Pharmacokinetic and Pharmacodynamic Evaluation of Ravulizumab in Adults with Severe Coronavirus Disease 2019.

INTRODUCTION: Terminal complement amplification is hypothesized to be a key contributor to the clinical manifestations of severe coronavirus disease 2019 (COVID-19). Ravulizumab, a humanized monoclonal antibody that binds with high affinity to complement protein C5 and inhibits terminal complement activation, is being evaluated as a treatment for COVID-19-related severe pneumonia, acute lung injury, and acute respiratory distress syndrome in an ongoing phase 3 randomized controlled trial (ALXN1210-COV-305). To address the overactivation of terminal complement in severe COVID-19 compared to the diseases in which ravulizumab is currently approved, a modified dosing regimen was adopted. This analysis evaluates preliminary pharmacokinetic/pharmacodynamic data to confirm the modified dosing regimen. METHODS: Weight-based ravulizumab doses were administered on days 1, 5, 10, and 15. Serum levels of ravulizumab and free C5 were measured before and after administration of ravulizumab and any time on day 22. Free C5 levels < 0.5 µg/mL indicate complete C5 inhibition. The pharmacokinetic target was defined as ravulizumab concentrations at the end of the dosing interval > 175 µg/mL, the concentration above which C5 is completely inhibited. RESULTS: Twenty-two patients were included in this evaluation. At baseline, mean C5 concentration was 240 ± 67 µg/mL. In all patients and at all individual timepoints after the first dose was administered, ravulizumab concentrations remained > 175 µg/mL and free C5 concentrations remained < 0.5 µg/mL. CONCLUSION: High levels of baseline C5 observed in patients with severe COVID-19 contribute to the growing body of evidence that suggests this disease is marked by amplification of terminal complement activation. Data from this preliminary pharmacokinetic/pharmacodynamic evaluation of 22 patients with severe COVID-19 show that the modified ravulizumab dosing regimen achieved immediate and complete terminal complement inhibition, which can be sustained for up to 22 days. These data support the continued use of this dosage regimen in the ongoing phase 3 study. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04369469.

While many people have no or mild COVID-19 symptoms, a small number of people become very sick and require hospitalization in intensive care units. One part of their immune system, known as complement, overreacts and attacks the lungs and other organs. Researchers are looking for a way to keep the immune system from attacking the body instead of protecting it. Ravulizumab is a medication currently used to do this in other diseases. Ravulizumab is being studied to see if it can reduce the destructive and deadly effects of the coronavirus infection. In this evaluation, ravulizumab effectively reduced complement in patients with severe COVID-19.

Limited sampling strategies for accurate determination of extended half-life factor VIII pharmacokinetics in severe haemophilia A patients.

BACKGROUND: Extended half-life (EHL) factor VIII (FVIII) products may decrease the burden of prophylactic treatment in haemophilia A by reducing infusion frequency. However, these products still exhibit wide inter-patient variability and benefit from pharmacokinetic (PK) tailoring. OBJECTIVE: Identify limited sampling strategies for rFVIIIFc, an EHL FVIII product, that produce accurate estimates of PK parameters and relevant troughs. METHODS: We performed a limited sampling analysis on simulated populations of adults, adolescents, and children based on published population PK data. Sampling strategies were evaluated by comparing the error in estimates of half-life, clearance, and trough levels, to a full 6-sample design. Furthermore, we assessed the impact of incorporating knowledge about prior doses, and the day of the PK study within the regimen. We also evaluated the potential inappropriate dose adjustment rate (IDAR) among the modelled sampling strategies. RESULTS: Many sampling strategies, including several 2-sample designs, accurately predicted the PK and exposure measures (median absolute error <10%). When samples are only collected during a single visit (i.e., predose + peak), inclusion of prior dose information reduces median half-life error from >20% to ~5% for adults/adolescents. In this same scenario, appropriate scheduling of the PK study decreases likelihood of unmeasurable predose samples, reducing median error on the 72-h trough from 25% to <12% in the youngest population. CONCLUSIONS: The PK of rFVIIIFc can be accurately estimated using only peak and trough samples, provided that knowledge of prior doses is incorporated and the PK study is planned on an appropriate day within the dosing regimen.

