Previous Pharmacokinetic Research Articles

Pharmacokinetics and safety of mavacamten in healthy Chinese participants with different CYP2C19 phenotypes.

Obstructive hypertrophic cardiomyopathy (oHCM) is a subtype of HCM characterized by left ventricular outflow tract obstruction resulting from cardiac muscle hypertrophy and anatomic alterations in the mitral valve and apparatus. Mavacamten, a cardiac myosin inhibitor metabolized primarily by CYP2C19 in the liver, is the first and only targeted medication approved for the treatment of symptomatic New York Heart Association (NYHA) class II-III oHCM. Previous pharmacokinetic (PK) results of mavacamten in healthy Caucasian, Japanese, and Asian participants demonstrated that mavacamten exposure was affected by CYP2C19 metabolism status. This open-label, parallel-group, phase I trial aimed to determine the PK and safety of mavacamten in healthy Chinese participants with different CYP2C19 genotypes. The primary outcome was to define the PK of mavacamten in healthy Chinese participants; the secondary outcome was to examine safety and tolerability. After a single oral dose of 15 or 25 mg mavacamten in fasted healthy adult Chinese individuals, Cmax was reached within a median Tmax of 0.6-1.5 h, indicating rapid absorption. Inter-individual variability was moderate, and individuals carrying non-functional CYP2C19 alleles (*2/*2, *3/*3, or *2/*3) exhibited longer half-life and increased total exposure. After stratification of CYP2C19 genotypes, total mavacamten exposures were similar among different ethnic groups when compared with prior PK studies. No significant adverse events were observed in this study. Single oral administration of mavacamten at 15 mg was well tolerated across all CYP2C19 genotypes, and 25 mg dose was well tolerated in healthy participants with CYP2C19 genotypes UM/RM/NM. The PK profile of mavacamten in the healthy Chinese population was consistent with that in other healthy populations.

On inductive biases for the robust and interpretable prediction of drug concentrations using deep compartment models

Conventional pharmacokinetic (PK) models contain several useful inductive biases guiding model convergence to more realistic predictions of drug concentrations. Implementing similar biases in standard neural networks can be challenging, but might be fundamental for model robustness and predictive performance. In this study, we build on the deep compartment model (DCM) architecture by introducing constraints that guide the model to explore more physiologically realistic solutions. Using a simulation study, we show that constraints improve robustness in sparse data settings. Additionally, predicted concentration–time curves took on more realistic shapes compared to unconstrained models. Next, we propose the use of multi-branch networks, where each covariate can be connected to specific PK parameters, to reduce the propensity of models to learn spurious effects. Another benefit of this architecture is that covariate effects are isolated, enabling model interpretability through the visualization of learned functions. We show that all models were sensitive to learning false effects when trained in the presence of unimportant covariates, indicating the importance of selecting an appropriate set of covariates to link to the PK parameters. Finally, we compared the predictive performance of the constrained models to previous relevant population PK models on a real-world data set of 69 haemophilia A patients. Here, constrained models obtained higher accuracy compared to the standard DCM, with the multi-branch network outperforming previous PK models. We conclude that physiological-based constraints can improve model robustness. We describe an interpretable architecture which aids model trust, which will be key for the adoption of machine learning-based models in clinical practice.

Quantitative modeling of tumor dynamics and development of drug resistance in non-small cell lung cancer patients treated with erlotinib.

Insight into the development of treatment resistance can support the optimization of anticancer treatments. This study aims to characterize the tumor dynamics and development of drug resistance in patients with non-small cell lung cancer treated with erlotinib, and investigate the relationship between baseline circulating tumor DNA (ctDNA) data and tumor dynamics. Data obtained for the analysis included (1) intensively sampled erlotinib concentrations from 29 patients from two previous pharmacokinetic (PK) studies, and (2) tumor sizes, ctDNA measurements, and sparsely sampled erlotinib concentrations from 18 patients from the START-TKI study. A two-compartment population PK model was first developed which well-described the PK data. The PK model was subsequently applied to investigate the exposure-tumor dynamics relationship. To characterize the tumor dynamics, models accounting for intra-tumor heterogeneity and acquired resistance with or without primary resistance were investigated. Eventually, the model assumed acquired resistance only resulted in an adequate fit. Additionally, models with or without exposure-dependent treatment effect were explored, and no significant exposure-response relationship for erlotinib was identified within the observed exposure range. Subsequently, the correlation of baseline ctDNA data on EGFR and TP53 variants with tumor dynamics' parameters was explored. The analysis indicated that higher baseline plasma EGFR mutation levels correlated with increased tumor growth rates, and the inclusion of ctDNA measurements improved model fit. This result suggests that quantitative ctDNA measurements at baseline have the potential to be a predictor of anticancer treatment response. The developed model can potentially be applied to design optimal treatment regimens that better overcome resistance.

