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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. 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. 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. The analyses demonstrated the effectiveness of finerenone dose titration in managing serum potassium and provide a quantitative basis to guide safe clinical use.

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.

Anticoagulant plasma concentrations and patient characteristics might affect the benefit–risk balance of therapy. This study assessed the impact of model-predicted rivaroxaban exposure and patient characteristics on outcomes in patients receiving rivaroxaban for venous thromboembolism treatment (VTE-T) using data from the phase 3 EINSTEIN–DVT and EINSTEIN–PE studies. In the absence of measured rivaroxaban exposure, exposure estimates were predicted based on individual increases in prothrombin time (PT) and the known correlation between rivaroxaban plasma concentrations and PT dynamics. The composite efficacy outcomes evaluated were recurrent deep-vein thrombosis (DVT) and pulmonary embolism (PE) and recurrent DVT, PE and all-cause death; safety outcomes were major bleeding and the composite of major or non-major clinically relevant (NMCR) bleeding. Exposure–response relationships were evaluated using multivariate logistic and Cox regression for the twice-daily (BID) and once-daily (OD) dosing periods, respectively. Predicted rivaroxaban exposure and CrCl were significantly associated with both efficacy outcomes in the BID period. In the OD period, exposure was significantly associated with recurrent DVT and PE but not recurrent DVT, PE and all-cause death. The statistically significant exposure–efficacy relationships were shallow. Exposure–safety relationships were absent within the investigated exposure range. During both dosing periods, low baseline hemoglobin and prior bleeding were associated with the composite of major or NMCR bleeding. In conclusion, based on the underlying data and analysis, no reliable target window for exposure with improved benefit–risk could be identified within the investigated exposure range. Therefore, monitoring rivaroxaban levels is unlikely to be beneficial in VTE-T. Electronic supplementary material The online version of this article (10.1007/s11239-020-02073-z) contains supplementary material, which is available to authorized users.

Bayesian forecasting for dose individualization of prophylactic factor VIII replacement therapy using pharmacokinetic samples is challenged by large interindividual variability in the bleeding risk. A pharmacokinetic‐repeated time‐to‐event model‐based forecasting approach was developed to contrast the ability to predict the future occurrence of bleeds based on individual (i) pharmacokinetic, (ii) bleeding, and (iii) pharmacokinetic, bleeding and covariate information using observed data from the Long‐Term Efficacy Open‐Label Program in Severe Hemophilia A Disease (LEOPOLD) clinical trials (172 severe hemophilia A patients taking prophylactic treatment). The predictive performance assessed by the area under receiver operating characteristic (ROC) curves was 0.67 (95% confidence interval (CI), 0.65–0.69), 0.78 (95% CI, 0.76–0.80), and 0.79 (95% CI, 0.77–0.81) for patients ≥ 12 years when using pharmacokinetics, bleeds, and all data, respectively, suggesting that individual bleed information adds value to the optimization of prophylactic dosing regimens in severe hemophilia A. Further steps to optimize the proposed tool for factor VIII dose adaptation in the clinic are required.

Background Prophylaxis with factor VIII (FVIII) should be individualized based on patient characteristics, including FVIII pharmacokinetics. Population pharmacokinetic (popPK) modeling simplifies pharmacokinetic studies by obviating the need for multiple samples. Objective The objective of this study was to characterize the pharmacokinetics and inter-individual variability (IIV) of BAY 94-9027 in relation to patient characteristics in support of a popPK-tailored approach, including identifying the optimal number and timing of pharmacokinetic samples. Methods Pharmacokinetic samples from 198 males (aged 2‒62 years) with severe hemophilia A, enrolled in BAY 94-9027 clinical trials, were analyzed. Baseline age, height, weight, body mass index, lean body weight (LBW), von Willebrand factor (VWF) level, and race were evaluated. A popPK model was developed and used to simulate pharmacokinetic endpoints difficult to observe from measured FVIII levels, including time to maintain FVIII levels above 1, 3, and 5 IU/dL after different BAY 94-9027 doses. Results A one-compartment model adequately described BAY 94-9027 pharmacokinetics. Clearance and central volume of distribution were significantly associated with LBW; clearance was inversely correlated with VWF. Due to the monophasic pharmacokinetics and well-understood IIV sources, identification of patient pharmacokinetics was achievable with sparse blood sampling. Median predicted time to maintain FVIII levels > 1 IU/dL in patients aged ≥ 12 years ranged from 120.1 to 127.2 h after single BAY 94-9027 doses of 45‒60 IU/kg. Conclusions This analysis evaluated the pharmacokinetics of BAY 94-9027 and its sources of IIV. Using the model, determination of individual patient pharmacokinetics was possible with few FVIII samples, and a sparse sampling design to support pharmacokinetic-guided dosing was identified.

