Model-based evaluation of the impact of formulation and food intake on the complex oral absorption of mavoglurant in healthy subjects.

PURPOSE: To compare the pharmacokinetics of intravenous (IV), oral immediate-release (IR) and oral modified-release (MR) formulations of mavoglurant in healthy subjects, and to assess the food effect on the MR formulation's input characteristics. METHODS: Plasma concentration-time data from two clinical studies in healthy volunteers were pooled and analysed using NONMEM®. Drug entry into the systemic circulation was modelled using a sum of inverse Gaussian (IG) functions as an input rate function, which was estimated specifically for each formulation and food state. RESULTS: Mavoglurant pharmacokinetics was best described by a two-compartment model with a sum of either two or three IG functions as input function. The mean absolute bioavailability from the MR formulation (0.387) was less than from the IR formulation (0.436). The MR formulation pharmacokinetics were significantly impacted by food: bioavailability was higher (0.508) and the input process was shorter (complete in approximately 36 versus 12 h for the fasted and fed states, respectively). CONCLUSIONS: Modelling and simulation of mavoglurant pharmacokinetics indicate that the MR formulation might provide a slightly lower steady-state concentration range with lower peaks (possibly better drug tolerance) than the IR formulation, and that the MR formulation's input properties strongly depend on the food conditions at drug administration.

Population Pharmacokinetic-B Cell Modeling for Ofatumumab in Patients with Relapsing Multiple Sclerosis.

BACKGROUND: Ofatumumab, a fully human anti-CD20 monoclonal antibody indicated for the treatment of relapsing forms of multiple sclerosis (RMS), binds to a unique conformational epitope, thereby depleting B cells very efficiently and allowing subcutaneous administration at lower doses. OBJECTIVES: The aims were to characterize the relationship between ofatumumab concentration and B cell levels, including the effect of covariates such as body weight, age, or baseline B cell count, and use simulations to confirm the chosen therapeutic dose. METHODS: Graphical and regression analyses previously performed based on data from a dose-range finding study provided the B cell depletion target used in the present work. All available adult phase 2/3 data for ofatumumab in RMS patients were pooled to develop a population pharmacokinetics (PK)-B cell count model, using nonlinear mixed-effects modeling. The population PK-B cell model was used to simulate B cell depletion and repletion times and the effect of covariates on PK and B cell metrics, as well as the dose response across a range of subcutaneous ofatumumab monthly doses. RESULTS: The final PK-B cell model was developed using data from 1486 patients. The predetermined B cell target was best achieved and sustained with the 20-mg dose regimen, with median B cell count reaching 8 cells/µL in 11 days and negligible repletion between doses. Only weight had a significant effect on PK, which did not translate into any clinically relevant effect on B cell levels. CONCLUSION: The PK-B cell modeling confirms the dose chosen for the licensed ofatumumab regimen and demonstrates no requirement for dose adjustment based on adult patient characteristics.

Model-based analyses of bioequivalence crossover trials using the stochastic approximation expectation maximisation algorithm.

In this work, we develop a bioequivalence analysis using nonlinear mixed effects models (NLMEM) that mimics the standard noncompartmental analysis (NCA). We estimate NLMEM parameters, including between-subject and within-subject variability and treatment, period and sequence effects. We explain how to perform a Wald test on a secondary parameter, and we propose an extension of the likelihood ratio test for bioequivalence. We compare these NLMEM-based bioequivalence tests with standard NCA-based tests. We evaluate by simulation the NCA and NLMEM estimates and the type I error of the bioequivalence tests. For NLMEM, we use the stochastic approximation expectation maximisation (SAEM) algorithm implemented in monolix. We simulate crossover trials under H(0) using different numbers of subjects and of samples per subject. We simulate with different settings for between-subject and within-subject variability and for the residual error variance. The simulation study illustrates the accuracy of NLMEM-based geometric means estimated with the SAEM algorithm, whereas the NCA estimates are biased for sparse design. NCA-based bioequivalence tests show good type I error except for high variability. For a rich design, type I errors of NLMEM-based bioequivalence tests (Wald test and likelihood ratio test) do not differ from the nominal level of 5%. Type I errors are inflated for sparse design. We apply the bioequivalence Wald test based on NCA and NLMEM estimates to a three-way crossover trial, showing that Omnitrope®; (Sandoz GmbH, Kundl, Austria) powder and solution are bioequivalent to Genotropin®; (Pfizer Pharma GmbH, Karlsruhe, Germany). NLMEM-based bioequivalence tests are an alternative to standard NCA-based tests. However, caution is needed for small sample size and highly variable drug.