P966 The intra-patient variability of adalimumab clearance during an intensive sampling study of Crohn’s disease patients receiving maintenance therapy

Abstract Background Lower adalimumab (ADA) clearance (CL) is associated with improved outcomes in Crohn’s disease (CD) and may be a superior pharmacokinetic (PK) measure than ADA concentrations. We compared intra-patient variability in ADA CL and concentrations within a 14-day treatment cycle and across two consecutive cycles under maintenance treatment. Methods In a previous PK study of CD patients receiving maintenance ADA 40mg fortnightly, samples were collected intensively at 3 visits (day 4-6, 7-9, and 13-14 post dose) across 2 consecutive cycles. Available sera from this cohort were subsequently used to measure ADA concentrations (lower limit quantification: <1.6 µg/mL) and antibody to adalimumab (ATA) status using a drug tolerant homogeneous mobility shift assay, and albumin. Apparent ADA CL (L/day) was calculated incorporating these measure parameters in a nonlinear mixed effect model with Bayesian priors (under steady state assumption) with dose and inter-dose interval with ATA and albumin as covariate. Rates of sustained clinical and biochemical remission (Harvey Bradshaw Index (HBI) score consistently <5 and CRP levels consistently <3 mg/L) were estimated for each patient. Longitudinal changes in PK parameters within-and-across cycles were evaluated using intra-patient coefficient of variation and linear mixed effect models. Results Sera was available from 70 study visits in 12 patients (6 males, mean age 36 years). Median ADA concentrations and CL were 8 µg/mL (IQR 6.0-10.4) and 0.374 L/day (IQR 0.29-0.43), respectively, with ATA detected in one patient (#9). Estimated ADA concentrations and CL is presented in the Table. Intra-patient variability in CL was much lower across the two 14-day cycle (9% and 7%, respectively) compared to intra-patient variability in ADA concentration (15% and 13%, respectively). Linear mixed effect models confirmed these findings with no impact of sampling time on CL (intercept=0.46±0.12 L/day; slope estimate=0.002±0.002 L/day; p=0.16) as compared to significant change in ADA concentrations (intercept=10.6±1.2 µg/mL; slope estimate=-0.25±0.03 µg/mL; p<0.01) over inter-dose interval sampling time. Sustained clinical and biochemical remission was achieved in 5/12 patients (42%); none presented with CL >0.8 L/day (a cut-off previously associated with worse outcomes). Of 7 patients without sustained clinical and biochemical remission, two presented with optimal concentrations (> 10 µg/mL), thus suggestive of mechanistic failure, and one developed ATA, lower concentration and higher ADA CL. Conclusion CL is subject to less intra-patient variability than ADA concentrations, supporting its assessment at any time point within a 14-day treatment cycle.

Pharmacokinetic-Pharmacodynamic Modeling of the Ponesimod Effect on Heart Rate in Patients With Multiple Sclerosis.

The purpose of this study was to characterize the ponesimod effect on the heart rate (HR) in patients with multiple sclerosis (MS). A previous pharmacokinetic (PK) and pharmacodynamic model developed in healthy participants was updated using data from phase II and III trials conducted in patients with MS. Clinically relevant covariates were assessed. Simulations were conducted to evaluate the impact of the lack of adherence to ponesimod treatment and provide guidance in cases of treatment re-initiation. The maximal effect parameter of the PK/HR model was lower in patients with MS (23.5% decrease) compared with healthy volunteers (43.2%). The effect of patient covariates on PK/HR was similar to those identified in healthy participants and not clinically relevant in patients with MS. The population PK/HR model well characterized the effect of ponesimod on the time course of HR in patients with MS. After 2 weeks of treatment with 10 mg or higher doses, the model indicated full tolerance development. After repeated dosing at 20 mg, tolerance was maintained > 60% of the steady-state tolerance for up to 4 days after the last dose. Re-initiating with gradual uptitration is recommended if drug discontinuation lasts ≥ 4 days. This managed the negative chronotropic effects of ponesimod. No bradycardia events were observed within the first 2 weeks of treatment in patients with relapsing MS with a baseline HR > 55 bpm. This justifies the recommendation included in the human prescription drug labeling to monitor HR after the first ponesimod dose in these patients.

