Physiologically based pharmacokinetic (PBPK) modeling is a mechanistic cornerstone of model-informed drug development (MIDD), providing evidence for regulatory decisions. PBPK models integrate physiological and pharmacological data and have been applied across a plethora of contexts of use, including assessing drug-drug interactions (DDIs), optimizing dosing for special populations (e.g., pediatrics and those with organ impairment), and supporting clinical study waivers. However, despite the established history of PBPK modeling, a significant gap persists between the quality of submitted PBPK analyses and regulatory expectations. Recent reviews by the European Medicines Agency (EMA) and other regulatory bodies indicate that many PBPK models are not deemed adequately qualified for their intended application. This discrepancy highlights the need for consolidated guidance on model development, evaluation, and application, particularly to harmonize terminology and expectations with the ICH M15 guideline. To address this challenge, this paper provides comprehensive best-practice guidance for the development, verification, validation, and applicability assessment of PBPK models. We delineate strategies for defining explicit technical criteria to ensure models are appropriately qualified and demonstrably fit-for-purpose for a specific context of use. This guidance aims to enhance the quality, consistency, and regulatory acceptance of PBPK analyses, thereby strengthening the reliability of MIDD evidence supporting drug development and approval.

Physiologically Based Biopharmaceutics Modeling (PBBM) links in vitro solubility and dissolution kinetics of oral drugs to Physiologically Based Pharmacokinetic (PBPK) models, enabling the prediction of drug bioavailability. This approach reduces reliance on animal experimentation during drug development. Part 1 of this series introduces a novel, open-source PBBM workflow using the Open Systems Pharmacology (OSP) Software Suite. It combines the newly developed OSP solubility toolbox to estimate drug aqueous solubility and bile salt micelle partitioning from in vitro data, with an updated MoBi® dissolution model that accounts for factors such as hydrodynamic diffusion layer thickness changes and micelle partitioning. This approach was applied to poorly soluble, highly permeable vericiguat, a first-in-class soluble guanylate cyclase (sGC) stimulator for the treatment of chronic heart failure. The solubility models effectively described the aqueous solubility-pH profile and bile salt partitioning, while the dissolution model captured the in vitro dissolution kinetics of various tablet formulations. Part 2 focuses on integrating developed PBBM sub-models into PBPK models using PK-Sim® to predict vericiguat's clinical pharmacokinetics after oral administration. This PBBM workflow demonstrates potential for diverse applications, including predictive bioavailability and bioequivalence assessments, in silico formulation optimization, formulation bridging, dose selection, and setting dissolution specifications.

This manuscript introduces a novel, free and open-source physiologically based biopharmaceutics modeling (PBBM) workflow to support decision-making during oral drug product development. Developed within the Open Systems Pharmacology (OSP) framework, this workflow combines three open-source tools to predict in vivo absorption by integrating solubility, dissolution, and systemic pharmacokinetics. The PBBM workflow was successfully applied by 1) deriving solubility and dissolution parameters for vericiguat from in vitro experiments as detailed in the accompanying Part 1 publication (Vrenken et al., 2025); 2) then integrating these parameters into a physiologically based pharmacokinetic (PBPK) model. This model incorporates updates to luminal parameters, including pH and bile salt concentration, and employs a new dissolution model accounting for bile salt effects and hydrodynamics. Simulations of vericiguat pharmacokinetics in fasted, fed, and proton pump inhibitor (PPI)-treated states showed good agreement with observed clinical data. Further refinements that could enhance the PBBM workflow's capabilities were identified. However, the successful application to vericiguat highlights its potential for PBBM applications, including virtual bioequivalence assessments, formulation bridging, and dose selection. While validation across additional case studies is necessary, this free and open-source approach provides a robust foundation for advancing PBBM.

