NT-proBNP for Predicting All-Cause Death and Heart Transplant in Children and Adults with Heart Failure.

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).

Systemic exposure to aflibercept after intravitreal injection in premature neonates with retinopathy of prematurity: results from the FIREFLEYE randomized phase 3 study.

BACKGROUND: There are no data on pharmacokinetics, pharmacodynamics, and immunogenicity of intravitreal aflibercept in preterm infants with retinopathy of prematurity (ROP). FIREFLEYE compared aflibercept 0.4 mg/eye and laser photocoagulation in infants with acute-phase ROP requiring treatment. METHODS: Infants (gestational age ≤32 weeks or birthweight ≤1500 g) with treatment-requiring ROP in ≥1 eye were randomized 2:1 to receive aflibercept 0.4 mg or laser photocoagulation at baseline in this 24-week, randomized, open-label, noninferiority, phase 3 study. Endpoints include concentrations of free and adjusted bound aflibercept in plasma, pharmacokinetic/pharmacodynamic exploration of systemic anti-vascular endothelial growth factor effects, and immunogenicity. RESULTS: Of 113 treated infants, 75 received aflibercept 0.4 mg per eye at baseline (mean chronological age: 10.4 weeks), mostly bilaterally (71 infants), and with 1 injection/eye (120/146 eyes). Concentrations of free aflibercept were highly variable, with maximum concentration at day 1, declining thereafter. Plasma concentrations of adjusted bound (pharmacologically inactive) aflibercept increased from day 1 to week 4, decreasing up to week 24. Six infants experienced treatment-emergent serious adverse events within 30 days of treatment; aflibercept concentrations were within the range observed in other infants. There was no pattern between free and adjusted bound aflibercept concentrations and blood pressure changes up to week 4. A low-titer (1:30), non-neutralizing, treatment-emergent anti-drug antibody response was reported in 1 infant, though was not clinically relevant. CONCLUSIONS: 24-week data suggest intravitreal aflibercept for treatment of acute-phase ROP is not associated with clinically relevant effects on blood pressure, further systemic adverse events, or immunogenicity. GOV IDENTIFIER: NCT04004208.

Pharmacokinetics and pharmacodynamics of finerenone in patients with chronic kidney disease and type 2 diabetes: Insights based on FIGARO-DKD and FIDELIO-DKD.

AIMS: To perform dose-exposure-response analyses to determine the effects of finerenone doses. MATERIALS AND METHODS: Two randomized, double-blind, placebo-controlled phase 3 trials enrolling 13 026 randomized participants with type 2 diabetes (T2D) from global sites, each with an estimated glomerular filtration rate (eGFR) of 25 to 90 mL/min/1.73 m2 , a urine albumin-creatinine ratio (UACR) of 30 to 5000 mg/g, and serum potassium ≤ 4.8 mmol/L were included. Interventions were titrated doses of finerenone 10 or 20 mg versus placebo on top of standard of care. The outcomes were trajectories of plasma finerenone and serum potassium concentrations, UACR, eGFR and kidney composite outcomes, assessed using nonlinear mixed-effects population pharmacokinetic (PK)/pharmacodynamic (PD) and parametric time-to-event models. RESULTS: For potassium, lower serum levels and lower rates of hyperkalaemia were associated with higher doses of finerenone 20 mg compared to 10 mg (p < 0.001). The PK/PD model analysis linked this observed inverse association to potassium-guided dose titration. Simulations of a hypothetical trial with constant finerenone doses revealed a shallow but increasing exposure-potassium response relationship. Similarly, increasing finerenone exposures led to less than dose-proportional increasing reductions in modelled UACR. Modelled UACR explained 95% of finerenone's treatment effect in slowing chronic eGFR decline. No UACR-independent finerenone effects were identified. Neither sodium-glucose cotransporter-2 (SGLT2) inhibitor nor glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment significantly modified the effects of finerenone in reducing UACR and eGFR decline. Modelled eGFR explained 87% of finerenone's treatment effect on kidney outcomes. No eGFR-independent effects were identified. CONCLUSIONS: The analyses provide strong evidence for the effectiveness of finerenone dose titration in controlling serum potassium elevations. UACR and eGFR are predictive of kidney outcomes during finerenone treatment. Finerenone's kidney efficacy is independent of concomitant use of SGLT2 inhibitors and GLP-1RAs.