Development and evaluation of the population pharmacokinetic models for FVIII and FIX concentrates of the WAPPS-Hemo project.

BACKGROUND: The Web-Accessible Population Pharmacokinetic Service (WAPPS) project generates individually predicted pharmacokinetic (PK) profiles and tailored prophylactic treatment regimens for haemophilic patients, which rely on a set of population PK (PopPK) models providing concentrate-specific priors for the Bayesian forecasting methodology. AIM: To describe the predictive performance of the WAPPS PopPK models in use on the WAPPS-Hemo platform. METHODS: Data for modelling include dense PK data obtained from industry sponsored and independent PK studies, and dense and sparse data accumulated through WAPPS-Hemo. WAPPS PopPK models were developed via non-linear mixed-effect modelling taking into account the effects of covariates and between-individual-and sometimes between-occasion-variability. Model evaluation consisted of (a) prediction-corrected Visual Predictive Check (pcVPC), (b) Limited Sampling Analysis (LSA) and (c) repeated hold-out cross-validation. RESULTS: Thirty-three WAPPS PopPK models built on data from 3188 patients (ages 1-78 years) under treatment by factor VIII or IX products (FVIII, FIX) were evaluated. Overall, models exhibit excellent performance characteristics. The pcVPC shows that the observed PK data fall within acceptable 90% interpercentile predictive bands. A slight overprediction beyond the expected half-life, an anticipated result of using sparse data, occurs for some models. The LSA results in lower than 3% of relative error for FVIII and FIX products and 16% for engineered FIX products. Cross-Validation analysis yields relative errors lower than 1.5% and 1.4% in estimates of half-life and time to 0.02 IU/mL, respectively. CONCLUSION: The WAPPS-Hemo models consistently showed excellent performance characteristics for the intended use for Bayesian forecasting of individual PK profiles.

Clinical application of Web Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo): Patterns of blood sampling and patient characteristics among clinician users.

BACKGROUND: Use of population pharmacokinetics (PopPK) to facilitate PK-informed prophylaxis in clinical practice has gained momentum among haemophilia providers due to the accessibility of tools such as the Web Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) and availability of extended half-life (EHL) factor concentrates. It is unknown how clinicians implement PopPK. AIM: To investigate the evolution of PopPK use in clinical practice by comparing blood sampling strategies, patient features, and factor group between initial and recent periods of WAPPS-Hemo availability. METHODS: PK data for haemophilia A and haemophilia B patients from two time periods were extracted from the WAPPS-Hemo database: early availability (10/2015-09/2016) and recent use (10/2017-09/2018). We compared patient characteristics (age, body weight, haemophilia type), product type and dose, and blood sampling times between the time frames. RESULTS: Over 1900 eligible infusions were submitted to WAPPS-Hemo during the periods studied, with 85% representing FVIII concentrates. In the recent cohort, PK profiles were requested for younger patients (median age 18 vs 26 years), with increased proportional EHL FVIII use (29% vs 14% of infusions). High-use centres generally submitted fewer blood samples per infusion than non-high-use centres, although the number of samples collected by non-high-use centres decreased significantly over time. During both periods, blood sample timing was generally consistent with ISTH recommended windows. CONCLUSION: The use of WAPPS-Hemo by haemophilia providers grew by over threefold between the time periods investigated. While sampling times have included key time points proposed first by Björkman since early WAPPS-Hemo usage, a trend towards minimizing sampling was observed.

Development and evaluation of a generic population pharmacokinetic model for standard half-life factor VIII for use in dose individualization.

Hemophilia A is a rare bleeding disorder resulting from a lack of functional factor VIII (FVIII). Therapy consists of replacement with exogenous FVIII, but is complicated by high inter-patient variability. A population pharmacokinetics (PopPK) approach can facilitate the uptake of an individualized approach to hemophilia therapy. We developed a PopPK model using data from seven brands of standard half-life FVIII products. The final model consists of a 2-compartment structure, with a proportional residual error model and between-subject variability on clearance and central volume. Fat-free mass, age, and brand were found to significantly affect pharmacokinetic (PK) parameters. Internal and external evaluations found that the model is fit for Bayesian forecasting and capable of predicting PK for brands not included in the modelling dataset, and useful for determining individualized prophylaxis regimens for hemophilia A patients.

