater than 400 mg/L × hr. Using the pharmacokinetics model, the median (range) calculated initial daily dose, taking into account age, bodyweight, and serum creatinine concentration, was 53 (36-69) mg/kg/d resulting in a simulated day 1 area under the curve of 409 (341-593) mg/L × h with a theoretical pharmacokinetic target attainment of 57%. The current continuous infusion of vancomycin dosing scheme used in our population was inappropriate and led to underexposure. Using pharmacokinetic approaches such as covariate-adjusted initial dosing and Bayesian estimation of exposure should prove useful for achieving the pharmacokinetic target.

The effect of veno-venous ECMO on the pharmacokinetics of Ritonavir, Darunavir, Tenofovir and Lamivudine

IntroductionTo our knowledge, there is no published data on the pharmacokinetic (PK) profile of antiretroviral (ART) drugs on patients undergoing extracorporeal membrane oxygenation (ECMO) therapy. We present PK analyses of Ritonavir, Darunavir, Lamivudine and Tenofovir in a patient with HIV who required veno-venous ECMO (VV ECMO). MethodsPlasma concentrations for Ritonavir, Darunavir, Tenofovir and Lamivudine were obtained while the patient was on ECMO following pre-emptive dose adjustments. Published population PK models were used to simulate plasma concentration profiles for the drugs. The population prediction and the observed plasma concentrations were then overlaid with the expected drug profiles using the individual Bayesian post-hoc parameter estimates. ResultsFollowing dose adjustments, the PK profiles of Ritonavir, Darunavir and Tenofovir fell within the expected range and appeared similar to the population prediction, although slightly different for Ritonavir. The observed data for Lamivudine and its PK profile were completely different from the data available in the literature. ConclusionsTo our knowledge, this is the first study reporting the PK profile of ART drugs during ECMO therapy. Based on our results, dose adjustment of ART drugs while on VV ECMO may be advisable. Further study of the PK profile of Lamivudine is required.

Recombinant full-length factor VIII (FVIII) and extended half-life FVIII products in prophylaxis--new insight provided by pharmacokinetic modelling.

The pharmacokinetics (PK) of extended half-life factor VIII (FVIII) products might allow longer dosing intervals in prophylaxis, potentially affecting its efficacy. We used published population PK models of a recombinant full-length FVIII (rAHF-PFM) and a recombinant B-domain-deleted FVIII Fc fusion product (rFVIIIFc) to assess the time spent weekly with FVIII levels below 3IUdL(-1) or above 10IUdL(-1) . These FVIII levels were chosen based on the observation that trough levels of 1IUdL(-1) may not be sufficient in all patients. This approach was applied to a simulated population of 1000 severe haemophilia A subjects with dosing regimens included in the prescribing information or evaluated in clinical trials. FVIII levels remained ≥3IUdL(-1) in 57% of patients treated with rAHF-PFM 30IUkg(-1) every 48h compared with 41.1%, 18.3%, 0.9% and 0% of patients treated with rFVIIIFc 30IUkg(-1) every 72h, 50IUkg(-1) every 96h or 120h and 65IUkg(-1) every 168h respectively. Patients on rAHF-PFM 30IUkg(-1) every 48h spent more time weekly with FVIII levels above 10IUdL(-1) than those on rFVIIIFc 50IUkg(-1) every 96h or 120h, and 65IUkg(-1) every 168h. In conclusion, PK modelling indicates that choice and dosing intervals of standard and extended half-life FVIII products require careful evaluation of individual PK to allow more time at protective levels, especially in patients with active lifestyles.

Prediction of flunixin tissue residue concentrations in livers from diseased cattle

Flunixin, a widely used non-steroidal anti-inflammatory drug, was a leading cause of violative residues in cattle. The objective of this analysis was to explore how the changes in pharmacokinetic (PK) parameters that may be associated with diseased animals affect the predicted liver residue of flunixin in cattle. Monte Carlo simulations for liver residues of flunixin were performed using the PK model structure and relevant PK parameter estimates from a previously published population PK model for flunixin in cattle. The magnitude of a change in the PK parameter value that resulted in a violative residue issue in more than one percent of a cattle population was compared. In this regard, elimination clearance and volume of distribution affected withdrawal times. Pathophysiological factors that can change these parameters may contribute to the occurrence of violative residues of flunixin.