Nifurtimox (LAMPIT) has been used for decades for the treatment of Chagas disease, a chronic and potentially life-threatening disease caused by the parasite Trypanosoma cruzi. The pharmacokinetic (PK) information on nifurtimox in humans derived from controlled clinical studies is very limited. The objective was to investigate and compare the population PK of nifurtimox in adult and pediatric patients with Chagas disease to confirm the clinical dosing regimen in children, which was based on allometric approaches using the concept that a dose-equivalent exposure would reach equivalent antiparasitic efficacy as in adults. The resulting adult model adequately described the PK in adults. Significant predictors of the availability in PK were food intake, tablet formulation (fast- vs slow-dissolution tablet), study, and body weight. As the resulting adult model could not adequately predict the sparse sampled pediatric patient data, these data were analyzed separately to derive exposure estimates for comparison with adult exposure. In the population PK model for pediatric patients, significant covariates were body weight and age. As compared to adults, children aged2 years were estimated to have 50.6% higher apparent clearance. No hints of dose nonlinearity were observed in a dose range of 30 to 240 mg single dose in adults and 15 to 300 mg 3 times daily (8-20 mg/kg) in children. Altogether, this study retroactively showed that the current mg/kg dosing regimen in children reached similar exposure as in adults receiving an 8 mg/kg total daily dose.

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.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.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.The analyses demonstrated the effectiveness of finerenone dose titration in managing serum potassium and provide a quantitative basis to guide safe clinical use.

Introduction Vericiguat is a soluble guanylate cyclase stimulator developed for the treatment of symptomatic chronic heart failure (HF) in patients with ejection fraction less than 45% who had a previous decompensation event. A dedicated, randomised, Phase Ib, QT study of vericiguat (NCT03504982) in 74 adult patients with stable coronary artery disease demonstrated no clinically significant prolongation of the time-matched, placebo-adjusted change from baseline in the Fridericia-corrected QT interval (QTcF) after vericiguat 10 mg once daily at steady state. Purpose We conducted a concentration–QTc (C-QTc) modelling analysis, on data from the QT study, to investigate the potential effect of vericiguat on QTcF and define the vericiguat plasma concentration window within which a relevant prolongation in QTcF can be excluded. Methods In the QT study, the effect of vericiguat once daily (2.5 mg titrated to 5 mg and then to 10 mg [treatments A, B, C] over 42±9 days) on the QT interval was investigated. The positive control was a single dose of moxifloxacin 400 mg (treatment D) on Day 8 or Day 50 (7 days before the first vericiguat dose or 7 days after the last vericiguat dose), depending on the treatment sequence (Figure 1). Baseline electrocardiogram assessments were performed 24 h before the start of treatment (“baseline”) and at follow-up (“back-up baseline”; Figure 1). Time-matched, baseline- and placebo-adjusted QTcF (ΔΔQTc) mean values and 90% confidence intervals (CIs) were calculated. Two analytical approaches were used to calculate ΔΔQTc. The first one (“single baseline ΔΔQTc” approach) was data-driven, where ΔΔQTc was adjusted with placebo- and either “baseline” or “back-up baseline”. The second one (“modelled baseline ΔΔQTc”) accounted for individual baseline and placebo effects, such as diurnal time course, used linear mixed effects and integrated all individual baseline and placebo data. Calculated ΔΔQTc values were then related to observed vericiguat concentrations in the C-QTc modelling step, performed with linear mixed effects implemented in R (R, the R Foundation for Statistical Computing, version 3.2.5). Results The C-QTc modelling of ΔΔQTc calculated with the “single baseline ΔΔQTc” approach indicated a positive, but non-significant, slope (Figure 2A). The “modelled baseline ΔΔQTc” approach indicated a positive and statistically significant slope (Figure 2B). In both cases, the upper limits of the 90% CI were below the threshold of clinical relevance of 10 ms within the investigated exposure range (up to 745 μg/l). Conclusion Based on the presented analysis, a clinically meaningful QT prolongation was robustly excluded within the plasma concentration range associated with the recommended target dose of vericiguat 10 mg. The C-QTc analysis supports the conclusion of the primary study statistical analysis that administration of vericiguat between 2.5 and 10 mg is not associated with a clinically meaningful QTc prolongation. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Funding was provided by Bayer AG, Berlin, Germany and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA Figure 1Figure 2