Bioequivalence tests based on individual estimates using non-compartmental or model-based analyses: evaluation of estimates of sample means and type I error for different designs.

PURPOSE: The main objective of this work is to compare the standard bioequivalence tests based on individual estimates of the area under the curve and the maximal concentration obtained by non-compartmental analysis (NCA) to those based on individual empirical Bayes estimates (EBE) obtained by nonlinear mixed effects models. METHODS: We evaluate by simulation the precision of sample means estimates and the type I error of bioequivalence tests for both approaches. Crossover trials are simulated under H ( 0 ) using different numbers of subjects (N) and of samples per subject (n). We simulate concentration-time profiles with different variability settings for the between-subject and within-subject variabilities and for the variance of the residual error. RESULTS: Bioequivalence tests based on NCA show satisfactory properties with low and high variabilities, except when the residual error is high, which leads to a very poor type I error, or when n is small, which leads to biased estimates. Tests based on EBE lead to an increase of the type I error, when the shrinkage is above 20%, which occurs notably when NCA fails. CONCLUSIONS: For small n or data with high residual error, tests based on a global data analysis should be considered instead of those based on individual estimates.

Comparison of the Efficacy of Brolucizumab with Natural Disease Progression in Wet AMD Using Clinical Data from the Phase III HAWK and HARRIER Trials and Modelled Placebo Data.

Aim: To compare the treatment effect of brolucizumab, a novel anti-vascular endothelial growth factor therapeutic, with a putative placebo in patients with wet age-related macular degeneration. Materials and Methods: Clinical treatment-effect data from patients receiving brolucizumab 6 mg in the HAWK and HARRIER studies were compared with modelled placebo data using a previously developed and validated indirect response, non-linear, mixed effects model describing the natural visual acuity decline in wet age-related macular degeneration. The placebo model incorporated patient-level data from the sham injection arms of the MARINA and PIER studies, corrected for baseline best corrected visual acuity and age difference between these studies and the HAWK and HARRIER studies. Results: Compared with a modelled placebo, brolucizumab treatment was associated with an overall best corrected visual acuity gain of approximately 22 Early Treatment Diabetic Retinopathy Study letters at Week 48 and 28 letters at Week 96. Conclusions: As anti-vascular endothelial growth factor therapy is now a standard of care for wet age-related macular degeneration, it is not feasible to conduct placebo-controlled trials for new wet age-related macular degeneration treatments. By allowing comparison with the natural decline in visual acuity without treatment, this analysis conveys the clinical importance of brolucizumab for the treatment of wet age-related macular degeneration.

Dose-response analysis of ranibizumab as-needed regimens for visual improvement in patients with diabetic macular edema using a modelling approach.