Individualized optimization of colistin loading doses.

Colistin remains one of the few available options for the treatment of infections caused by resistant bacteria. Pharmacokinetic (PK) studies have been successful in estimating the appropriate colistin methanesulfonate (CMS) dose to achieve a target colistin concentration. Currently, there is a consensus that the dose of CMS should vary according to the patient renal function since CMS is mainly eliminated by renal route. For this same reason, the loading dose should vary according to the patient's renal capacity; however, this is not the current clinical practice. In this study we develop a framework to determine two key parameters for the loading dose regimen: (1) the optimal dose according to the characteristics (renal function and weight) of the patient; (2) the waiting time before the maintenance dose. Based on a previous PK model, our framework allows a fast parameter sweep so as to select optimal loading dose and waiting time minimizing the deviation between the plasma concentration and a target value. The results showed that patients presenting low creatinine clearance (CrCL) should receive a lower CMS loading dose with longer interval to start maintenance treatment to avoid nephrotoxic colistin concentrations. In cases of high CrCL, the dose should be higher and the interval to the next dose shorter to avoid subtherapeutic concentrations. Optimization of the loading dose should considerably improve colistin therapy, as the target concentration is reached more quickly, without reaching toxic values.

162P Population pharmacokinetic modeling of tremelimumab in patients (pts) with advanced solid tumors

Tremelimumab, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) human monoclonal antibody of the immunoglobulin G2 kappa isotype, has been studied in oncology clinical trials as both monotherapy (MONO) and in combination with durvalumab (COMBO). Previous pharmacokinetic (PK) analyses showed that tremelimumab as monotherapy exhibits linear PK and that higher clearance (CL) may be associated with higher disease burden or poorer efficacy outcomes. Here we used updated/newly available data to build and validate an up-to-date population PK model for tremelimumab.

Continuous infusion of piperacillin-tazobactam significantly improves target attainment in children with cancer and fever.

BackgroundChildren with febrile neutropenia commonly exhibit alterations of pharmacokinetic (PK) parameters, leading to decreased β‐lactam concentrations.AimsThis study evaluated piperacillin PK and probability of target attainment (PTA) with continuous infusion of piperacillin‐tazobactam, in order to optimize the dosing regimen.MethodsThis prospective PK study included children with cancer, aged 1–17 years, who were treated with piperacillin‐tazobactam for suspected or verified infection. A piperacillin‐tazobactam loading dose (100 mg/kg) was administered followed by continuous infusion (300 mg/kg/day). The unbound fraction of piperacillin was quantified by high‐performance liquid chromatography and PK were described using population PK modeling. PK data was used to update and extend a previous PK model built on data following intermittent administration. Monte Carlo simulations were performed to assess PTA for targets of 100% time above the minimum inhibitory concentration (100% fT > MIC) and 50% fT > 4xMIC.ResultsWe included 68 fever episodes among 38 children with a median (IQR) age of 6.5 years and body weight of 27.4 kg (15.1–54.0). A three‐compartment model adequately described the concentration‐time data. Median (95% confidence interval) estimates for clearance and piperacillin concentration at steady state were 14.2 L/h/70 kg (13.0; 15.3) and 47.6 mg/L (17.2; 129.5), respectively. Body weight or lean body weight was significantly associated with the PK parameters, and body weight was integrated in the final PK model. Based on piperacillin exposure, continuous infusion was the only dosing regimen to achieve optimal PTA for the P. aeruginosa breakpoint (16 mg/L) with the target of 100% fT > MIC, and a daily dose of 300 mg/kg reached optimal PTA. The strict target of 50% fT > 4xMIC (64 mg/L) was not feasibly attained by any dosing regimen at recommended doses.ConclusionUnlike conventional piperacillin intermittent administration and extended infusion regimens, continuous infusion allows the target of 100% fT > MIC to be reached for children with febrile neutropenia.

CC-92480, a Potent, Novel Cereblon E3 Ligase Modulator (CELMoD) Agent, in Combination with Dexamethasone (DEX) and Bortezomib (BORT) in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM): Preliminary Results from the Phase 1/2 Study CC-92480-MM-002

CC-92480, a Potent, Novel Cereblon E3 Ligase Modulator (CELMoD) Agent, in Combination with Dexamethasone (DEX) and Bortezomib (BORT) in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM): Preliminary Results from the Phase 1/2 Study CC-92480-MM-002

Pharmacometric analysis linking immunoglobulin exposure to clinical efficacy outcomes in chronic inflammatory demyelinating polyneuropathy.