The Pharmacokinetics of the Nonsteroidal Mineralocorticoid Receptor Antagonist Finerenone.

Finerenone, a selective and nonsteroidal antagonist of the mineralocorticoid receptor, has received regulatory approval with the indication of cardiorenal protection in patients with chronic kidney disease associated with type 2 diabetes. It is rapidly and completely absorbed and undergoes first-pass metabolism in the gut wall and liver resulting in a bioavailability of 43.5%. Finerenone can be taken with or without food. The pharmacokinetics of finerenone are linear and its half-life is 2 to 3 h in the dose range of up to 20 mg. Cytochrome P450 (CYP) 3A4 (90%) and CYP2C8 (10%) are involved in the extensive biotransformation of finerenone to pharmacologically inactive metabolites, which are excreted via both renal (80%) and biliary (20%) routes. Moderate or severe renal impairment, or moderate hepatic impairment result in area-under-the-curve increases of finerenone (< 40%), which do not require a dose adjustment per se, as the starting dose is based on estimated glomerular filtration rate (eGFR) and titrated according to serum potassium levels and eGFR decline. No relevant effects of age, sex, body size or ethnicity on systemic finerenone exposure were identified. Modulators of CYP3A4 activity were found to affect finerenone exposure, consistent with its classification as a sensitive CYP3A4 substrate. Serum potassium should be monitored during drug initiation or dosage adjustment of either a moderate or weak CYP3A4 inhibitor or finerenone, and the dose of finerenone should be adjusted as appropriate. Its use with strong inhibitors is contraindicated and strong or moderate inducers of CYP3A4 should be avoided. Finerenone has no potential to affect relevant CYP enzymes and drug transporters.

Finerenone is a drug that is used to treat patients with chronic kidney disease and type 2 diabetes. Many of these patients take several medicines to treat other conditions. This review summarizes several studies showing the suitability of finerenone for these patients. Taken as a daily tablet, the dose circulates in the body before being quickly removed. The age, sex, body weight, and ethnicity of a patient do not affect dosing. As finerenone can cause an increase of serum potassium levels, potassium levels and kidney function should be measured before a patient starts treatment. The starting dose will depend on a patient's kidney function, with the dose changed according to potassium levels and changes in kidney function. A protein called cytochrome P450 3A4 (CYP3A4) is key to removing finerenone from the body. Anyone taking medicines that strongly inhibit CYP3A4 should not take finerenone. Serum potassium levels should be measured before starting finerenone or changing the dose of either finerenone or 'moderate' or 'weak' CYP3A4 inhibitors, with the dose of finerenone adjusted as appropriate. Finerenone should not be taken alongside drugs that result in 'moderate' or 'strong' increases in CYP3A4 activity. In patients with moderate hepatic impairment, potassium should be monitored and finerenone doses be adjusted as appropriate. Finerenone is not expected to affect other drugs. Finerenone slows decline in kidney function, a treatment effect associated with reducing urine albumin. Potassium level-guided starting dose and dose changes support finerenone being effectively used and well tolerated in patients.

Evaluating Kidney Function Decline in Children with Chronic Kidney Disease Using a Multi-Institutional Electronic Health Record Database.