Plasma N-terminal prohormone B-type natriuretic peptide (NT-proBNP) concentration is a heart failure (HF) biomarker in adults and children. Its prognostic value for HF-related events has been established only in adults. Therefore, we aimed to test the hypothesis that plasma NT-proBNP concentrations predicted the risk of heart transplantation or death in children with HF. We studied the medical records of 109 children with HF enrolled in the IBM Watson Explorys database and from 150 children enrolled in the Pediatric Cardiomyopathy Registry (PCMR). Nonlinear regression was used to assess the relationship between plasma NT-proBNP concentrations and the risk of events in the two cohorts. All children in the PCMR cohort had dilated cardiomyopathy. The Explorys cohort also included children with congenital cardiovascular malformations. Median plasma NT-proBNP concentrations were 1250 pg/mL and 184 pg/mL in the Explorys and PCMR cohorts, respectively. The percentage of deaths/heart transplantations was 7%/22%, over 2 years in the Explorys cohort and 3%/16% over 5 years in the PCMR cohort. Mean estimates of plasma NT-proBNP concentration indicative of half-maximum relative risk for events (EC50 values) at 2 and 5 years were 3730 pg/mL and 4199 pg/mL, respectively, values both close to the mean of 3880 pg/mL established for adults with HF. The plasma NT-proBNP concentration is suitable for estimating relative risk of mortality and heart transplantation in children with HF, independent of etiology and shows similar relations to clinical outcomes as in adults, indicating its likely value as a surrogate marker both for adult and pediatric HF.ClinicalTrials.gov Identifiers: NCT00005391 (May 26, 2000), NCT01873976 (June 10, 2013).

BAY 2413555 is a novel selective and reversible positive allosteric modulator of the type 2 muscarinic acetylcholine (M2) receptor, aimed at enhancing parasympathetic signaling and restoring cardiac autonomic balance for the treatment of heart failure (HF). This study tested the safety, tolerability and pharmacokinetics of this novel therapeutic option. REMOTE-HF was a multicenter, double-blind, randomized, placebo-controlled, phase Ib dose-titration study with two active arms. Study participants had an established diagnosis of HF with NYHA Class I-III and LVEF <= 45%. Patients were required to have an implanted cardiac defibrillator (ICD) or cardiac resynchronization therapy (CRT) device because of the potential for bradycardia or AV conduction delay, which may be induced by BAY 2413555. The study period included a screening and run-in period, followed by a treatment period of over 28 days, consisting of two parts, A and B, comprising 14 days each. Participants were randomized into 1 of 3 arms: a placebo arm and two BAY 2413555 arms-one receiving 1.25 mg in both Part A and Part B (BAY 1.25 mg-1.25 mg) and the other receiving 1.25 mg in Part A followed by 5 mg in Part B (BAY 1.25 mg-5 mg). The primary safety endpoint was the number of participants with treatment-emergent adverse events (TEAEs). Secondary endpoints included number of participants with high degree AV block or symptomatic pauses/ bradycardia and changes from baseline in resting heart rate after 2 and 4 weeks of dosing with BAY 2413555. Changes from baseline in heart rate recovery (HRR) at 1 and 2 min after exercise testing and chronotropic reserve (CR) were also assessed. Of the anticipated 129 participants, 22 participants were randomized: 7 to placebo, 8 to BAY 1.25 mg-1.25 mg, and 7 to BAY 1.25 mg-5 mg. The study was terminated early based on new and unexpected preclinical findings from a chronic animal toxicology study in monkeys in which evidence of increased vascular inflammation was observed, leading to a no longer favorable risk-benefit balance for the intended long-term (i.e., life-long) treatment of heart failure patients. Comparable adverse events were not encountered in REMOTE-HF. Overall, until the termination of the study, BAY 2413555 was safe and well tolerated, with no deaths or TEAEs leading to discontinuation, and no symptomatic bradycardia or AV blocks observed. There was a larger change in the mean HRR at 60 s in the pooled BAY 2413555 treatment arms in Part A (1.25 mg) compared to the placebo (+ 7.3 vs. -6.7 bpm), indicating enhanced cardiac parasympathetic activity. Administration of 1.25 mg and 5 mg BAY 2413555 was safe and well tolerated in both active treatment arms, with no concerning safety findings observed. However, due to the limited number of subjects resulting from early termination, the results should be considered with caution and viewed as exploratory. There were promising signs of target engagement, providing grounds for further exploration of the mechanism

