Development of a population pharmacokinetic model for the novel long-acting injectable antipsychotic risperidone ISM®.

AIMS: The aims of this study were to develop a population pharmacokinetic (PK) model for risperidone ISM® and to investigate the relationships between active moiety exposure, as described by apparent clearance (CL40), and several covariates using all data from five clinical studies. METHODS: A population PK model was developed using active moiety concentrations from a study in healthy volunteers and two studies in patients with schizophrenia. Data from a comparative bioavailability study in medically stable patients and a Phase III study in patients with acute exacerbation of schizophrenia were then incorporated, using empirical Bayesian feedback and model refinement in NONMEM. Finally, covariate analysis was performed on CL40. RESULTS: The final model adequately described the pharmacokinetics of 6288 active moiety concentrations in 17 healthy volunteers and 430 patients with schizophrenia. This one-compartment disposition model had a complex absorption process, combining a small amount immediately entering the central active moiety compartment, two first-order absorption processes and a combined zero-order and first order process, with first-order elimination from the central compartment. Significant covariates on CL40 were BMI and sex. Goodness-of-fit (GOF) plots and visual predictive checks (VPC) confirmed acceptable description of the data. CONCLUSIONS: The population PK model adequately described active moiety concentrations from five clinical studies after risperidone ISM® administration. Relationships between active moiety exposure and covariates were defined in order to facilitate simulations for future studies. The model showed that risperidone ISM® rapidly achieves therapeutic plasma levels within the first hours after the first injection that are maintained sustainedly throughout the whole dosing interval following once-monthly gluteal injections of 100 mg and 75 mg.

Emapalumab in primary haemophagocytic lymphohistiocytosis and the pathogenic role of interferon gamma: A pharmacometric model-based approach.

AIM: Primary haemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening, hyperinflammatory syndrome generally occurring in early childhood. The monoclonal antibody emapalumab binds and neutralises interferon γ (IFNγ). This study aimed to determine an emapalumab dosing regimen when traditional dose-finding approaches are not applicable, using pharmacokinetic-pharmacodynamic analyses to further clarify HLH pathogenesis and confirm IFNγ neutralisation as the relevant therapeutic target in pHLH. METHODS: Initial emapalumab dosing (1 mg/kg) for pHLH patients participating in a pivotal multicentre, open-label, single-arm, phase 2/3 study was based on anticipated IFNγ levels and allometrically scaled pharmacokinetic parameters estimated in healthy volunteers. Emapalumab dosing was adjusted based on estimated IFNγ-mediated clearance and HLH clinical and laboratory criteria. Frequent dosing and emapalumab dose adaptation were used to account for highly variable IFNγ levels and potential target-mediated drug disposition. RESULTS: High inter- and intra-individual variability in IFNγ production (assessed by total IFNγ levels, range: 102 -106  pg/mL) was observed in pHLH patients. Administering emapalumab reduced IFNγ activity, resulting in significant improvements in clinical and laboratory parameters and a reduced risk of adverse events, mainly related to pHLH. Modelled outcomes supported dose titration starting from 1 mg/kg, with possible increases to 3, 6 or 10 mg/kg based on re-evaluation of parameters of disease activity every 3 days. CONCLUSIONS: The variable and unanticipated extremely high IFNγ concentrations in patients with pHLH are reflected in parameters of disease activity. Improved outcomes can be achieved by neutralising IFNγ using frequent emapalumab dosing and dose adaptation guided by clinical and laboratory observations.

Mathematical Disease Progression Modeling in Type 2/3 Spinal Muscular Atrophy.

INTRODUCTION: We propose a mathematical model to empirically describe spinal muscular atrophy (SMA) progression assessed by the 3 domains of the motor function measure (MFM) scale. The model implements development and deterioration of muscle function. METHODS: Nonlinear mixed-effects modeling was applied to data from 2 observational studies and 1 prospective clinical efficacy study comprising 190 healthy participants and 277 patients with type 2/3 SMA. RESULTS: The model evidenced correlations between parameter estimates for different MFM domains. Slower development in MFM domain D1 (standing and transfers) was associated with faster deterioration for MFM domains D2 (proximal and axial motricity) and D3 (distal motor function). DISCUSSION: The model describes all individual data well, although sparseness and variability of observational data prevented numerically stable estimation of parameters. Treatment duration in clinical studies was too limited to determine a proper drug-effect model that could differentiate between symptomatic and disease modifying effects. Muscle Nerve 58: 528-535, 2018.

Use of an integrated modelling and simulation approach to develop a simplified peginterferon alfa-2a dosing regimen for children with hepatitis C.