Introduction: CHRONOS-3 randomized patients (pts) with relapsed iNHL to the PI3K inhibitor copanlisib 60 mg administered on Day 1, 8, 15 of 28-day cycle in combination with standard rituximab (C+R) or placebo plus rituximab (P+R) and demonstrated superior progression-free survival (PFS) of C+R vs. P+R (hazard ratio[HR]: 0.52; Matasar et al. Lancet Oncol 2021). In an updated 1-year follow-up analysis, the benefit of C+R was confirmed in the overall relapsed iNHL population (Zinzani et al., EHA 2022) and in the subset of pts with FL (see Capra et al. AACR Lymphoma 2022 abstract). We investigated popPK and ER relationships for copanlisib efficacy and safety from a pooled analysis, with a particular focus on the 1-year follow-up of CHRONOS-3 to confirm copanlisib dose selection. Methods: A comprehensive popPK model for copanlisib was developed using plasma concentrations from 712 pts across 9 copanlisib clinical Phase 1-3 studies. Demographic, laboratory, and comedication covariates were investigated for their influence on copanlisib between-patient PK variability. Individual static and time-varying exposure estimates for pts enrolled in CHRONOS-3 were derived to investigate relationships to efficacy (PFS, overall response rate [ORR], complete response [CR]) and key treatment-emergent safety events using multivariate cox proportional hazards (CPH) and logistic regression analyses, after accounting for predefined potentially prognostic demographic, laboratory, and/or disease related baseline covariates. Results: Copanlisib PK was best described by a 3-compartment PK model with first-order elimination from the central compartment following intravenous infusion. Copanlisib PK was dose proportional and time independent with no accumulation. Covariates statistically selected as influencing copanlisib PK included rifampin (strong CYP3A inducer) and itraconazole (strong CYP3A inhibitor) co-administration, female sex, Japanese pts, mild or worse hepatic impairment, and a CHRONOS-3 study effect, however all identified covariates, aside from rifampin/itraconazole, had no clinically relevant effect (≤ 35%) on copanlisib AUC. In CHRONOS-3, CPH analyses demonstrated a statistically significant positive ER relationship for PFS where greater copanlisib exposure was associated with prolonged PFS. Relative to P+R, the HR for C+R at the 5th and 95th percentile of copanlisib time-varying exposure was 0.875 and 0.217, respectively. Thus, lower copanlisib doses may result in reduced efficacy in relapsed iNHL. CPH and/or logistic regression analyses demonstrated no significant ER relationship for ORR and investigated adverse events. Based on the modelling, lower starting doses of copanlisib are not anticipated to improve safety and tolerability. The ER analyses support the overall positive benefit/risk assessment of copanlisib reported from the clinical efficacy and results of CHRONOS-3 in iNHL. Conclusions: PopPK and ER analyses support copanlisib 60 mg administered on Day 1, 8, 15 of 28-day cycle dose selection in the relapsed iNHL population. Citation Format: Jonathan Moss, Dirk Garmann, Rupert Austin, Florian Hiemeyer, Patricia DeLora, Matthew J Matasar, Pier Luigi Zinzani, Vita Beckert, Lidia Mongay Soler, Barrett H Childs, Peter N Morcos. Copanlisib population pharmacokinetics (popPK) and exposure-response (ER) in relapsed indolent non-Hodgkin lymphoma (iNHL): Analysis from the 1-year follow-up of the phase III, randomized CHRONOS-3 trial [abstract]. In: Proceedings of the Third AACR International Meeting: Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2022 Jun 23-26; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2022;3(5_Suppl):Abstract nr A25.