The two main objectives of this analysis were to (i) characterize the relationship between immunoglobulin (Ig) exposure and chronic inflammatory demyelinating polyneuropathy (CIDP) disease severity using data from 171 patients with CIDP who received either subcutaneous Ig (IgPro20; Hizentra®) or placebo (PATH study), and to (ii) simulate and compare exposure coverage with various dosing approaches considering weekly dosing to be the reference dose. IgG pharmacokinetic (PK) parameters, including those from a previous population PK model, were used to predict individual IgG profile and exposure metrics. Treatment‐related changes in Inflammatory Neuropathy Cause and Treatment (INCAT) scores were best described by a maximum effect (Emax) model as a function of ΔIgG (total serum IgG at INCAT score assessment minus baseline IgG levels before intravenous Ig restabilization). Simulations indicate that flexible dosing from daily to biweekly (every other week) provide an exposure coverage equivalent to that of a weekly Ig dose.

Model-based approach to sampling optimization in studies of antibacterial drugs for infants and young children.

Clinical trials for pediatric indications and new pediatric drugs face challenges, including the limited blood volume due to the patients’ small bodies. In Japan, the Evaluation Committee on Unapproved or Off‐labeled Drugs with High Medical Needs has discussed the necessity of pediatric indications against the background of a lack of Japanese pediatric data. The limited treatment options regarding antibiotics for pediatric patients are associated with the emergence of antibiotic‐resistant bacteria. Regulatory guidelines promote the use of model‐based drug development to reduce practical and ethical constraints for pediatric patients. Sampling optimization is one of the key study designs for pediatric drug development. In this simulation study, we evaluated the precision of the empirical Bayes estimates of pharmacokinetic (PK) parameters based on the sampling times optimized by published pediatric population PK models. We selected three previous PK studies of cefepime and ciprofloxacin in infants and young children as paradigms. The number of sampling times was reduced from original full sampling times to two to four sampling times based on the Fisher information matrix. We observed that the precision of empirical Bayes estimates of the key PK parameters and the predicted efficacy based on the reduced sampling times were generally comparable to those based on the original full sampling times. The model‐based approach to sampling optimization provided a maximization of PK information with a minimum burden on infants and young children for the future development of pediatric drugs.

Safety, Tolerability, and Pharmacokinetics of a New Formulation of Nemiralisib Administered via a Dry Powder Inhaler to Healthy Individuals

PurposeNemiralisib, a phosphoinositide 3-kinase δ inhibitor, is being investigated as an immunomodulatory agent with anti-inflammatory properties in chronic obstructive pulmonary disease. This study evaluated the pharmacokinetic (PK) properties and safety of a new formulation of nemiralisib that contains 0.4% magnesium stearate. MethodsIn this randomized, double-blind, parallel-group study, healthy individuals received a single dose of 500 or 750 μg of nemiralisib administered via the Ellipta dry powder inhaler (DPI) (n = 6 in each treatment group). Aerodynamic particle size distribution (APSD) data comparing previous and new formulations were available before the study. Serial PK analyses for plasma exposure and safety assessments were performed during the first 24 h after dosing, with follow-up measurements on days 3 and 6 in clinic. FindingsAPSD had increases of approximately 6-fold and 2-fold in very fine particle mass and fine particle mass over the previous (Diskus) formulation. In humans, systemic exposure (AUC) was greater after inhalation of 750 versus 500 μg of nemiralisib (AUC0–t: 17,200 h∙pg/mL; 95% CI, 10,900–27,200 h∙pg/mL and 13,100; 95% CI, 8130–21,000 h∙pg/mL, respectively). A low frequency of individual adverse events and no serious adverse events were reported after both doses. ImplicationsAfter single-dose inhalation of 500 and 750 μg of nemiralisib from the Ellipta DPI in healthy individuals, plasma PK data were well defined, and as predicted based on previous PK and APSD data, exposure was increased with the new formulation. Nemiralisib was well tolerated with no new safety issues identified. These data supported progression of nemiralisib to a Phase IIb study in patients with chronic obstructive pulmonary disease. ClinicalTrials.gov identifier: NCT03189589.