AIM: The aim of the study was to simplify the dosing regimen of peginterferon alfa-2a in paediatric patients with chronic hepatitis C. METHODS: A population pharmacokinetic (PK) model was developed using PK data from 14 children aged 2-8 years and 402 adults. Simulations were produced to identify a simplified dosing regimen that would provide exposures similar to those observed in the paediatric clinical trials and in the range known to be safe/efficacious in adults. Model predictions were evaluated against observed adult and paediatric data to reinforce confidence of the proposed dosing regimen. RESULTS: The final model was a two compartment model with a zero order resorption process. Covariates included a linear influence of body surface area (BSA) on apparent oral clearance (CL/F) and a linear influence of body weight on apparent volume of distribution of the central compartment (V1 /F). A simplified dosing regimen was developed which is expected to provide exposures in children aged ≥5 years similar to the dosing formula used in the paediatric clinical trial and within the range that is safe/efficacious in adults. This simplified regimen is approved in the EU and in other countries for the treatment of chronic hepatitis C in treatment-naive children/adolescents aged ≥5 years in combination with ribavirin. CONCLUSION: Pre-existing adult PK data were combined with relatively limited paediatric PK data to develop a PK model able to predict exposure in both populations adequately. This provided increased confidence in characterizing PK in children and helped in the development of a simplified dosing regimen of peginterferon alfa-2a in paediatric patients.

The dose-response relationship of peginterferon alfa-2a and ribavirin in the treatment of patients coinfected with HIV-HCV.

PURPOSE: The relationship between peginterferon/ribavirin exposure and the probability of achieving a sustained virologic response (SVR) in HIV-HCV coinfected patients is not well described. We conducted a retrospective analysis of HIV-HCV coinfected patients randomized to 48 weeks of treatment with peginterferon alfa-2a (40 kD) 180 µg/week and ribavirin 800 mg/day in the multinational APRICOT study to define optimal exposure thresholds. METHOD: Actual drug exposure was estimated in 287 patients, taking into consideration dose reductions for adverse events or laboratory abnormalities. RESULTS: SVR overall and SVR in those completing treatment was, respectively, 29% and 37% among HCV genotype-1 patients and 59% and 68% among genotype non-1 patients. No patients with ≤40% exposure to ribavirin achieved an SVR. Receiver operating characteristic analysis identified that threshold exposures to both drugs of >75% (genotype-1) and >60% (genotype non-1) are associated with SVR. An existing generalized additive model populated with data from HCV monoinfected patients was updated to predict an overall SVR of 37% if genotype-1 patients received ribavirin 1000 or 1200 mg/day but at the cost of a higher incidence of anemia (23%). CONCLUSION: Completion of scheduled treatment and exceeding certain thresholds for exposure to peginterferon alfa 2a (40 kD) and ribavirin is associated with higher SVR rates.

Predicting efficacy and safety outcomes in patients with hepatitis C virus genotype 1 and persistently 'normal' alanine aminotransferase levels treated with peginterferon alpha-2a (40KD) plus ribavirin.

BACKGROUND: Currently, the approved dosage of ribavirin has not been studied in patients with 'normal' alanine aminotransferase (ALT) levels. METHODS: Modelling and simulations were performed using generalised additive models (GAMs) to predict the incidence of anaemia and rate of sustained virological response (SVR) in patients with hepatitis C virus (HCV) genotype 1 and persistently 'normal' ALT levels treated with peginterferon alpha-2a (40KD) 180 microg/week plus ribavirin 1000/1200 mg/day for 48 weeks. RESULTS: Model-based simulations predicted that SVR rates would increase from 39 to 48% if patients with genotype 1 and persistently 'normal' ALT levels had received the standard weight-adjusted dose of ribavirin. This was similar to the predicted 49% SVR rate for genotype 1 patients with elevated ALT levels. The incidence of anaemia was predicted to increase from 13% to 23% in patients with persistently 'normal' ALT activity and was higher than that predicted for patients with elevated ALT levels; however, the difference appeared to be largely explained by the higher proportion of women in the former group. CONCLUSIONS: Simulations based on GAM suggest that regimens for patients with HCV genotype 1 should include the standard weight-adjusted dose of ribavirin, as similar SVR rates are predicted to be achieved, regardless of patients' ALT status at baseline.

Modeling and simulation of intravenous levetiracetam pharmacokinetic profiles in children to evaluate dose adaptation rules.