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. Electronic supplementary material The online version of this article (10.1007/s40262-019-00820-x) contains supplementary material, which is available to authorized users.

Prothrombin time (PT) is a measure of coagulation status and was assessed in the majority of patients in the rivaroxaban phase II and III clinical trials as a pharmacodynamic marker. In the absence of sufficient phase III pharmacokinetic (PK) data to provide individual exposure measures for input into rivaroxaban exposure-response analyses, the aim of the present study was to investigate the use of PT-adjustment approaches (i.e., the use of observed individual PT measurements) to enhance the prediction of individual rivaroxaban exposure metrics (derived using a previously developed integrated population PK model) based on the observed linear relationship between PT and rivaroxaban plasma concentrations. The PT-adjustment approaches were established using time-matched PK and PT measurements, which were available from 1,779 patients across four phase II trials and one phase III trial of rivaroxaban. PT-adjusted exposure estimates improved the identification of statistically significant effects when compared with covariate-only exposure estimates.

Background 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%. Objective 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). Methods Vericiguat and NT-proBNP plasma concentrations in 454 and 432 patients in SOCRATES-REDUCED, respectively, were analyzed using nonlinear mixed-effects modeling. Results 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]. Conclusions 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. Clinical Trial Identifier NCT01951625. Supplementary Information The online version contains supplementary material available at 10.1007/s40262-021-01024-y.

The population pharmacokinetics (PK) of rivaroxaban have been evaluated in several population-specific models. We developed an integrated population PK model using pooled data from 4,918 patients in 7 clinical trials across all approved indications. Effects of gender, age, and weight on apparent clearance (CL/F) and apparent volume of distribution (V/F), renal function, and comedication on CL/F, and relative bioavailability as a function of dose (F) were analyzed. Virtual subpopulations for exposure simulations were defined by age, creatinine clearance (CrCL) and body mass index (BMI). Rivaroxaban PK were adequately described by a one-compartment disposition model with a first-order absorption rate constant. Significant effects of CrCL, use of comedications, and study population on CL/F, age, weight, and gender on V/F, and dose on F were identified. CrCL had a modest influence on exposure, whereas age and BMI had a minor influence. The model was suitable to predict rivaroxaban exposure in patient subgroups of special interest.