BACKGROUND: The objectives of this study were to use electronic health record data from a US national multicenter pediatric network to identify a large cohort of children with CKD, evaluate CKD progression, and examine clinical risk factors for kidney function decline. METHODS: This retrospective cohort study identified children seen between January 1, 2009, to February 28, 2022. Data were from six pediatric health systems in PEDSnet. We identified children aged 18 months to 18 years who met criteria for CKD: two eGFR values <90 and ≥15 ml/min per 1.73 m2 separated by ≥90 days without an intervening value ≥90. CKD progression was defined as a composite outcome: eGFR <15 ml/min per 1.73 m2, ≥50% eGFR decline, long-term dialysis, or kidney transplant. Subcohorts were defined based on CKD etiology: glomerular, nonglomerular, or malignancy. We assessed the association of hypertension (≥2 visits with hypertension diagnosis code) and proteinuria (≥1 urinalysis with ≥1+ protein) within 2 years of cohort entrance on the composite outcome. RESULTS: Among 7,148,875 children, we identified 11,240 (15.7 per 10,000) with CKD (median age 11 years, 50% female). The median follow-up was 5.1 (interquartile range 2.8-8.3) years, the median initial eGFR was 75.3 (interquartile range 61-83) ml/min per 1.73 m2, 37% had proteinuria, and 35% had hypertension. The following were associated with CKD progression: lower eGFR category (adjusted hazard ratio [aHR] 1.44 [95% confidence interval (95% CI), 1.23 to 1.69], aHR 2.38 [95% CI, 2.02 to 2.79], aHR 5.75 [95% CI, 5.05 to 6.55] for eGFR 45-59 ml/min per 1.73 m2, 30-44 ml/min per 1.73 m2, 15-29 ml/min per 1.73 m2 at cohort entrance, respectively, when compared with eGFR 60-89 ml/min per 1.73 m2), glomerular disease (aHR 2.01 [95% CI, 1.78 to 2.28]), malignancy (aHR 1.79 [95% CI, 1.52 to 2.11]), proteinuria (aHR 2.23 [95% CI, 1.89 to 2.62]), hypertension (aHR 1.49 [95% CI, 1.22 to 1.82]), proteinuria and hypertension together (aHR 3.98 [95% CI, 3.40 to 4.68]), count of complex chronic comorbidities (aHR 1.07 [95% CI, 1.05 to 1.10] per additional comorbid body system), male sex (aHR 1.16 [95% CI, 1.05 to 1.28]), and younger age at cohort entrance (aHR 0.95 [95% CI, 0.94 to 0.96] per year older). CONCLUSIONS: In large-scale real-world data for children with CKD, disease etiology, albuminuria, hypertension, age, male sex, lower eGFR, and greater medical complexity at start of follow-up were associated with more rapid decline in kidney function.

Dose-Exposure-Response Analysis of the Nonsteroidal Mineralocorticoid Receptor Antagonist Finerenone on UACR and eGFR: An Analysis from FIDELIO-DKD.

BACKGROUND AND OBJECTIVE: Finerenone reduces the risk of kidney failure in patients with chronic kidney disease and type 2 diabetes. Changes in the urine albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) are surrogates for kidney failure. We performed dose-exposure-response analyses to determine the effects of finerenone on these surrogates in the presence and absence of sodium glucose co-transporter-2 inhibitors (SGLT2is) using individual patient data from the FIDELIO-DKD study. METHODS: Non-linear mixed-effects population pharmacokinetic/pharmacodynamic models were used to quantify disease progression in terms of UACR and eGFR during standard of care and pharmacodynamic effects of finerenone in the presence and absence of SGLT2i use. RESULTS: The population pharmacokinetic/pharmacodynamic models adequately described effects of finerenone exposure in reducing UACR and slowing eGFR decline over time. The reduction in UACR achieved with finerenone during the first year predicted its subsequent effect in slowing progressive eGFR decline. SGLT2i use did not modify the effects of finerenone. The population pharmacokinetic/pharmacodynamic model demonstrated with 97.5% confidence that finerenone was at least 94.1% as efficacious in reducing UACR in patients using an SGLT2i compared with patients not using an SGLT2i based on the 95% confidence interval of the SGLT2i-finerenone interaction from 94.1 to 122%. The 95% confidence interval of the SGLT2i-finerenone interaction for the UACR-mediated effect on chronic eGFR decline was 9.5-144%. CONCLUSIONS: We developed a model that accurately describes the finerenone dose-exposure-response relationship for UACR and eGFR. The model demonstrated that the early UACR effect of finerenone predicted its long-term effect on eGFR decline. These effects were independent of concomitant SGLT2i use.

Finerenone Dose-Exposure-Serum Potassium Response Analysis of FIDELIO-DKD Phase III: The Role of Dosing, Titration, and Inclusion Criteria.