Safety of Chinese Patent Medicine for treatment of caner: a review on randomized control trials published in Chinese

Nemiralisib, a phosphoinositide 3-kinase δ inhibitor, is being investigated as an immunomodulatory agent with anti-inflammatory properties in chronic obstructive pulmonary disease. This study evaluated the pharmacokinetic (PK) properties and safety of a new formulation of nemiralisib that contains 0.4% magnesium stearate.In this randomized, double-blind, parallel-group study, healthy individuals received a single dose of 500 or 750 μg of nemiralisib administered via the Ellipta dry powder inhaler (DPI) (n = 6 in each treatment group). Aerodynamic particle size distribution (APSD) data comparing previous and new formulations were available before the study. Serial PK analyses for plasma exposure and safety assessments were performed during the first 24 h after dosing, with follow-up measurements on days 3 and 6 in clinic.APSD had increases of approximately 6-fold and 2-fold in very fine particle mass and fine particle mass over the previous (Diskus) formulation. In humans, systemic exposure (AUC) was greater after inhalation of 750 versus 500 μg of nemiralisib (AUC0–t: 17,200 h∙pg/mL; 95% CI, 10,900–27,200 h∙pg/mL and 13,100; 95% CI, 8130–21,000 h∙pg/mL, respectively). A low frequency of individual adverse events and no serious adverse events were reported after both doses.After single-dose inhalation of 500 and 750 μg of nemiralisib from the Ellipta DPI in healthy individuals, plasma PK data were well defined, and as predicted based on previous PK and APSD data, exposure was increased with the new formulation. Nemiralisib was well tolerated with no new safety issues identified. These data supported progression of nemiralisib to a Phase IIb study in patients with chronic obstructive pulmonary disease. ClinicalTrials.gov identifier: NCT03189589.

Predicting the dose of vancomycin in ICU patients receiving different types of RRT therapy: a model-based meta-analytic approach.

Previous pharmacokinetic (PK) studies have proposed various dosing regimens for vancomycin in intensive care unit (ICU) patients undergoing renal replacement therapy (RRT), but all are restricted to specific RRT modalities. To be useful in practice, a population PK model would need to predict vancomycin clearance during any RRT modality. Development of such a model is feasible using meta-analysis of published summarized estimates of vancomycin PK parameters. Our aims were: (i) to develop and validate a population PK model for vancomycin that takes into account any RRT modalities, and (ii) to predict vancomycin dosing for RRT patients in ICU. Vancomycin pharmacokinetics were assumed to be two-compartmental, total body clearance being the sum of non-RRT clearance and RRT-induced clearance. Drug disposition and non-RRT clearance parameters were estimated by systematic review and meta-analysis of previously published parameter estimates. The relationship between RRT-induced clearance and RRT flowrate settings was assessed using a model-based meta-analysis. Prediction performances of the PK model were assessed using external data. The meta-analyses of disposition parameters, non-RRT clearance and RRT-induced clearance included 11, 6 and 38 studies (84 RRT clearance measurements) respectively. The model performed well in predicting external individual PK data. Individual vancomycin concentrations during RRT were accurately predicted using Bayesian estimation based solely on pre-RRT measurements. The PK model allowed accurate prediction of the vancomycin pharmacokinetics during RRT in ICU patients. Based on the model of RRT-induced clearance, an appropriate adjustment of the vancomycin dosing regimen could be proposed for any kind of flowrate settings.

Population pharmacodynamic modelling of midazolam induced sedation in terminally ill adult patients.

AimsMidazolam is the drug of choice for palliative sedation and is titrated to achieve the desired level of sedation. A previous pharmacokinetic (PK) study showed that variability between patients could be partly explained by renal function and inflammatory status. The goal of this study was to combine this PK information with pharmacodynamic (PD) data, to evaluate the variability in response to midazolam and to find clinically relevant covariates that may predict PD response.MethodA population PD analysis using nonlinear mixed effect models was performed with data from 43 terminally ill patients. PK profiles were predicted by a previously described PK model and depth of sedation was measured using the Ramsay sedation score. Patient and disease characteristics were evaluated as possible covariates. The final model was evaluated using a visual predictive check.ResultsThe effect of midazolam on the sedation level was best described by a differential odds model including a baseline probability, Emax model and interindividual variability on the overall effect. The EC50 value was 68.7 μg l–1 for a Ramsay score of 3–5 and 117.1 μg l–1 for a Ramsay score of 6. Comedication with haloperidol was the only significant covariate. The visual predictive check of the final model showed good model predictability.ConclusionWe were able to describe the clinical response to midazolam accurately. As expected, there was large variability in response to midazolam. The use of haloperidol was associated with a lower probability of sedation. This may be a result of confounding by indication, as haloperidol was used to treat delirium, and deliria has been linked to a more difficult sedation procedure.