To compare the pharmacokinetics (PK) of the progestin levonorgestrel for various routes of administration, an integrated population PK analysis was performed. This analysis integrated data from 10 clinical pharmacology studies and resulted in a single, comprehensive population PK model (and its applications) describing the PK of levonorgestrel and its variability for 6 levonorgestrel-containing contraceptives: 3 intrauterine systems (IUSs; levonorgestrel [LNG]-IUS 20 [Mirena® ], LNG-IUS 12 [Kyleena® ], and LNG-IUS 8 [Jaydess® /Skyla® ]); 2 oral contraceptives (the progestin-only pill [Microlut® /Norgeston® ] and the combined oral contraceptive [Miranova® ]); and a subdermal implant (Jadelle® ). The levonorgestrel-containing contraceptives administered orally or as an implant act mainly via their systemic (unbound) levonorgestrel exposure, whereas levonorgestrel administered via an IUS is released directly into the uterine cavity, resulting in lower systemic levonorgestrel concentrations. The integrated population PK analysis revealed that the combined oral contraceptive led to the highest levonorgestrel exposure, followed by the progestin-only pill and the implant, which led to similar levonorgestrel exposure, and the IUSs, which led to the lowest levonorgestrel exposure (in decreasing order: LNG-IUS 20, LNG-IUS 12, and LNG-IUS 8). The difference was even more distinct at the end of the indicated duration of use of 3 years (LNG-IUS 8) and 5 years (LNG-IUS 20 and LNG-IUS 12). Comparing the 3 IUSs and the implant, in vivo release rates were highest for the implant, followed by LNG-IUS 20, then LNG-IUS 12, and were lowest for LNG-IUS 8. This is in line with the comparison of the total levonorgestrel concentrations.

The population pharmacokinetics (PK) of rivaroxaban have been evaluated in several population‐specific models. We developed an integrated population PK model using pooled data from 4,918 patients in 7 clinical trials across all approved indications. Effects of gender, age, and weight on apparent clearance (CL/F) and apparent volume of distribution (V/F), renal function, and comedication on CL/F, and relative bioavailability as a function of dose (F) were analyzed. Virtual subpopulations for exposure simulations were defined by age, creatinine clearance (CrCL) and body mass index (BMI). Rivaroxaban PK were adequately described by a one‐compartment disposition model with a first‐order absorption rate constant. Significant effects of CrCL, use of comedications, and study population on CL/F, age, weight, and gender on V/F, and dose on F were identified. CrCL had a modest influence on exposure, whereas age and BMI had a minor influence. The model was suitable to predict rivaroxaban exposure in patient subgroups of special interest.

Introduction The pharmacokinetics (PK), safety and efficacy of BAY 81-8973, a full-length, unmodified, recombinant human factor VIII (FVIII), were evaluated in the LEOPOLD trials. Aim The aim of this study was to develop a population PK model based on pooled data from the LEOPOLD trials and to investigate the importance of including samples with FVIII levels below the limit of quantitation (BLQ) to estimate half-life. Methods The analysis included 1535 PK observations (measured by the chromogenic assay) from 183 male patients with haemophilia A aged 1‒61 years from the 3 LEOPOLD trials. The limit of quantitation was 1.5 IU dL−1 for the majority of samples. Population PK models that included or excluded BLQ samples were used for FVIII half-life estimations, and simulations were performed using both estimates to explore the influence on the time below a determined FVIII threshold. Results In the data set used, approximately 16.5% of samples were BLQ, which is not uncommon for FVIII PK data sets. The structural model to describe the PK of BAY 81-8973 was a two-compartment model similar to that seen for other FVIII products. If BLQ samples were excluded from the model, FVIII half-life estimations were longer compared with a model that included BLQ samples. Conclusions It is essential to assess the importance of BLQ samples when performing population PK estimates of half-life for any FVIII product. Exclusion of BLQ data from half-life estimations based on population PK models may result in an overestimation of half-life and underestimation of time under a predetermined FVIII threshold, resulting in potential underdosing of patients.

Background: Cisplatin resistance has been mainly associated with decreased cellular accumulation and increased intracellular glutathione (GSH) levels. ATP is known to increase the membrane permeability of cells and to decrease intracellular GSH levels. Our study aimed at using extracellular ATP to sensitize ovarian carcinoma cells towards cisplatin. Methods: The MTT assay was used to determine the EC50 of cisplatin in the human ovarian carcinoma cell line A2780 and its cisplatin-resistant variant A2780cis. Intracellular platinum concentrations were determined using flameless atomic absorption spectrometry. Results: Preincubation and concomitant incubation with ATP did not alter the EC50 of cisplatin. The presence of 100 µM ATP along with cisplatin decreased cell survival in A2780 but not in A2780cis cells. Extracellular ATP did not increase the cellular accumulation of cisplatin in both A2780 and A2780cis cells. Conclusion: The presence of extracellular ATP during treatment with cisplatin leads to additive cytotoxicity in the sensitive A2780 but not in cisplatin-resistant A2780cis cells.