BACKGROUND: Finerenone is a nonsteroidal selective mineralocorticoid receptor antagonist (MRA) that demonstrated efficacy in delaying the progression of chronic kidney disease (CKD) and reducing cardiovascular events in patients with CKD and type 2 diabetes mellitus in FIDELIO-DKD, where 5734 patients were randomized 1:1 to receive either finerenone or placebo, with a median follow-up of 2.6 years. Doses of finerenone 10 or 20 mg once daily were titrated based on (serum) potassium and estimated glomerular filtration rate. The MRA mode of action increases potassium. METHODS: Nonlinear mixed-effects population pharmacokinetic/pharmacodynamic models were used to analyze the finerenone dose-exposure-response relationship for potassium in FIDELIO-DKD. Individual time-varying exposures from pharmacokinetic analyses were related to the potassium response via a maximal effect, indirect-response model informed by 148,384 serum potassium measurements. RESULTS: Although observed potassium levels decreased with increasing dose (i.e., inverse relation), model-based simulations for a fixed-dose setting (i.e., no dose titration) revealed the intrinsic finerenone dose-exposure-potassium response, with potassium levels increasing in a dose- and exposure-dependent manner, thus explaining the apparent conflict. The potassium limit for inclusion and uptitration from finerenone 10 to 20 mg in FIDELIO-DKD was ≤ 4.8 mmol/L. Modified limits of ≤ 5.0 mmol/L were simulated, resulting in higher hyperkalemia frequencies for both the finerenone and the placebo arms, whereas the relative hyperkalemia risk of a finerenone treatment compared with placebo did not increase. CONCLUSIONS: The analyses demonstrated the effectiveness of finerenone dose titration in managing serum potassium and provide a quantitative basis to guide safe clinical use.

Physiologically-based pharmacokinetic modeling to predict CYP3A4-mediated drug-drug interactions of finerenone.

Finerenone is a nonsteroidal, selective mineralocorticoid receptor antagonist that recently demonstrated its efficacy to delay chronic kidney disease (CKD) progression and reduce cardiovascular events in patients with CKD and type 2 diabetes. Here, we report the development of a physiologically-based pharmacokinetic (PBPK) model for finerenone and its application as a victim drug of cytochrome P450 3A4 (CYP3A4)-mediated drug-drug interactions (DDIs) using the open-source PBPK platform PK-Sim, which has recently been qualified for this application purpose. First, the PBPK model for finerenone was developed using physicochemical, in vitro, and clinical (including mass balance) data. Subsequently, the finerenone model was validated regarding the contribution of CYP3A4 metabolism to total clearance by comparing to observed data from dedicated clinical interaction studies with erythromycin (simulated geometric mean ratios of the area under the plasma concentration-time curve [AUCR] of 3.46 and geometric mean peak plasma concentration ratios [Cmax Rs] of 2.00 vs. observed of 3.48 and 1.88, respectively) and verapamil (simulated AUCR of 2.91 and Cmax R of 1.86 vs. observed of 2.70 and 2.22, respectively). Finally, the finerenone model was applied to predict clinically untested DDI studies with various CYP3A4 modulators. An AUCR of 6.31 and a Cmax R of 2.37 was predicted with itraconazole, of 5.28 and 2.25 with clarithromycin, 1.59 and 1.40 with cimetidine, 1.57 and 1.38 with fluvoxamine, 0.19 and 0.32 with efavirenz, and 0.07 and 0.14 with rifampicin. This PBPK analysis provides a quantitative basis to guide the label and clinical use of finerenone with concomitant CYP3A4 modulators.

Finerenone Dose-Exposure-Response for the Primary Kidney Outcome in FIDELIO-DKD Phase III: Population Pharmacokinetic and Time-to-Event Analysis.

BACKGROUND: Finerenone is a nonsteroidal selective mineralocorticoid receptor antagonist that recently demonstrated efficacy in delaying chronic kidney disease progression and reducing cardiovascular events in patients with chronic kidney disease and type 2 diabetes in FIDELIO-DKD, where 5734 patients were randomized 1:1 to receive either titrated finerenone doses of 10 or 20 mg once daily or placebo, with a median follow-up of 2.6 years. METHODS: Nonlinear mixed-effects population pharmacokinetic models were used to analyze the pharmacokinetics in FIDELIO-DKD, sparsely sampled in all subjects receiving finerenone. Post-hoc model parameter estimates together with dosing histories allowed the computation of individual exposures used in subsequent parametric time-to-event analyses of the primary kidney outcome. RESULTS: The population pharmacokinetic model adequately captured the typical pharmacokinetics of finerenone and its variability. Either covariate effects or multivariate forward-simulations in subgroups of interest were contained within the equivalence range of 80-125% around typical exposure. The exposure-response relationship was characterized by a maximum effect model estimating a low half-maximal effect concentration at 0.166 µg/L and a maximal hazard decrease at 36.1%. Prognostic factors for the treatment-independent chronic kidney disease progression risk included a low estimated glomerular filtration rate and a high urine-to-creatinine ratio increasing the risk, while concomitant sodium-glucose transport protein 2 inhibitor use decreased the risk. Importantly, no sodium-glucose transport protein 2 inhibitor co-medication-related modification of the finerenone treatment effect per se could be identified. CONCLUSIONS: None of the tested pharmacokinetic covariates had clinical relevance in FIDELIO-DKD. Finerenone effects on kidney outcomes approached saturation towards 20 mg once daily and sodium-glucose transport protein 2 inhibitor use provided additive benefits.