Impact of Adopting Population Pharmacokinetics for Tailoring Prophylaxis in Haemophilia A Patients: A Historically Controlled Observational Study.

BACKGROUND: Performing individual pharmacokinetics (PK) studies in clinical practice can be simplified by adopting population PK-based profiling on limited post-infusion samples. The objective of this study was to assess the impact of population PK in tailoring prophylaxis in patients with haemophilia A. PATIENTS AND METHODS: Individual weekly treatment plans were developed considering predicted plasma factor activity levels and patients' lifestyle. Patients were trained using a visual traffic-light scheme to help modulate their level of physical activity with respect to factor infusions timing. Annualized joint bleeding rate (ABJR), haemophilia-specific quality of life questionnaire for adults (Haemo-QoL-A) and factor utilization were measured for 12 months before and after tailoring, compared within patients and analysed separately for those previously on prophylaxis (P), situational prophylaxis (SP) or on-demand (OD). RESULTS: Sixteen patients previously on P, 10 on SP and 10 on OD were enrolled in the study. The median (lower, upper quartile) ABJR changed from 2.0 (0, 4.0) to 0 (0, 1.6) for P (p = 0.003), from 2.0 (2.0, 13.6) to 3.0 (1.4, 7.2) for SP (p = 0.183) and from 16.0 (13.0, 25.0) to 2.3 (0, 5.0) for OD (p = 0.003). The Haemo-QoL-A total score improved for 58% of P, 50% of SP and 29% of OD patients. Factor utilization (IU/kg/patient/year) increased by 2,400 (121; 2,586) for P, 1,052 (308; 1,578) for SP and 2,086 (1,498; 2,576) for OD. One of 138 measurements demonstrated a factor activity level below the critical threshold of 0.03 IU/mL while the predicted level was above the threshold. CONCLUSION: Implementing tailored prophylaxis using a Bayesian forecasting approach in a routine clinical practice setting may improve haemophilia clinical outcomes.

Modeling of Body Weight Metrics for Effective and Cost-Efficient Conventional Factor VIII Dosing in Hemophilia A Prophylaxis.

The total body weight-based dosing strategy currently used in the prophylactic treatment of hemophilia A may not be appropriate for all populations. The assumptions that guide weight-based dosing are not valid in overweight and obese populations, resulting in overdosing and ineffective resource utilization. We explored different weight metrics including lean body weight, ideal body weight, and adjusted body weight to determine an alternative dosing strategy that is both safe and resource-efficient in normal and overweight/obese adult patients. Using a validated population pharmacokinetic model, we simulated a variety of dosing regimens using different doses, weight metrics, and frequencies; we also investigated the implications of assuming various levels of endogenous factor production. Ideal body weight performed the best across all of the regimens explored, maintaining safety while moderating resource consumption for overweight and obese patients.

Cytochrome P450 binding studies of novel tacrine derivatives: Predicting the risk of hepatotoxicity.

The 1,2,3,4-tetrahydroacridine derivative tacrine was the first drug approved to treat Alzheimer's disease (AD). It is known to act as a potent cholinesterase inhibitor. However, tacrine was removed from the market due to its hepatotoxicity concerns as it undergoes metabolism to toxic quinonemethide species through the cytochrome P450 enzyme CYP1A2. Despite these challenges, tacrine serves as a useful template in the development of novel multi-targeting anti-AD agents. In this regard, we sought to evaluate the risk of hepatotoxicity in a series of C9 substituted tacrine derivatives that exhibit cholinesterase inhibition properties. The hepatotoxic potential of tacrine derivatives was evaluated using recombinant cytochrome (CYP) P450 CYP1A2 and CYP3A4 enzymes. Molecular docking studies were conducted to predict their binding modes and potential risk of forming hepatotoxic metabolites. Tacrine derivatives compound 1 (N-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroacridin-9-amine) and 2 (6-chloro-N-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroacridin-9-amine) which possess a C9 3,4-dimethoxybenzylamino substituent exhibited weak binding to CYP1A2 enzyme (1, IC50=33.0µM; 2, IC50=8.5µM) compared to tacrine (CYP1A2 IC50=1.5µM). Modeling studies show that the presence of a bulky 3,4-dimethoxybenzylamino C9 substituent prevents the orientation of the 1,2,3,4-tetrahydroacridine ring close to the heme-iron center of CYP1A2 thereby reducing the risk of forming hepatotoxic species.