The development of resistance is one of the major limitations for the use of platinum (Pt) complexes in cancer chemotherapy. As reduced cellular uptake is a well-known resistance mechanism of cisplatin we explored the potential to overcome resistance in cisplatin-resistant A2780 ovarian carcinoma cells by means of macromolecular prodrugs exploiting endocytosis as alternative uptake mechanism. Two Pt-albumin (PL04-HSA, PL07-HSA) complexes and one Pt-polyethylene glycol complex (PEG(10k)-(Mal-Pt-DACH)(2)) were investigated. Intracellular platinum accumulation was quantified by FAAS. Cytotoxic activity was measured using the MTT assay. Endocytosis mechanisms were investigated by co-incubation experiments with bafilomycin A(1) and methyl-beta-cyclodextrin, inhibitors of the clathrin-mediated and caveolae-mediated endocytosis, respectively. Whereas the intracellular accumulation of the low molecular precursors PL04 and PL07 was reduced in the resistant cell variant, no difference between sensitive and resistant cells was observed for the three macromolecular complexes. In the presence of bafilomycin A(1) intracellular accumulation of all investigated macromolecular complexes was decreased whereas methyl-beta-cyclodextrin only affected the Pt-PEG complex. The Pt-PEG complex exhibited a higher cytotoxic activity than the albumin conjugates but also showed cross-resistance with cisplatin. In conclusion, cellular accumulation of macromolecular platinum complexes is not altered in cisplatin-resistant A2780 cells as these complexes enter the cells mainly via endocytotic pathways. Macromolecular platinum complexes specially designed to circumvent reduced cellular accumulation may be a promising approach to overcome cisplatin resistance.

Background: The relationship between factor VIII (FVIII) level or time spent below a certain FVIII level and bleeding rate has previously been analyzed using different regression analysis methods (Collins PW, et al. J Thromb Haemost. 2009;7[3]:413-420; Ahnström J, et al. Haemophilia. 2004;10[6]:689-697; den Uijl IE, et al. Haemophilia. 2011;17[1]:41-44). Although a relationship could be generally confirmed, results were not fully consistent. Nevertheless pharmacokinetic (PK)-guided dosing that targets a certain trough FVIII level, usually 1 IU/dL, is used in clinical practice. Objectives: To establish a PK/pharmacodynamic (PD) relationship between FVIII replacement and the occurrence of repeated bleeds and to investigate the effect of PK-guided dosing by simulations Patients/methods: Data from 121 patients aged 12-61 years with severe hemophilia A (FVIII Results: A relationship between FVIII concentrations over time and bleeding hazard could be identified. In addition, a time-dependent effect was significant in the analysis, resulting in a decrease in bleeding risk when patients were treated prophylactically with BAY 81-8973. Documented bleeds in the year before the study gave insight into the different bleeding risks of patients. Simulation results show that a fixed dose of FVIII on a study level might be as effective as PK-guided dosing. Conclusion: The patient's documented bleeding history (phenotype) should be considered when dosing decisions for replacement therapy are being made. Disclosures Garmann: Bayer Pharma AG: Employment. Frede:Bayer Pharma AG: Employment. Shah:Bayer HealthCare: Employment. Ploeger:Bayer Pharma AG: Employment.