Vericiguat is an oral soluble guanylate cyclase stimulator and enhances the cyclic guanosine monophosphate pathway independently of nitric oxide as well as synergistically in normal- and low-nitric oxide conditions. This review describes the pharmacokinetic and pharmacodynamic profile of vericiguat and summarizes the effect of vericiguat on cardiac electrophysiology and population pharmacokinetic/pharmacodynamic relationships. Vericiguat demonstrates virtually complete absorption and increased exposure with food. Vericiguat has high oral bioavailability when taken with food (93.0%) with dose-proportional pharmacokinetics in healthy volunteers. Vericiguat has slightly less than dose-proportional pharmacokinetics with a slight decrease in bioavailability at higher doses in patients with heart failure (HF) with reduced ejection fraction (HFrEF). Vericiguat is a low-clearance drug, with a half-life of approximately 20 h in healthy volunteers and 30 h in patients with HFrEF. Most drug metabolism is achieved by glucuronidation. Vericiguat has pharmacodynamic effects as expected from its pharmacological mechanism of action (i.e., relaxation of the smooth muscles in the vasculature leading to changes in hemodynamics). In the VICTORIA trial (NCT02861534), which enrolled patients with HFrEF, no meaningful exposure-response relationships for the incidence of symptomatic hypotension or syncope were evident. There were no significant imbalances in the incidence of undesirable hemodynamic-related effects (symptomatic hypotension and syncope) in subgroups with HFrEF defined by sex, age, race, and renal impairment. In addition, most patients achieved the 10-mg target dose per the blood pressure-guided titration regimen. No dose adjustments due to body weight, age, sex, race, or hepatic/renal impairment are necessary in adult patients with HFrEF. Observed and predicted changes in vericiguat exposure when co-administered with perpetrator drugs were small and not clinically meaningful. In addition, vericiguat has low potential as a perpetrator to affect exposure and/or pharmacodynamic effects of drugs commonly prescribed in patients with heart failure; therefore, no dose adjustment of these drugs is required in patients taking vericiguat. There is limited experience on the combined use of vericiguat with long-acting nitrates in patients with HFrEF. The ongoing VICTOR trial (NCT05093933), which is investigating vericiguat in patients with HFrEF, permits the co-administration of long-acting nitrates. Combined use of vericiguat and phosphodiesterase type-5 inhibitors has not been studied in patients with HFrEF and is therefore not recommended because of the potential increased risk for symptomatic hypotension. Vericiguat was not associated with electrophysiological abnormalities in preclinical and clinical studies up to the approved dose of 10 mg at steady state. Vericiguat is approved for the treatment of recently decompensated patients with worsening HFrEF. Vericiguat's safety and efficacy profile in patients with HFrEF will be further characterized by the VICTOR trial (NCT05093933) in adults without recent decompensation and in a pediatric population with HF due to left ventricular systolic dysfunction (VALOR trial, NCT05714085).

The PATENT‐CHILD study investigated riociguat in children aged ≥ 6 to <18 years with pulmonary arterial hypertension (PAH) treated with tablets or an oral pediatric suspension based on bodyweight‐adjusted dosing of up to 2.5 mg three times daily. PATENT‐CHILD demonstrated an acceptable riociguat safety profile and individual plasma concentrations in pediatric patients were consistent with those in adult patients.