抗真菌薬ボリコナゾールを安全に使用するための薬物動態パラメータの検討

Voriconazole (VRCZ) is a triazole antifungal agent that exhibits large inter-individual variability in plasma concentration. Reasons for this include non-linear pharmacokinetics due to its saturated metabolism and genetic polymorphism in CYP2C19. Because VRCZ has the potential to produce adverse reactions such as hepatotoxicity and visual disturbances, therapeutic drug monitoring is required to optimize treatment. Therefore, this study aimed to evaluate the predictive performance of published population pharmacokinetic (PPK) models of VRCZ. Demographic and laboratory data were retrospectively collected from the medical records of 39 patients who underwent VRCZ treatment. Patients were classified into lower and higher concentration groups by visual inspection of observed weight- and dose-normalized trough concentration. We assumed that the patients in the lower concentration group were more extensive metabolizers of CYP2C19 versus patients in the higher concentration group. We calculated PPK-predicted concentrations of VRCZ for each patient after taking the estimated genotype into account. Next, we examined their predictive performance by calculating the mean prediction error (ME), mean absolute prediction error (MAE), and root mean squared error (RMSE). Thirty and 9 patients were included in the lower and higher concentration groups, respectively. The predictive performance of the PPK model constructed from a Japanese phase Ⅲ study was significantly smaller than that from the other PPK studies (r = 0.868 vs 0.694, P = 0.001; ME －0.27 µg/mL, MAE ＋0.90 µg/mL, and RMSE ＋1.15 µg/mL for the Japanese PPK model). Finally, we constructed a suggested VRCZ safe dose schedule. Our findings provide useful information for adjusting the VRCZ dosage to improve clinical safety and effectiveness.

A Modeling and Simulation Approach to Characterize Methadone QT Prolongation Using Pooled Data From Five Clinical Trials in MMT Patients

Pharmacokinetic (PK)-pharmacodynamic modeling and simulation were used to establish a link between methadone dose, concentrations, and Fridericia rate-corrected QT (QTcF) interval prolongation, and to identify a dose that was associated with increased risk of developing torsade de pointes. A linear relationship between concentration and QTcF described the data from five clinical trials in patients on methadone maintenance treatment (MMT). A previously published population PK model adequately described the concentration-time data, and this model was used for simulation. QTcF was increased by a mean (90% confidence interval (CI)) of 17 (12, 22) ms per 1,000 ng/ml of methadone. Based on this model, doses >120 mg/day would increase the QTcF interval by >20 ms. The model predicts that 1-3% of patients would have ΔQTcF >60 ms, and 0.3-2.0% of patients would have QTcF >500 ms at doses of 160-200 mg/day. Our predictions are consistent with available observational data and support the need for electrocardiogram (ECG) monitoring and arrhythmia risk factor assessment in patients receiving methadone doses >120 mg/day.

Fixed Dosing Versus Body Size—Based Dosing of Monoclonal Antibodies in Adult Clinical Trials

Although without clear scientific rationale, body size-based dosing is often used for administering monoclonal antibodies (mAbs). This simulation study compared the performance of body size-based and fixed dosing in reducing pharmacokinetic (PK) and/or pharmacodynamic (PD) variability in adults for 12 mAbs with published population PK and/or PD models. At the population level, 95th percentile intervals of concentration-time profiles, distribution, and variability of exposure for 1000 subjects after both dosing approaches were examined. At the individual level, the difference between the exposures of patients with extreme body sizes from the typical exposure following both approaches was compared. The results show that the 2 dosing approaches perform similarly across the mAbs investigated with fixed dosing being better for some mAbs and body size-based dosing being better for the others. Based on this finding, we recommend using fixed dosing in first-in-human (FIH) adult studies because it offers other advantages. When sufficient data become available, a full assessment of body size effect on PK/PD should be conducted to determine the optimal dosing approach for phase 3 trials. Other factors that may affect the selection of dosing approach were also discussed. Dosing approach for mAbs in the pediatric population is out of the scope of this study.