Pharmacokinetics of obinutuzumab in Chinese patients with B-cell lymphomas

AimThe Phase Ib GERSHWIN study (NCT01680991) assessed the pharmacokinetic (PK) profile of obinutuzumab following multiple intravenous (i.v.) doses to Chinese patients with B‐cell lymphomas, and compared findings with previous obinutuzumab PK studies in mainly Caucasian (non‐Chinese) patients.MethodsGERSHWIN was an open‐label, single‐arm intervention study. Patients aged >18 years with CD20+ relapsed/refractory chronic lymphocytic leukaemia (CLL), diffuse large B‐cell lymphoma (DLBCL) or follicular lymphoma (FL) were enrolled from four centres in China. The treatment period was 24 weeks; patients received obinutuzumab 1000 mg i.v. on Days (D)1, 8 and 15 of Cycle (C)1 (CLL patients: first infusion split over 2 days) and on D1 of C2–8 (all cycles: 21 days). PK parameters were estimated using non‐compartmental analysis (NCA), and a population PK analysis was used to determine whether observed GERSHWIN PK data were in accordance with previous obinutuzumab PK studies in non‐Chinese patients.ResultsThe PK analysis population included 48 patients: 28 patients completed all treatment cycles. NCA showed a similar PK profile in Chinese patients with FL, DLBCL and CLL. Steady‐state concentrations of obinutuzumab appeared to be reached at the start of C2 irrespective of histology. There was no apparent relationship between body weight and systemic exposure. Most PK profiles observed in GERSHWIN lay within the 90% prediction interval of simulated profiles.ConclusionsObinutuzumab exposure was comparable in CLL, DLBCL and FL patients. NCA and population PK analysis indicate that PK characteristics of Chinese patients with B‐cell lymphomas are similar to those in non‐Chinese patients.

Optimising meropenem dosing in critically ill Australian Indigenous patients with severe sepsis

Currently there are no pharmacokinetic (PK) data to guide antibiotic dosing in critically ill Australian Indigenous patients with severe sepsis. This study aimed to determine whether the population pharmacokinetics of meropenem were different between critically ill Australian Indigenous and critically ill Caucasian patients. Serial plasma and urine samples as well as clinical and demographic data were collected over two dosing intervals from critically ill Australian Indigenous patients. Plasma meropenem concentrations were assayed by validated chromatography. Concentration–time data were analysed with data from a previous PK study in critically ill Caucasian patients using Pmetrics. The population PK model was subsequently used for Monte Carlo dosing simulations to describe optimal doses for these patients. Six Indigenous and five Caucasian subjects were included. A two-compartment model described the data adequately, with meropenem clearance and volume of distribution of the central compartment described by creatinine clearance (CLCr) and patient weight, respectively. Patient ethnicity was not supported as a covariate in the final model. Significant differences were observed for meropenem clearance between the Indigenous and Caucasian groups [median 11.0 (range 3.0–14.1) L/h vs. 17.4 (4.3–30.3) L/h, respectively; P < 0.01]. Standard dosing regimens (1 g intravenous every 8 h as a 30-min infusion) consistently achieved target exposures at the minimum inhibitory concentration breakpoint in the absence of augmented renal clearance. No significant interethnic differences in meropenem pharmacokinetics between the Indigenous and Caucasian groups were detected and CLCr was found to be the strongest determinant of appropriate dosing regimens.

Perioperative Efficacy of an Extended Half-Life, Pegylated, Full-Length, Recombinant Factor VIII (BAX 855) in Individual Procedures