Vericiguat is a soluble guanylate cyclase stimulator indicated to reduce the risk of cardiovascular death and hospitalization due to heart failure. A dedicated QTc study in patients with chronic coronary syndromes demonstrated no clinically relevant QTc effect of vericiguat for exposures across the therapeutic dose range (2.5–10 mg). Interval prolongation concentration-QTc (C-QTc) modeling was performed to complement the statistical evaluations of QTc in the dedicated QTc study. Individual time-matched, baseline- and placebo-corrected Fridericia-corrected QT interval values (ΔΔQTcF) were derived. Two approaches for ΔΔQTcF calculation were investigated: (1) ΔΔQTcF correction with data from a single baseline (as in the primary statistical analysis); and (2) ΔΔQTcF correction with a modeled baseline (considering all available individual non-treatment baselines). The ΔΔQTcF values were related to observed vericiguat concentrations with linear mixed-effects modeling. For both modeling approaches, a positive relationship was found between ΔΔQTcF and vericiguat concentration; however, the slope for the single-baseline approach was not statistically significant, whereas the slope from the modeled-baseline approach was statistically significant. The upper bound of the two-sided 90

Abstract Vericiguat (Verquvo; US: Merck, other countries: Bayer) is a novel drug for the treatment of chronic heart failure. Preclinical studies have demonstrated that the primary route of metabolism for vericiguat is glucuronidation, mainly catalyzed by uridine diphosphate‐glucuronosyltransferase (UGT)1A9 and to a lesser extent UGT1A1. Whereas a drug–drug interaction (DDI) study of the UGT1A9 inhibitor mefenamic acid showed a 20% exposure increase, the effect of UGT1A1 inhibitors has not been assessed clinically. This modeling study describes a physiologically‐based pharmacokinetic (PBPK) approach to complement the clinical DDI liability assessment and support prescription labeling. A PBPK model of vericiguat was developed based on in vitro and clinical data, verified against data from the mefenamic acid DDI study, and applied to assess the UGT1A1 DDI liability by running an in silico DDI study with the UGT1A1 inhibitor atazanavir. A minor effect with an area under the plasma concentration‐time curve (AUC) ratio of 1.12 and a peak plasma concentration ratio of 1.04 was predicted, which indicates that there is no clinically relevant DDI interaction anticipated. Additionally, the effect of potential genetic polymorphisms of UGT1A1 and UGT1A9 was evaluated, which showed that an average modest increase of up to 1.7‐fold in AUC may be expected in the case of concomitantly reduced UGT1A1 and UGT1A9 activity for subpopulations expressing non‐wild‐type variants for both isoforms. This study is a first cornerstone to qualify the PK‐Sim platform for use of UGT‐mediated DDI predictions, including PBPK models of perpetrators, such as mefenamic acid and atazanavir, and sensitive UGT substrates, such as dapagliflozin and raltegravir.

Background Electronic health record (EHR)-based identification of heart failure with preserved ejection fraction (HF-pEF) in the clinical setting may facilitate screening for clinical trials by improving the understanding of its epidemiology and outcomes; yet, previous data have yielded variable results. We sought to characterize groups identified with HFpEF by different EHR screening strategies and their associated long-term outcomes across a large and diverse population.Methods We retrospectively analyzed 116,499 consecutive patients from an academic referral center who underwent echocardiography, and 9,263 patients who underwent echocardiography within 6 months of right heart catheterization (RHC), between 2008 and 2018. EHR-based screening strategies identified patients with HFpEF using 1) International Clas-sification of Diseases (ICD)-9/10 codes, 2) H2FpEF score >6 and ejection fraction (EF) >50%, or 3) RHC wedge pressure >15 mmHg and EF >50%, when available. Primary outcomes were 1) cumulative incident heart failure hospitalization (HFH), and 2) death, over 10 years.Results There were 33,461 (29%) patients who met either ICD or H2FpEF-HFpEF definition, of whom 5,310 (16%) met both criteria. Compared to ICD-HFpEF, patients with H2FpEF-HFpEF were more likely older (median age 72 vs 67), White (78% vs 64%), and had atrial fibrillation (97% vs 41%). Among those also with RHC, 6,353 (69%) patients met any HFpEF criteria, of whom only 783 (12%) satisfied all three criteria. Female sex was more common among RHC-HFpEF (55%) compared to other methods (H2FpEF-HFpEF, 47%; ICD-HFpEF, 43%). Atrial fibrillation was substantially higher among HFpEF identified by the H2FpEF score (97%) compared to other methods (49% for ICD and 47% for RHC). Across HFpEF screening methods, 10-year cumulative incidence rates for HFH was 32% to 45% for echocardiography only and 43% to 52% for echocardiography and RHC populations; 10-year risk of death was 54% to 56% for echocardiography only and 52% to 57% for echocardiography and RHC populations.Conclusions Different EHR-based HFpEF definitions identified cohorts with modest overlap and varying baseline char-acteristics. Yet, long-term risk for HFH and death were similarly high for cohorts identified among both populations undergoing echocardiography only or echocardiography and RHC. These data aid in identifying relevant subgroups in clinical trials of HFpEF.