Decreased influx represents one of the major resistance mechanisms of platinum complexes. In order to address the question if this mechanism of resistance can be overcome by enhancing the lipophilicity of platinum complexes, we investigated the influence of lipophilicity on cellular accumulation and cytotoxicity in a panel of oxaliplatin analogues with different carrier ligands. Cellular accumulation, DNA platination and cytotoxicity were measured in a cisplatin-sensitive and -resistant ovarian carcinoma (A2780/A2780cis) and in an oxaliplatin-sensitive and -resistant ileocecal colorectal adenocarcinoma (HCT-8/HCT-8ox) cell line pair. Platinum concentrations were determined by flameless atomic absorption spectrometry or adsorptive stripping voltammetry. Passive diffusion represented the main influx mechanism of oxaliplatin analogues during the first minutes of incubation as indicated by a correlation between lipophilicity and early influx rate. Afterwards, the predominant influx mechanism was lipophilicity-independent. More lipophilic complexes showed a reduced cytotoxic activity, although the early influx rate was increased. The resistance profiles of the two cell line pairs were found to be different: HCT-8ox cells were less resistant against more lipophilic complexes, whereas A2780cis cells exhibited a comparable degree of resistance against all investigated compounds. However, the reduction in resistance factor of HCT-8ox cells cannot be explained by increased influx suggesting that other resistance mechanisms are circumvented upon exposure to more lipophilic compounds. Though resistance against more lipophilic platinum complexes analogues is lower we conclude that enhancing lipophilicity is not a successful strategy to overcome platinum resistance as higher lipophilicity is also associated with lower cytotoxic activity.

Four platinum (II) complexes (13-16) were synthesized by reacting either [Pt trans-DACH](NO(3))(2) with a 6-maleimidocaproic acid, a 15-maleimido-4,7,10,13-tetroxapentadecanoic acid, and a 6-maleimido-4-oxacaproic ester derivative of cyclobutane-1,1-dicarboxylic acid (CDBA) or [Pt(NH(3))(2)](NO(3))(2) with a 6-maleimido-4-oxacaproic ester derivative of CBDA. Both complexes containing the 6-maleimido-4-oxacaproic ester (15, 16) showed good water solubility (>/=8 mg/mL) and CE experiments revealed rapid binding to human serum albumin and the formation of biadducts with dGMP and dAMP. In the MaTu xenograft model in nude mice, both complexes showed an improved antitumor effect at their maximum tolerated dose (2 x 50 mg/kg carboplatin equivalents) compared to therapy with carboplatin at equimolar dose or at its optimal dose (2 x 75 mg/kg).

Background BAY 81-8973 is a full-length, unmodified, recombinant human factor VIII (FVIII) for the treatment of hemophilia A. Objective The aim of this study was to compare the pharmacokinetic (PK) profile of BAY 81-8973 with antihemophilic factor (recombinant) plasma/albumin-free method (rAHF-PFM) Patients/Methods In this phase I, open-label, crossover study, men aged 18–65 years with severe hemophilia A and ≥150 exposure days to FVIII were randomized to receive a single intravenous infusion of 50 IU/kg BAY 81-8973 or rAHF-PFM, followed by crossover to a single infusion of the other treatment. FVIII levels were measured in plasma over 48 h using one-stage and chromogenic assays. PK parameters, including area under the curve from time zero to the last data point (AUClast; primary outcome) and half-life (t ½) were calculated. A population PK model was developed to simulate various treatment scenarios. Results Eighteen patients were randomized and analyzed. Using both assays, geometric mean (coefficient of variation [%CV]) AUClast was significantly higher, and t ½ was significantly longer, for BAY 81-8973 versus rAHF-PFM (one-stage, AUClast: 1660 IU·h/dL [29.4] vs. 1310 IU·h/dL [29.0], p 1 IU/dL could be maintained with 14.4 IU/kg BAY 81-8973 or 39.1 IU/kg rAHF-PFM 3×/week. Conclusions BAY 81-8973 showed a superior PK profile versus rAHF-PFM. The same FVIII trough threshold level could be achieved with lower doses of BAY 81-8973 versus rAHF-PFM. ClinicalTrials.gov: NCT02483208.