Predictive Performance of Physiology-Based Pharmacokinetic Dose Estimates for Pediatric Trials: Evaluation With 10 Bayer Small-Molecule Compounds in Children.

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.

Durability of VEGF Suppression With Intravitreal Aflibercept and Brolucizumab: Using Pharmacokinetic Modeling to Understand Clinical Outcomes.

Purpose: To investigate whether vascular endothelial growth factor (VEGF)-suppression durations contribute to our understanding of clinical trial outcomes by simulating vitreous molar concentrations (Cvm) of intravitreal aflibercept (IVT-AFL) and brolucizumab (IVT-BRO) using pharmacokinetic (PK) modeling. Methods: A PK model simulated Cvm after single-dose IVT-AFL, IVT-BRO, and ranibizumab (IVT-RAN), and extrapolated intraocular VEGF-suppression thresholds and durations. Vitreous PK after multidose regimens used in studies of IVT-AFL versus IVT-BRO were simulated and compared with best-corrected visual acuity (BCVA) data. Results: Cvm peaked higher (Cmax) and decreased more quickly to the VEGF-suppression threshold and minimum (Cmin) levels with IVT-BRO than with IVT-AFL, consistent with their molar doses calculated using molecular weights and vitreous half-lives (26 kDa and 115 kDa; 4.4-5.1 and 9.1-11 days, respectively). The mean VEGF suppression durations were 71 days for IVT-AFL 2 mg and 51 (48-59) days for IVT-BRO 6 mg. Based on dosing in OSPREY (matched dosing to week [w]32 for both agents; thereafter, IVT-AFL every eight weeks [q8w] and IVT-BRO q12w for the last two doses [w32→w44 and w44→w56]), IVT-BRO showed wider Cmax-Cmin fluctuations than IVT-AFL. The IVT-BRO Cmin fell below the VEGF-suppression threshold at timepoints near w56, when decreases in BCVA were also observed. The IVT-AFL vitreous Cmin remained above the suppression threshold through w56, where BCVA gains were maintained. Conclusions: The PK-modeled mean VEGF-suppression duration for IVT-BRO was substantially shorter than that published for IVT-AFL and may not be sufficient to effectively suppress VEGF throughout q12w dosing. Translational Relevance: The PK modeling suggests that more patients may be maintained on ≥q12w dosing with IVT-AFL than with IVT-BRO.

NT-proBNP Qualifies as a Surrogate for Clinical End Points in Heart Failure.

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 Emax model. The NT-proBNP independent baseline risk (R0 , 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 (Rmax : 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 (EC50 : 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.

Integration of physiological changes during the postpartum period into a PBPK framework and prediction of amoxicillin disposition before and shortly after delivery.

The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model for amoxicillin for non-pregnant, pregnant and postpartum populations by compiling a database incorporating reported changes in the anatomy and physiology throughout the postpartum period. A systematic literature search was conducted to collect data on anatomical and physiological changes in postpartum women. Empirical functions were generated describing the observed changes providing the basis for a generic PBPK framework. The fraction unbound ([Formula: see text]) of predominantly albumin-bound drugs was predicted in postpartum women and compared with experimentally observed values. Finally, a specific amoxicillin PBPK model was newly developed, verified for non-pregnant populations and translated into the third trimester of pregnancy (29.4-36.9 gestational weeks) and early postpartum period (drug administration 1.5-3.8 h after delivery). Pharmacokinetic predictions were evaluated using published clinical data. The literature search yielded 105 studies with 1092 anatomical and physiological data values on 3742 postpartum women which were used to generate various functions describing the observed trends. The [Formula: see text] could be adequately scaled to postpartum women. The pregnancy PBPK model predicted amoxicillin disposition adequately as did the postpartum PBPK model, although clearance was somewhat underestimated. While more research is needed to establish fully verified postpartum PBPK models, this study provides a repository of anatomical and physiological changes in postpartum women that can be applied to future modeling efforts. Ultimately, structural refinement of the developed postpartum PBPK model could be used to investigate drug transfer to the neonate via breast-feeding in silico.