Vericiguat, a novel stimulator of soluble guanylate cyclase (sGC), is indicated for the treatment of patients following a hospitalization for heart failure or need for outpatient intravenous diuretics, with symptomatic chronic heart failure and ejection fraction less than 45%. Pharmacokinetic (PK) data from the phase II trial SOCRATES‐REDUCED (Soluble Guanylate Cyclase Stimulator in Heart Failure Study) and the phase III trial VICTORIA (Vericiguat Global Study in Patients With Heart Failure With Reduced Ejection Fraction) were used to characterize vericiguat PK. A total of 8,092 concentration records from 2,321 participants (362 from SOCRATES‐REDUCED and 1,959 from VICTORIA) were utilized for the development of the population PK model. The final PK model was a one‐compartment model with first‐order absorption and linear elimination. Baseline body weight and time‐varying body weight were identified as statistically significant covariates affecting apparent clearance (CL/ F ) and volume of distribution, respectively. Age, sex, race, bilirubin, estimated glomerular filtration rate, and albumin did not affect vericiguat PK. Baseline disease‐related factors, such as left ventricular ejection fraction, New York Heart Association (NYHA) class, and N‐terminal pro B‐type natriuretic peptide, also did not influence vericiguat PK. Since vericiguat is a titrated drug, the impact of vericiguat PK on the titration to and maintenance of the target dose in VICTORIA was assessed. The distribution of steady‐state doses in VICTORIA was similar across CL/ F quartiles, suggesting that the ability to reach and maintain dosing at the target 10‐mg dose was not related to vericiguat exposure.

Vericiguat, a stimulator of soluble guanylate cyclase, has been developed as a first-in-class therapy for worsening chronic heart failure in adults with left ventricular ejection fraction < 45%. The objective of this article was to characterize the pharmacokinetics and pharmacokinetic variability of vericiguat combined with guideline-directed medical therapy (standard of care), and identify exposure–response relationships for safety (hemodynamics) and pharmacodynamic markers of efficacy (N-terminal pro-B-type natriuretic peptide concentration [NT-proBNP]) in patients with heart failure and left ventricular ejection fraction < 45% in the SOCRATES-REDUCED study (NCT01951625). Vericiguat and NT-proBNP plasma concentrations in 454 and 432 patients in SOCRATES-REDUCED, respectively, were analyzed using nonlinear mixed-effects modeling. Vericiguat pharmacokinetics were well described by a one-compartment model with apparent clearance, apparent volume of distribution, and absorption rate constant. Age, bodyweight, plasma bilirubin, and creatinine clearance were identified as significant covariates on apparent clearance; sex and bodyweight on apparent volume of distribution; and bodyweight and plasma albumin level on absorption rate constant. Pharmacokinetic/pharmacodynamic analysis showed initial minor and transient effects of vericiguat on blood pressure with low clinical impact. There were no changes in heart rate following initial or repeated vericiguat administration. An exposure-dependent and time-dependent turnover pharmacokinetic/pharmacodynamic model for NT-proBNP described production and elimination rates and an demonstrated exposure-dependent reduction in [NT-proBNP] by vericiguat plus standard of care compared with placebo plus standard of care. This effect was dependent on baseline [NT-proBNP]. Vericiguat has predictable pharmacokinetics, with no long-term effects on blood pressure in patients with heart failure and left ventricular ejection fraction < 45%. A pharmacokinetic/pharmacodynamic model described a vericiguat exposure-dependent reduction of NT-proBNP. NCT01951625.