BACKGROUND: Ranibizumab and aflibercept are anti-vascular endothelial growth factor therapies for diabetic macular edema (DME) but have only been directly compared in one study: the Protocol T study, a 24-month randomized controlled trial which compared the safety and efficacy of three anti-VEGF agents (ranibizumab 0.3 mg, aflibercept 2.0 mg and bevacizumab 1.25 mg). The ranibizumab dose used in Protocol T is not licensed for use outside of the US, where a higher ranibizumab dose of 0.5 mg is approved. Therefore, the relevance of the head-to-head Protocol T study findings to healthcare providers in Europe is limited. The purpose of this research was to predict the visual outcomes that may have been achieved in Protocol T with ranibizumab 0.5 mg. METHODS: A simplified dose-response model was constructed to describe the relationship between average monthly dose and one-year best corrected visual acuity (BCVA) change from baseline. A linear mixed effects model was evaluated and Bayesian Monte-Carlo Markov chains method was used to estimate the model parameters. RESULTS: If ranibizumab 0.5 mg PRN had been studied in Protocol T, it would have resulted in a BCVA gain of 14-15 early treatment diabetic retinopathy study (ETDRS) letters; 3-4 letters more than the actual BCVA gain reported with ranibizumab 0.3 mg PRN. In Protocol T patients with poor baseline BCVA (<69 letters), a similar additional letter gain would have been achieved. CONCLUSION: The relevance of the Protocol T study findings are limited due to the use of ranibizumab 0.3 mg PRN which, based on the modelling approach reported herein, resulted in sub-optimal visual gains.

The pharmacokinetics, CNS pharmacodynamics and adverse event profile of brivaracetam after multiple increasing oral doses in healthy men.

AIMS: Brivaracetam is a novel synaptic vesicle protein 2A ligand that has shown potent activity in animal models of epilepsy. This study examined the pharmacokinetics, central nervous system pharmacodynamics and adverse event profile of multiple oral doses of brivaracetam in healthy male subjects. METHODS: Three successive panels of 12 healthy male subjects received double-blind brivaracetam 200, 400 or 800 mg day(-1) (all doses well above the expected therapeutic range) or placebo (9 : 3), in two divided doses, for 14 days. RESULTS: Brivaracetam was rapidly absorbed (t(max) approximately 2 h) and eliminated (t(1/2) 7-8 h). Volume of distribution was slightly lower than total body water. A small fraction of the dose (5-8%) was excreted unchanged in urine together with significant levels of metabolites, suggesting predominantly metabolic clearance. Based on 6-beta-hydroxycortisol/cortisol ratios in urine, there was no evidence of induction of CYP3A4 activity. Saliva and plasma brivaracetam levels were highly correlated. Adverse events were mostly mild to moderate, central nervous system-related and resolved within the first day of treatment. No clinically relevant changes were observed in laboratory tests, vital signs, physical examinations or ECGs. Pharmacodynamic tests showed dose-related sedation and decreased alertness that only persisted at 800 mg daily. CONCLUSIONS: Brivaracetam was well tolerated by healthy male volunteers at doses of 200-800 mg daily for 2 weeks, well above the expected clinically effective dose range. Brivaracetam had a favourable pharmacokinetic profile in this population, characterized by rapid absorption, volume of distribution limited to total body water, apparent single-compartment elimination and dose proportionality.

Neovascular Age-Related Macular Degeneration: A Visual Acuity Model of Natural Disease Progression and Ranibizumab Treatment Effect.

Intravitreal ranibizumab is a first-line therapy for neovascular age-related macular degeneration (nAMD), but there is a need to optimize patient outcomes while minimizing treatment burden. Here, we developed an indirect response, nonlinear, mixed effects model of disease progression and drug effect in anti-vascular endothelial growth factor (VEGF) treatment-naïve patients. A total of 1,524 treatment-naïve patients and 29,754 visual acuity observations from the ANCHOR, MARINA, PIER, and EXCITE clinical trials informed the model. The model accurately described natural nAMD disease progression and predicted mean visual acuity gains in the HARBOR study, notably with a 2.0 mg ranibizumab dose not used for model development. Furthermore, individualized treatment regimens were shown by simulation to be a viable alternative to the commonly used pro re nata or fixed monthly dosing regimen approaches. Therefore, this model could be a useful tool to predict the outcomes of different, more patient-tailored treatment regimens in nAMD.

Population pharmacokinetics of levetiracetam in Japanese and Western adults.