Development of a Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo): Study Protocol.

BACKGROUND: Individual pharmacokinetic assessment is a critical component of tailored prophylaxis for hemophilia patients. Population pharmacokinetics allows using individual sparse data, thus simplifying individual pharmacokinetic studies. Implementing population pharmacokinetics capacity for the hemophilia community is beyond individual reach and requires a system effort. OBJECTIVE: The Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) project aims to assemble a database of patient pharmacokinetic data for all existing factor concentrates, develop and validate population pharmacokinetics models, and integrate these models within a Web-based calculator for individualized pharmacokinetic estimation in patients at participating treatment centers. METHODS: Individual pharmacokinetic studies on factor VIII and IX concentrates will be sourced from pharmaceutical companies and independent investigators. All factor concentrate manufacturers, hemophilia treatment centers (HTCs), and independent investigators (identified via a systematic review of the literature) having on file pharmacokinetic data and willing to contribute full or sparse pharmacokinetic data will be eligible for participation. Multicompartmental modeling will be performed using a mixed-model approach for derivation and Bayesian forecasting for estimation of individual sparse data. NONMEM (ICON Development Solutions) will be used as modeling software. RESULTS: The WAPPS-Hemo research network has been launched and is currently joined by 30 HTCs from across the world. We have gathered dense individual pharmacokinetic data on 878 subjects, including several replicates, on 21 different molecules from 17 different sources. We have collected sparse individual pharmacokinetic data on 289 subjects from the participating centers through the testing phase of the WAPPS-Hemo Web interface. We have developed prototypal population pharmacokinetics models for 11 molecules. The WAPPS-Hemo website (available at www.wapps-hemo.org, version 2.4), with core functionalities allowing hemophilia treaters to obtain individual pharmacokinetic estimates on sparse data points after 1 or more infusions of a factor concentrate, was launched for use within the research network in July 2015. CONCLUSIONS: The WAPPS-Hemo project and research network aims to make it easier to perform individual pharmacokinetic assessments on a reduced number of plasma samples by adoption of a population pharmacokinetics approach. The project will also gather data to substantially enhance the current knowledge about factor concentrate pharmacokinetics and sources of its variability in target populations. TRIAL REGISTRATION: ClinicalTrials.gov NCT02061072; https://clinicaltrials.gov/ct2/show/NCT02061072 (Archived by WebCite at http://www.webcitation.org/6mRK9bKP6).

Data Analysis Protocol for the Development and Evaluation of Population Pharmacokinetic Models for Incorporation Into the Web-Accessible Population Pharmacokinetic Service - Hemophilia (WAPPS-Hemo).

BACKGROUND: Hemophilia is an inherited bleeding disorder caused by a deficiency in a specific clotting factor. This results in spontaneous bleeding episodes and eventual arthropathy. The mainstay of hemophilia treatment is prophylactic replacement of the missing factor, but an optimal regimen remains to be determined. Rather, individualized prophylaxis has been suggested to improve both patient safety and resource utilization. However, uptake of this approach has been hampered by the demanding sampling schedules and complex calculations required to obtain individual estimates of pharmacokinetic (PK) parameters. The use of population pharmacokinetics (PopPK) can alleviate this burden by reducing the number of plasma samples required for accurate estimation, but few tools incorporating this approach are readily available to clinicians. OBJECTIVE: The Web-accessible Population Pharmacokinetic Service - Hemophilia (WAPPS-Hemo) project aims to bridge this gap by providing a Web-accessible service for the reliable estimation of individual PK parameters from only a few patient samples. This service is predicated on the development of validated brand-specific PopPK models. METHODS: We describe the data analysis plan for the development and evaluation of each PopPK model to be incorporated into the WAPPS-Hemo platform. The data sources and structure of the dataset are discussed first, followed by the procedures for handling both data below limit of quantification (BLQ) and absence of such BLQ data. Next, we outline the strategies for building the appropriate structural and covariate models, including the possible need for a process algorithm when PK behavior varies between subjects or significant covariates are not provided. Prior to use in a prospective manner, the models will undergo extensive evaluation using a variety of techniques such as diagnostic plots, bootstrap analysis and cross-validation. Finally, we describe the incorporation of a validated PopPK model into the Bayesian post hoc model to produce individualized estimates of PK parameters. RESULTS: Dense PK data has been collected for more than 20 brands of factor concentrate from both industry-sponsored and investigator-driven studies. The model development process is underway for the majority of molecules, with refinement and validation to be completed in 2017. Further, the WAPPS-Hemo co-investigator network has contributed more than 300 PK assessments for use in model development and evaluation. This constitutes the largest repository of this type of PK data globally. CONCLUSIONS: The WAPPS-Hemo service aims to eliminate barriers to the uptake of individualized PK-tailored hemophilia treatment. By incorporating this tool into routine practice, clinicians can implement a personalized dosing strategy without performing rigorous sampling or complex calculations. This service is centred on validated models developed according to the robust approach to PopPK modeling described herein. CLINICALTRIAL: ClinicalTrials.gov NCT02061072; https://clinicaltrials.gov/ct2/show/NCT02061072 (Archived by WebCite at http://www.webcitation.org/6mRIXJh55).