Development and guidance of dosing schemes in children have been supported by physiology-based pharmacokinetic (PBPK) modeling for many years. PBPK models are built on a generic basis, where compound- and system-specific parameters are separated and can be exchanged, allowing the translation of these models from adults to children by accounting for physiological differences. Owing to these features, PBPK modeling is a valuable approach to support clinical decision making for dosing in children. In this analysis, we evaluate pediatric PBPK models for 10 small-molecule compounds that were applied to support clinical decision processes at Bayer for their predictive power in different age groups. Ratios of PBPK-predicted to observed PK parameters for the evaluated drugs in different pediatric age groups were estimated. Predictive performance was analyzed on the basis of a 2-fold error range and the bioequivalence range (ie, 0.8 ≤ predicted/observed ≤ 1.25). For all 10 compounds, all predicted-to-observed PK ratios were within a 2-fold error range (n = 27), with two-thirds of the ratios within the bioequivalence range (n = 18). The findings demonstrate that the pharmacokinetics of these compounds was successfully and adequately predicted in different pediatric age groups. This illustrates the applicability of PBPK for guiding dosing schemes in the pediatric population.

N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) is a well‐established biomarker in heart failure (HF) but controversially discussed as a potential surrogate marker in HF trials. We analyzed the NT‐proBNP/mortality relationship in real‐world data (RWD) of 108,330 HF patients from the IBM Watson Health Explorys database and compared it with the NT‐proBNP / clinical event end‐point relationship in 20 clinical HF studies. With a hierarchical statistical model, we quantified the functional relationship and interstudy variability. To independently qualify the model, we predicted outcome hazard ratios in five phase III HF studies solely based on NT‐proBNP measured early in the respective study. In RWD and clinical studies, the relationship between NT‐proBNP and clinical outcome is well described by an E max model. The NT‐proBNP independent baseline risk (R 0 , RWD/studies median (interstudy interquartile range): 5.5%/3.0% (1.7–4.9%)) is very low compared with the potential NT‐proBNP–associated maximum risk (R max : 55.2%/79.4% (61.5–89.0%)). The NT‐proBNP concentration associated with the half‐maximal risk is comparable in RWD and across clinical studies (EC 50 : 3,880/2,414 pg/mL (1,460–4,355 pg/mL)). Model‐based predictions of phase III outcomes, relying on short‐term NT‐proBNP data only, match final trial results with comparable confidence intervals. Our analysis qualifies NT‐proBNP as a surrogate for clinical outcome in HF trials. NT‐proBNP levels after short treatment durations of less than 10 weeks quantitatively predict hazard ratios with confidence levels comparable to final trial readout. Early NT‐proBNP measurement can therefore enable shorter and smaller but still reliable HF trials.

Background In the past years, several repositories for anatomical and physiological parameters required for physiologically based pharmacokinetic modeling in pregnant women have been published. While providing a good basis, some important aspects can be further detailed. For example, they did not account for the variability associated with parameters or were lacking key parameters necessary for developing more detailed mechanistic pregnancy physiologically based pharmacokinetic models, such as the composition of pregnancy-specific tissues. Objectives The aim of this meta-analysis was to provide an updated and extended database of anatomical and physiological parameters in healthy pregnant women that also accounts for changes in the variability of a parameter throughout gestation and for the composition of pregnancy-specific tissues. Methods A systematic literature search was carried out to collect study data on pregnancy-related changes of anatomical and physiological parameters. For each parameter, a set of mathematical functions was fitted to the data and to the standard deviation observed among the data. The best performing functions were selected based on numerical and visual diagnostics as well as based on physiological plausibility. Results The literature search yielded 473 studies, 302 of which met the criteria to be further analyzed and compiled in a database. In total, the database encompassed 7729 data. Although the availability of quantitative data for some parameters remained limited, mathematical functions could be generated for many important parameters. Gaps were filled based on qualitative knowledge and based on physiologically plausible assumptions. Conclusion The presented results facilitate the integration of pregnancy-dependent changes in anatomy and physiology into mechanistic population physiologically based pharmacokinetic models. Such models can ultimately provide a valuable tool to investigate the pharmacokinetics during pregnancy in silico and support informed decision making regarding optimal dosing regimens in this vulnerable special population.