Physiologically Based Pharmacokinetic Modeling of Monoclonal Antibodies in Pediatric Populations Using PK-Sim.

Physiologically based pharmacokinetic (PBPK) models are increasingly used to support pediatric dose selection for small molecule drugs. In contrast, only a few pediatric PBPK models for therapeutic antibodies have been published recently, and the knowledge on the maturation of the processes relevant for antibody pharmacokinetics (PK) is limited compared to small molecules. The aim of this study was, thus, to evaluate predictions from antibody PBPK models for children which were scaled from PBPK models for adults in order to identify respective knowledge gaps. For this, we used the generic PBPK model implemented in PK-Sim without further modifications. Focusing on general clearance and distribution mechanisms, we selected palivizumab and bevacizumab as examples for this evaluation since they show simple, linear PK which is not governed by drug-specific target mediated disposition at usual therapeutic dosages, and their PK has been studied in pediatric populations after intravenous application. The evaluation showed that the PK of palivizumab was overall reasonably well predicted, while the clearance for bevacizumab seems to be underestimated. Without implementing additional ontogeny for antibody PK-specific processes into the PBPK model, bodyweight normalized clearance increases only moderately in young children compared to adults. If growth during aging at the time of the simulation was considered, the apparent clearance is approximately 20% higher compared to simulations for which growth was not considered for newborns due to the long half-life of antibodies. To fully understand the differences and similarities in the PK of antibodies between adults and children, further research is needed. By integrating available information and data, PBPK modeling can contribute to reveal the relevance of involved processes as well as to generate and test hypothesis.

A Physiologically-Based Quantitative Systems Pharmacology Model of the Incretin Hormones GLP-1 and GIP and the DPP4 Inhibitor Sitagliptin.

Incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) play a major role in regulation of postprandial glucose and the development of type 2 diabetes mellitus. The incretins are rapidly metabolized, primarily by the enzyme dipeptidyl-peptidase 4 (DPP4), and the neutral endopeptidase (NEP), although the exact metabolization pathways are unknown. We developed a physiologically-based (PB) quantitative systems pharmacology model of GLP-1 and GIP and their metabolites that describes the secretion of the incretins in response to intraduodenal glucose infusions and their degradation by DPP4 and NEP. The model describes the observed data and suggests that NEP significantly contributes to the metabolization of GLP-1, and the traditional assays for the total GLP-1 and GIP forms measure yet unknown entities produced by NEP. We further extended the model with a PB pharmacokinetics/pharmacodynamics model of the DPP4 inhibitor sitagliptin that allows predictions of the effects of this medication class on incretin concentrations.

Population Pharmacokinetic and Exposure-Response Analysis of Finerenone: Insights Based on Phase IIb Data and Simulations to Support Dose Selection for Pivotal Trials in Type 2 Diabetes with Chronic Kidney Disease.

BACKGROUND: Finerenone (BAY 94-8862) is a potent non-steroidal, selective mineralocorticoid receptor antagonist being developed for the treatment of patients with type 2 diabetes and chronic kidney disease. METHODS: We present the population pharmacokinetics and pharmacodynamics (PD) analysis for efficacy and safety markers based on data from two clinical phase IIb studies: ARTS-DN (NCT01874431) and ARTS-DN Japan (NCT01968668). RESULTS: The pharmacokinetics of finerenone were adequately characterized, with estimated glomerular filtration rate (eGFR) and body weight as influencing covariates. The area under the plasma concentration-time curve in Japanese patients did not differ from that in the global population, and the investigated pharmacokinetics were dose- and time-linear. In addition, the pharmacokinetic model provided robust individual exposure estimates to study exposure-response. The concentration-effect relationship over time for the efficacy marker urinary albumin:creatinine ratio (UACR) was well-characterized by a maximum effect model indicating saturation at high exposures. For the safety markers, a log-linear model and a power model were identified for serum potassium concentration and eGFR, respectively, indicating attenuation of effect gains at high exposures. There was no apparent ethnic effect on the investigated pharmacokinetic-pharmacodynamic relationships. The model-predicted times to reach the full (99%) steady-state drug effect on UACR, serum potassium, and eGFR were 138, 20, and 85 days, respectively, while the pharmacokinetic half-life was 2-3 h and steady state was achieved after 2 days, indicating timescale separation. CONCLUSION: Our dose-exposure-response modeling and simulation indicates effects were largely saturated at finerenone 20 mg and doses of both 10 and 20 mg once daily appear safe and efficacious at reducing albuminuria.