PURPOSE: To develop a pharmacokinetic model for intravenous levetiracetam in children, based on adult intravenous data and pediatric oral data. METHODS: Data from two adult Phase-I studies in which levetiracetam was given intravenously were utilized to develop the adult population pharmacokinetic two-compartment intravenous model. After model qualification, combination with an existing pediatric one-compartment oral population pharmacokinetic model enabled simulation of twice-daily intravenous infusions of levetiracetam in children. Median and 90% confidence intervals for C(trough), C(max) (end of infusion) and AUC(tau) were simulated for 2000 children and compared to the values observed in adults. RESULTS: The population pharmacokinetic two-compartment model successfully described intravenous levetiracetam pharmacokinetics in healthy adults. After combination with the oral pediatric population model, steady-state concentrations at the end of 15-, 30- and 60 min b.i.d. levetiracetam intravenous infusions in children were predicted to be 29-41, 17-24 and 6-13% higher than those observed after oral dosing of 30 mg/kg b.i.d. Concentrations returned to the range of oral exposures within 1h after the infusion peak. The combined model predicted that steady-state peak plasma concentrations and AUC(tau) in children receiving 30 mg/kg twice daily as 15 min intravenous infusions were within the range of predicted and observed C(max,ss) and AUC(tau )values of adults receiving 15 min intravenous infusions of 1500 mg levetiracetam. CONCLUSIONS: The simulations suggest that levetiracetam may be administered intravenously in children as 15 min infusions.

Dose-response population analysis of levetiracetam add-on treatment in refractory epileptic patients with partial onset seizures.

In this post hoc analysis, individual seizure counts from four double-blind trials of adjunctive treatment with levetiracetam were analyzed by non-linear mixed-effects modeling (NONMEM). First, a model was fitted to the individual count data assuming a Poisson distribution, in order to classify the patients as either improving or deteriorating from baseline. In the second stage, the dose-response relationship in improving patients was determined by fitting the data to an E(max) model including a placebo effect. The percentage of improvers was 59% on placebo and 73%, 74%, 77% and 73% on levetiracetam 1, 2, 3 and 4g/day, respectively. The ED(50) of 1408mg/day was close to the current WHO Defined Daily Dose of levetiracetam (1500mg). The maximum recommended dose of 3000mg/day was predicted to reduce seizures by >or=90% in 10% of improving patients. Age, gender, body weight, race, and number of concomitant antiepileptic drugs neither affected the percentage of responders nor the extent of change in seizure frequency from baseline.

Predicting sustained virological response and anaemia in chronic hepatitis C patients treated with peginterferon alfa-2a (40KD) plus ribavirin.

AIM: To assess the likelihood of a sustained virological response (SVR) vs. the likelihood of anaemia in patients with chronic hepatitis C. METHODS: Data from 1732 patients treated with peginterferon alfa-2a (40KD) plus ribavirin in two randomized, multinational studies were pooled. Probabilities of SVR and anaemia were modelled using the generalized additive logistic model, with numerous clinical variables considered for entry into the model. Baseline haemoglobin was only considered in the analysis for anaemia. RESULTS: The probability of anaemia increased from 6 to 16% as a function of the ribavirin dose kg(-1) (12-16 mg kg(-1)), whereas the relationship between SVR and ribavirin dose kg(-1) was influenced by hepatitis C virus (HCV) genotype. The probability of an SVR was not influenced by the ribavirin dose kg(-1) in patients with HCV genotype 2 or 3 infection, but increased as a function of ribavirin dose kg(-1) in patients with HCV genotype 1 infection (40-50% increase in probability of SVR for 12-16 mg kg(-1) dose ribavirin increase). The probability of an SVR in patients included with HCV genotype 1 decreased with increasing HCV RNA level to about 3 million copies ml(-1), but was relatively independent of increasing HCV RNA level thereafter. In addition, older age, a higher ribavirin apparent oral clearance and cirrhosis had a negative impact on achieving an SVR, but improved with increasing alanine aminotransferase (ALT) quotient. Sex and ribavirin dose kg(-1) were the most important prognostic factors for anaemia, followed by baseline haemoglobin, age, baseline ALT quotient and cirrhosis. CONCLUSION: This study supports individualizing ribavirin dosages by HCV genotype and body weight, and highlights several clinical variables that influence the likelihood of an SVR compared with anaemia in chronic hepatitis C patients treated with peginterferon alfa-2a (40KD) plus ribavirin.

Pharmacokinetics of ribavirin in patients with hepatitis C virus.

AIM: A population pharmacokinetic analysis was performed using plasma concentration data (n = 7025) from 380 patients to examine the relationship between ribavirin dose and its pharmacokinetics. METHODS: Ribavirin pharmacokinetics were described by a three-compartment model with sequential zero-order and a first-order absorption processes. Interoccasion variability and food effects were included. RESULTS: Lean body weight (range 41-91 kg) was the only covariate with a clinically significant influence on ribavirin pharmacokinetics, affecting clearance (15.3-23.9 l h(-1)) and the volume of the larger peripheral compartment. CONCLUSION: The model provided a good description of the available data, confirmed by accurate estimates of parameter values and low residual variability (17%).