The use of pharmacokinetics in dose individualization of factor VIII in the treatment of hemophilia A.

INTRODUCTION: Hemophilia A is a bleeding disorder resulting from a lack of clotting factor VIII (FVIII), and treatment typically consists of prophylactic replacement of the deficient factor. However, high between subject variability precludes the development of a 'one size fits all' dosing strategy and necessitates an individualized approach. We sought to summarize the data on the pharmacokinetics of FVIII available as a basis for the development of population pharmacokinetic models to be used in dose tailoring. Areas covered: We reviewed the pharmacokinetics of FVIII as used for the treatment of hemophilia A, with a focus on the variability observed between patients and the application of pharmacokinetic methods to dose individualization. We also explored the covariates affecting pharmacokinetic parameters, the differences between plasma-derived and recombinant FVIII and the development of extended half-life products. Expert opinion: The pharmacokinetics of factor VIII in patients with hemophilia shows a high interpatient variability, and is affected by age, weight, level of von Willebrand factor, and blood group. A population approach to estimating individual pharmacokinetics is likely to provide the most successful strategy to tailor factor concentrate dosing to the individual needs and to ensure optimal patient outcomes, while also improving the cost-effectiveness of prophylactic replacement therapy.

Investigating the binding interactions of the anti-Alzheimer's drug donepezil with CYP3A4 and P-glycoprotein.

The anti-Alzheimer's agent donepezil is known to bind to the hepatic enzyme CYP3A4, but its relationship with the efflux transporter P-glycoprotein (P-gp) is not as well elucidated. We conducted in vitro inhibition studies of donepezil using human recombinant CYP3A4 and P-gp. These studies show that donepezil is a weak inhibitor of CYP3A4 (IC50=54.68±1.00µM) whereas the reference agent ketoconazole exhibited potent inhibition (CYP3A4 IC50=0.20±0.01µM). P-gp inhibition studies indicate that donepezil exhibits better inhibition relative to CYP3A4 (P-gp EC50=34.85±4.63µM) although it was less potent compared to ketoconazole (P-gp EC50=9.74±1.23µM). At higher concentrations, donepezil exhibited significant inhibition of CYP3A4 (69%, 84% and 87% inhibition at 100, 250 and 500µM, respectively). This indicates its potential to cause drug-drug interactions with other CYP3A4 substrates upon co-administration; however, this scenario is unlikely in vivo due to the low therapeutic concentrations of donepezil. Similarly, donepezil co-administration with P-gp substrates or inhibitors is unlikely to result in beneficial or adverse drug interactions. The molecular docking studies show that the 5,6-dimethoxyindan-1-one moiety of donepezil was oriented closer to the heme center in CYP3A4 whereas in the P-gp binding site, the protonated benzylpiperidine pharmacophore of donepezil played a major role in its binding ability. Energy parameters indicate that donepezil complex with both CYP3A4 and P-gp was less stable (CDOCKER energies=-15.05 and -4.91kcal/mol, respectively) compared to the ketoconazole-CYP3A4 and P-gp complex (CDOCKER energies=-41.89 and -20.03kcal/mol, respectively).