Application of Physiologically-Based and Population Pharmacokinetic Modeling for Dose Finding and Confirmation During the Pediatric Development of Moxifloxacin.

Moxifloxacin is a widely used fluoroquinolone for the treatment of complicated intra-abdominal infections. We applied physiologically-based pharmacokinetic (PBPK) and population pharmacokinetic (popPK) modeling to support dose selection in pediatric patients. We scaled an existing adult PBPK model to children based on prior physiological knowledge. The resulting model proposed an age-dependent dosing regimen that was tested in a phase I study. Refined doses were then tested in a phase III study. A popPK analysis of all clinical pediatric data confirmed the PBPK predictions, including the proposed dosing schedule in children, and supported pharmacokinetics-related safety/efficacy questions. The pediatric PBPK model adequately predicted the doses necessary to achieve antimicrobial efficacy while maintaining safety in the phase I and III pediatric studies. Altogether, this study retroactively demonstrated the robustness and utility of modeling to support dose finding and confirmation in pediatric drug development for moxifloxacin.

Physiologically Based Pharmacokinetic Models for Prediction of Complex CYP2C8 and OATP1B1 (SLCO1B1) Drug-Drug-Gene Interactions: A Modeling Network of Gemfibrozil, Repaglinide, Pioglitazone, Rifampicin, Clarithromycin and Itraconazole.

BACKGROUND: Drug-drug interactions (DDIs) and drug-gene interactions (DGIs) pose a serious health risk that can be avoided by dose adaptation. These interactions are investigated in strictly controlled setups, quantifying the effect of one perpetrator drug or polymorphism at a time, but in real life patients frequently take more than two medications and are very heterogenous regarding their genetic background. OBJECTIVES: The first objective of this study was to provide whole-body physiologically based pharmacokinetic (PBPK) models of important cytochrome P450 (CYP) 2C8 perpetrator and victim drugs, built and evaluated for DDI and DGI studies. The second objective was to apply these models to describe complex interactions with more than two interacting partners. METHODS: PBPK models of the CYP2C8 and organic-anion-transporting polypeptide (OATP) 1B1 perpetrator drug gemfibrozil (parent-metabolite model) and the CYP2C8 victim drugs repaglinide (also an OATP1B1 substrate) and pioglitazone were developed using a total of 103 clinical studies. For evaluation, these models were applied to predict 34 different DDI studies, establishing a CYP2C8 and OATP1B1 PBPK DDI modeling network. RESULTS: The newly developed models show a good performance, accurately describing plasma concentration-time profiles, area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) values, DDI studies as well as DGI studies. All 34 of the modeled DDI AUC ratios (AUC during DDI/AUC control) and DDI Cmax ratios (Cmax during DDI/Cmax control) are within twofold of the observed values. CONCLUSIONS: Whole-body PBPK models of gemfibrozil, repaglinide, and pioglitazone have been built and qualified for DDI and DGI prediction. PBPK modeling is applicable to investigate complex interactions between multiple drugs and genetic polymorphisms.

Physiologically-Based Pharmacokinetic Models for CYP1A2 Drug-Drug Interaction Prediction: A Modeling Network of Fluvoxamine, Theophylline, Caffeine, Rifampicin, and Midazolam.

This study provides whole-body physiologically-based pharmacokinetic models of the strong index cytochrome P450 (CYP)1A2 inhibitor and moderate CYP3A4 inhibitor fluvoxamine and of the sensitive CYP1A2 substrate theophylline. Both models were built and thoroughly evaluated for their application in drug-drug interaction (DDI) prediction in a network of perpetrator and victim drugs, combining them with previously developed models of caffeine (sensitive index CYP1A2 substrate), rifampicin (moderate CYP1A2 inducer), and midazolam (sensitive index CYP3A4 substrate). Simulation of all reported clinical DDI studies for combinations of these five drugs shows that the presented models reliably predict the observed drug concentrations, resulting in seven of eight of the predicted DDI area under the plasma curve (AUC) ratios (AUC during DDI/AUC control) and seven of seven of the predicted DDI peak plasma concentration (Cmax ) ratios (Cmax during DDI/Cmax control) within twofold of the observed values. Therefore, the models are considered qualified for DDI prediction. All models are comprehensively documented and publicly available, as tools to support the drug development and clinical research community.