OBJECTIVE: To assess the population pharmacokinetics of levetiracetam, a second-generation antiepileptic drug, in adult Japanese and Western populations. METHODS: Data were pooled from ten matched clinical trials conducted in Japan and in Europe and the USA, in which levetiracetam was administered orally to healthy subjects and subjects with epilepsy. Overall, 5408 plasma concentrations were available from 524 subjects in six clinical pharmacology studies and two confirmatory and two long-term safety studies of add-on treatment for partial epilepsy. A one-compartment open model with first-order absorption and elimination was fitted to the plasma concentrations using nonlinear mixed-effects modelling with first-order estimation. RESULTS: Ethnicity had no statistically significant effect on the pharmacokinetics of levetiracetam in the presence of the other covariates. Bodyweight, sex, creatinine clearance and concomitant intake of enzyme inducers or valproic acid had a statistically significant effect on apparent plasma clearance of levetiracetam. Bodyweight, disease and valproic acid had a statistically significant effect on the volume of distribution. Levetiracetam exposure (the area under the plasma concentration-time curve over the 12-hour dosing interval at steady state) was 12% higher in females than in males. Decreasing bodyweight from 70 kg to 40 kg was predicted to increase exposure by 16%, while halving creatinine clearance was predicted to increase exposure by 10%. Enzyme inducers reduced exposure by 8%, while valproic acid resulted in a 23% increase in exposure. The latter effect was assumed to arise from the known association between valproic acid and increased body fat, since levetiracetam is negligibly metabolised by cytochrome P450 enzymes. CONCLUSIONS: Population pharmacokinetic analysis points to the absence of ethnic differences in the pharmacokinetics of levetiracetam between Japanese and Western populations, other than those arising from bodyweight differences. Small, clinically non-relevant differences between individual demographic characteristics suggest that dose adjustment is usually not necessary.

Reduction of a Whole-Body Physiologically Based Pharmacokinetic Model to Stabilise the Bayesian Analysis of Clinical Data.

Whole-body physiologically based pharmacokinetic (PBPK) models are increasingly used in drug development for their ability to predict drug concentrations in clinically relevant tissues and to extrapolate across species, experimental conditions and sub-populations. A whole-body PBPK model can be fitted to clinical data using a Bayesian population approach. However, the analysis might be time consuming and numerically unstable if prior information on the model parameters is too vague given the complexity of the system. We suggest an approach where (i) a whole-body PBPK model is formally reduced using a Bayesian proper lumping method to retain the mechanistic interpretation of the system and account for parameter uncertainty, (ii) the simplified model is fitted to clinical data using Markov Chain Monte Carlo techniques and (iii) the optimised reduced PBPK model is used for extrapolation. A previously developed 16-compartment whole-body PBPK model for mavoglurant was reduced to 7 compartments while preserving plasma concentration-time profiles (median and variance) and giving emphasis to the brain (target site) and the liver (elimination site). The reduced model was numerically more stable than the whole-body model for the Bayesian analysis of mavoglurant pharmacokinetic data in healthy adult volunteers. Finally, the reduced yet mechanistic model could easily be scaled from adults to children and predict mavoglurant pharmacokinetics in children aged from 3 to 11 years with similar performance compared with the whole-body model. This study is a first example of the practicality of formal reduction of complex mechanistic models for Bayesian inference in drug development.

Population modeling of filgrastim PK-PD in healthy adults following intravenous and subcutaneous administrations.

Filgrastim is a recombinant human granulocyte colony stimulating factor (G-CSF) that stimulates production of neutrophils. The objective of this analysis was to develop a pharmacokinetic (PK) and pharmacodynamic (PD) model to account for an increase in G-CSF clearance on multiple dosing because of an increase of the G-CSF receptor-mediated endocytosis. Data from 4 randomized studies involving healthy volunteers were used for analysis. Subjects received filgrastim (Neupogen) via subcutaneous (SC) and intravenous (IV) routes. Filgrastim was administered SC daily for 1 week at 2.5, 5, and 10 µg/kg doses and as single IV infusions (5 µg/kg over 0.5 hours) and SC (1 µg/kg) doses. PK data comprised serum concentration-time measurements and the blood absolute neutrophil count (ANC) was used for PD evaluations. Population nonlinear mixed-effect modeling was done using NONMEM VI (Version 6.1.0, Icon Development Solutions, Ellicott City, Maryland). The model depicted the decaying trend in C(max) values with repeated doses and an increase in ANC(max) values consistently with an increase in the G-CSF receptor pool. Simulated time courses of the total clearance exhibited an increasing pattern. The increase in filgrastim clearance on multiple dosing was attributed to the increased neutrophil count in the bone marrow and blood paralleled by an increase in the total G-CSF receptor density.