Background Since pregnant women are considerably underrepresented in clinical trials, information on optimal dosing in pregnancy is widely lacking. Physiologically based pharmacokinetic (PBPK) modeling may provide a method for predicting pharmacokinetic changes in pregnancy to guide subsequent in vivo pharmacokinetic trials in pregnant women, minimizing associated risks. Objectives The goal of this study was to build and verify a population PBPK model that predicts the maternal pharmacokinetics of three predominantly renally cleared drugs (namely cefazolin, cefuroxime, and cefradine) at different stages of pregnancy. It was further evaluated whether the fraction unbound ( f u ) could be estimated in pregnant women using a proposed scaling approach. Methods Based on a recent literature review on anatomical and physiological changes during pregnancy, a pregnancy population PBPK model was built using the software PK-Sim ® /MoBi ® . This model comprised 27 compartments, including nine pregnancy-specific compartments. The PBPK model was verified by comparing the predicted maternal pharmacokinetics of cefazolin, cefuroxime, and cefradine with observed in vivo data taken from the literature. The proposed scaling approach for estimating the f u in pregnancy was evaluated by comparing the predicted f u with experimentally observed f u values of 32 drugs taken from the literature. Results The pregnancy population PBPK model successfully predicted the pharmacokinetics of cefazolin, cefuroxime, and cefradine at all tested stages of pregnancy. All predicted plasma concentrations fell within a 2-fold error range and 85% of the predicted concentrations within a 1.25-fold error range. The f u in pregnancy could be adequately predicted using the proposed scaling approach, although a slight underestimation was evident in case of drugs bound to α 1 -acidic glycoprotein. Conclusion Pregnancy population PBPK models can provide a valuable tool to predict a priori the pharmacokinetics of predominantly renally cleared drugs in pregnant women. These models can ultimately support informed decision making regarding optimal dosing regimens in this vulnerable special population

BACKGROUND AND OBJECTIVES:Sepsis is characterised by an excessive release of inflammatory mediators substantially affecting body composition and physiology, which can be further affected by intensive care management. Consequently, drug pharmacokinetics can be substantially altered. This study aimed to extend a whole-body physiologically based pharmacokinetic (PBPK) model for healthy adults based on disease-related physiological changes of critically ill septic patients and to evaluate the accuracy of this PBPK model using vancomycin as a clinically relevant drug.METHODS:The literature was searched for relevant information on physiological changes in critically ill patients with sepsis, severe sepsis and septic shock. Consolidated information was incorporated into a validated PBPK vancomycin model for healthy adults. In addition, the model was further individualised based on patient data from a study including ten septic patients treated with intravenous vancomycin. Models were evaluated comparing predicted concentrations with observed patient concentration-time data.RESULTS:The literature-based PBPK model correctly predicted pharmacokinetic changes and observed plasma concentrations especially for the distribution phase as a result of a consideration of interstitial water accumulation. Incorporation of disease-related changes improved the model prediction from 55 to 88% within a threshold of 30% variability of predicted vs. observed concentrations. In particular, the consideration of individualised creatinine clearance data, which were highly variable in this patient population, had an influence on model performance.CONCLUSION:PBPK modelling incorporating literature data and individual patient data is able to correctly predict vancomycin pharmacokinetics in septic patients. This study therefore provides essential key parameters for further development of PBPK models and dose optimisation strategies in critically ill patients with sepsis.