BAX 855 is a pegylated full-length recombinant factor VIII (PEG rFVIII) built on rFVIII (ADVATE) with an extended half-life and is intended for prophylaxis and the treatment of bleeding in patients with hemophilia A.1 This phase 3 surgery study is evaluating the efficacy and safety of BAX 855 for the perioperative control of hemostasis. Patients' informed consent and appropriate ethics committee approvals were obtained. Elective procedures were prospectively classified (major or minor) by the investigator/surgeon and major emergency surgeries were excluded. The target trough FVIII levels for major and minor surgeries were to be ≥80% and 30-60%, respectively. Each patient's pharmacokinetic (PK) profile was used to guide the BAX 855 dose and infusion frequency. BAX 855 PK were consistent with previous PK assessments with terminal half-life ranging from 8.81 to 18.06 hours for the 15 patients in this study.In this interim analysis, 15 male previously treated patients (PTPs) ranging from 19 to 52 years of age have undergone 15 procedures in 7 countries. Individual procedure profiles are compiled to evaluate the control of hemostasis for BAX 855. There were 11 major procedures: 6 orthopedic (3 knee replacements, 2 arthroscopic synovectomies, 1 elbow cyst extirpation) and 5 non-orthopedic procedures (3 dental [root canals for 2 teeth, 2 extractions of ≥4 teeth, 1 radicular cyst removal], 1 cardiovascular [mediport placement], 1 abdominal [gastric band insertion]). The 4 minor surgeries comprised 1 synoviorthesis, 1 dental, 1 dermatological and 1 endoscopy (radiosynovectomy) procedure.Efficacy was evaluated by the surgeon or investigator's rating of hemostatic control using 4-point scale which was based on blood loss and by comparing actual blood loss with predicted blood loss which was specified by the surgeon for non-hemophilia patients prior to the procedure. For all procedures, the hemostatic control of BAX 855 was rated "excellent" for the intraoperative (during the procedure), postoperative (24 hours after completion of the procedure), and perioperative (from start of the procedure until discharge or day 14) periods, except for 1 minor dental procedure in which postoperative efficacy was rated "good" and 1 minor procedure in which a postoperative rating was not provided (for both of these procedures intra- and perioperative ratings were "excellent").Actual blood loss (ABL) for the intraoperative and postoperative periods were compared with predicted average and maximum values. Intraoperative ABL for all minor and major procedures was less than or equal to predicted averages and maximums, except for 1 minor procedure in which the ABL was greater than the predicted average and maximum and 1 major procedure which did not have ABL recorded. Postoperative ABL was less than or equal to predicted averages and maximums for 4/4 minor procedures and 5 major procedures. For 4 major procedures, postoperative ABL was greater than or equal to predicted average, but less than predicted maximums. For the remaining major procedure (synovectomy with general anesthesia) with reported ABL, postoperative ABL was greater than the predicted the average and maximum - the efficacy assessments at all periods for this procedure were considered "excellent".These results demonstrate the efficacy of BAX 855 for the perioperative control of hemostasis in patients with severe hemophilia A.1 Konkle BA, Stasyshyn O, Chowdary P et al. Pegylated, full-length, recombinant factor VIII for prophylactic and on-demand treatment of severe hemophilia A. Blood. 2015; Link to Publisher's site: http://www.bloodjournal.org/content/bloodjournal/early/2015/07/08/blood-2015-03-630897.full.pdf DisclosuresBrand:CSL Behring: Consultancy; Pfizer: Consultancy; Bayer: Consultancy; Baxalta: Consultancy, Research Funding; Novo Nordisk: Consultancy; Biotest: Consultancy. Gruppo:Baxalta: Consultancy, Research Funding; Novo Nordisk: Consultancy; Pfizer: Consultancy; Alexion: Speakers Bureau. Wynn:Baxalta: Research Funding. Griskevicius:Novartis: Consultancy, Research Funding; Baxalta: Research Funding. Fernanda Lopez Fernandez:Baxalta: Research Funding. Dvorak:Baxalta: Employment, Equity Ownership. Patrone:Baxalta: Employment, Equity Ownership. Abbuehl:Baxalta: Employment, Equity Ownership.

Pharmacokinetics and Safety of Subcutaneous Pasireotide and Intramuscular Pasireotide Long-acting Release in Chinese Male Healthy Volunteers: A Phase I, Single-center, Open-label, Randomized Study