Population pharmacokinetic modelling of filgrastim in healthy adults following intravenous and subcutaneous administrations.

BACKGROUND AND OBJECTIVE: Filgrastim is a human granulocyte-colony stimulating factor (G-CSF). The biological activity of filgrastim is identical to that of endogenous G-CSF. It controls neutrophil production within the bone marrow by stimulating the proliferation, differentiation and survival of myeloid progenitor cells and some end-cell function activation. The purpose of this work is to propose a target-mediated drug disposition pharmacokinetic model of filgrastim. METHODS: A mechanism-based population pharmacokinetic model was developed to account for receptor-mediated endocytosis as a mechanism for nonlinear disposition of G-CSF. Time profiles of serum filgrastim concentrations following subcutaneous doses of 2.5, 5 and 10 microg/kg and intravenous infusion of 5 microg/kg over 0.5 hour were studied. The pharmacokinetic model included first-order elimination from the serum, receptor binding, turnover of free receptors and internalization of drug-receptor complexes. The proposed target-mediated drug disposition models served as a tool to study drug absorption and the impact of receptor binding on filgrastim clearance. RESULTS: Filgrastim was found to exhibit parallel absorption with first- and zero-order kinetics and bioavailability of 69.1%. The majority of the drug (58.6%) was absorbed by zero-order processes, presumably through the lymphatic system. The equilibrium dissociation constant (K(d)) was estimated as 16.38 pM. CONCLUSION: The proposed model predicts that clearance is initially mostly governed by the binding of filgrastim to G-CSF receptors. Subsequently, the clearance slows down because of the saturation of binding sites, and occurs mostly via the linear (renal) pathway. Finally, for G-CSF concentrations lower than the K(d), target-mediated clearance dominates. The presented receptor-mediated model adequately describes filgrastim serum concentrations and quantifies the role of receptor binding in G-CSF clearance.

The pharmacokinetics, CNS pharmacodynamics and adverse event profile of brivaracetam after single increasing oral doses in healthy males.

AIMS: The objective of the study was to evaluate the pharmacokinetics (and how they are affected by food), CNS pharmacodynamics and the adverse event profile of brivaracetam after single increasing doses. METHODS: Healthy males (n = 27, divided into three alternating panels of nine subjects) received two different single oral doses of brivaracetam (10-1400 mg) and one dose of placebo during three periods of a randomized, double-blind, placebo-controlled study. The effect of food on its pharmacokinetics was assessed using a standard two-way crossover design in a further eight subjects who received two single oral doses of brivaracetam (150 mg) in the fasting state and after a high fat meal. RESULTS: Adverse events, none of which were serious, were mostly CNS-related and included somnolence, dizziness, and decreased attention, alertness, and motor control. Their incidence, severity and duration were dose-related. The maximum tolerated dose was established to be 1000 mg. Severe somnolence lasting 1 day occurred in one subject following 1400 mg. Brivaracetam was rapidly absorbed under fasting conditions, with a median t(max) of approximately 1 h. C(max) was dose-proportional from 10 to 1400 mg, whereas AUC deviated from dose linearity above 600 mg. A high-fat meal had no effect on AUC (point estimate 0.99, 90%CI: 0.92-1.07) but delayed t(max) (3 h) and decreased C(max) (point estimate 0.72, 90%CI: 0.66-0.79). CONCLUSIONS: Brivaracetam was well tolerated after increasing single doses that represent up to several times the expected therapeutic dose. Brivaracetam was found to have desirable pharmacokinetic properties. The most common adverse events were somnolence and dizziness.