PurposeThe purpose of this study was to assess the pharmacokinetic (PK) properties and safety of single and multiple doses of subcutaneous (SC) pasireotide and a single-dose intramuscular (IM) long-acting release (LAR) formulation of pasireotide in Chinese healthy volunteers (HVs) versus the PK properties in Western HVs (pooled from previous PK studies). MethodsIn this phase I, single-center, open-label study, 45 Chinese male HVs were evenly randomized to 1 to 9 treatment sequences: each volunteer received a single dose of 300, 600, or 900 μg of pasireotide SC on day 1, followed by administration of the same dose BID from day 15 to the morning of day 19, and then a single IM dose of 20, 40, or 60 mg of pasireotide LAR on day 33. The PK parameters were assessed with noncompartmental analysis. Statistical comparison of PK parameters, including AUC, Cmax, and CL/F from both formulations, was made for Chinese versus Western male HVs. The safety profile was also assessed. Metabolic parameters, including blood glucose, insulin, and glucagon, and measures that reflect the effects of pasireotide LAR on relatively long-term glucose control, lipid metabolism, and systemic concentrations of pancreatic enzymes and thyrotropin were evaluated. FindingsOf the 45 randomized HVs, 42 completed the study per protocol, 1 withdrew his informed consent for personal reasons, and 2 prematurely discontinued the study because of adverse events (AEs). Concentration-time and safety profiles of both formulations were similar to those reported in Western HVs. Mean geometric mean ratios (GMRs) of Chinese versus Western HVs ranged from 0.79 to 1.42. For most primary PK parameters, 90% CIs for GMRs were within a predefined ethnic insensitivity interval (90% CI, 0.70–1.43). After considering age and weight as covariates in the statistical model, the GMRs and 90% CIs for other PK parameters were within the predefined interval (Cmax in single-dose SC administration) or significantly decreased (Cmin,ss in multiple BID SC doses and first peak Cmax in the single-dose LAR formulation). No serious AEs were reported. Both formulations were well tolerated; pasireotide SC caused transient changes in glucose metabolism. Owing to the differential binding affinity to the somatostatin receptor subtypes, pasireotide LAR elicited a concentration-dependent increase of fasting blood glucose, substantial reduction in triglyceride, and a mild decrease in cholesterol. The most frequently reported AEs after single-dose and multiple-dose pasireotide SC were injection site reaction, nausea, dizziness, and diarrhea; most HVs developed diarrhea with single-dose pasireotide LAR. ImplicationsThe pasireotide formulations had similar PK and safety profiles between Chinese and Western male HVs. Thus, no ethnic sensitivity was found for pasireotide SC or LAR.

Abstract LB-456: Evaluation of brain pharmacokinetics as a potential differentiation factor for the MEK inhibitors, MSC2015103 and pimasertib

Abstract MSC2015103 is an orally bio-available, selective, and highly potent small molecule inhibitor of MEK1/2. As a follower to the front-runner MEK inhibitor, pimasertib (MSC1936369/AS703026), a prime objective for the program is to differentiate the two compounds. Results from previous pharmacokinetic (PK) studies of MSC2015103 and pimasertib in mice had shown that both compounds could effectively cross the blood-brain barrier, but that MSC2015103 was retained in the brain longer than pimasertib. This was further confirmed in a study examining the whole-body distribution of radio-labeled compounds in mice. It is unclear whether the differential brain PK characteristics of the two agents will be clinically significant. To begin to address this, a series of pre-clinical studies were performed. Exposure levels and concurrent target modulation in normal murine brain tissue were examined over time following administration of multiple doses of MSC2015103 and pimasertib. Notable differences in the magnitude and temporal dynamics of exposure were observed; while concentrations of pimasertib in the brain peaked ∼1 hour post-administration (with a correlative decrease in phospho-ERK of ∼90%) with a relatively rapid clearance out of the tissue, concentrations of MSC2015103 increased in the brain over time and remained relatively elevated until 24 hours post-administration (the last time point) with only marginal target modulation observed. As more dramatic inhibition of pERK has previously been observed in subcutaneous tumors in mice in the presence of the same exposure of MSC2015103, murine brain orthotopic models of glioblastoma were employed to compare the relative target modulation of MSC2015103 and pimasertib in tumor tissue within the brain compartment, as well as their potential anti-tumor effects. Data from these orthotopic studies demonstrated similar high levels of phospho-ERK inhibition for both MSC2015103 and pimasertib in glioblastoma tumor tissue, which correlated with similar anti-tumor activity in the U87 model. The PK of MSC2015103 varied considerably from pimasertib, with a higher exposure (AUC1-24h) ratio of brain tumor-to-normal brain with MSC2015103 as compared with pimasertib. In line with the PK findings, MSC2015103 inhibited phospho-ERK in brain tumors but with relatively less target modulation in normal brain tissue, whereas pimasertib showed similar inhibition of phospho-ERK in both tissues. Collectively, these findings suggest a potential improvement in the safety/therapeutic index in the brain for MSC2015103. This may translate into other tissues, such as the eye, which has a similar blood barrier, and may be important in light of ocular toxicities observed in clinical trials with other MEK inhibitors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-456. doi:1538-7445.AM2012-LB-456