Population pharmacokinetics and covariate analysis of Sym004, an antibody mixture against the epidermal growth factor receptor, in subjects with metastatic colorectal cancer and other solid tumors.

Sym004 is an equimolar mixture of two monoclonal antibodies, futuximab and modotuximab, which non-competitively block the epidermal growth factor receptor (EGFR). Sym004 has been clinically tested for treatment of solid tumors. The present work characterizes the non-linear pharmacokinetics (PK) of Sym004 and its constituent antibodies and investigates two types of covariate models for interpreting the interindividual variability of Sym004 exposure. Sym004 serum concentration data from 330 cancer patients participating in four Phase 1 and 2 trials (n = 247 metastatic colorectal cancer, n = 87 various types advanced solid tumors) were pooled for non-linear mixed effects modeling. Dose regimens of 0.4-18 mg/kg Sym004 dosed by i.v. infusion weekly or every 2nd week were explored. The PK profiles for futuximab and modotuximab were parallel, and the parameter values for their population PK models were similar. The PK of Sym004 using the sum of the serum concentrations of futuximab and modotuximab was well captured by a 2-compartment model with parallel linear and saturable, Michaelis-Menten-type elimination. The full covariate model including all plausible covariates included in a single step showed no impact on Sym004 exposure of age, Asian race, renal and hepatic function, tumor type and previous anti-EGFR treatments. The reduced covariate model contained statistically and potentially clinically significant influences of body weight, albumin, sex and baseline tumor size. Population PK modeling and covariate analysis of Sym004 were feasible using the sum of the serum concentrations of the two constituent antibodies. Full and reduced covariate models provided insights into which covariates may be clinically relevant for dose modifications and thus may need further exploration.

Brivaracetam population pharmacokinetics in children with epilepsy aged 1 month to 16 years.

PURPOSE: The aims of the study were to develop a population pharmacokinetic model of orally administered brivaracetam in paediatric patients and to provide dosing suggestions. METHODS: Analysis included 600 brivaracetam plasma concentrations from a phase 2a study (NCT00422422; N01263) in 96 paediatric patients with epilepsy aged 1 month to 16 years, taking one to three concomitant antiepileptic drugs (AEDs). Pharmacokinetic analysis was performed using non-linear mixed effects modelling, and a stepwise covariate search was used to determine factors influencing brivaracetam clearance. Simulations were performed to investigate dosing regimens. RESULTS: The final model consisted of first-order absorption, single compartment distribution and first-order elimination components with allometric scaling of clearance and volume using lean body weight and fixed allometric exponents. Co-administration with phenobarbital or carbamazepine was associated with a 29% (95%CI 17%/39%) and 32% (22%/42%) decrease in exposure, respectively. Co-administration with valproate was associated with an 11% (1%/23%) increase in exposure. Simulations demonstrated that the majority of children were predicted to have an exposure similar to that in adults, using an age-independent dosing regimen of 2.0 mg/kg bid with a maximum of 100 mg bid for body weight >50 kg. CONCLUSIONS: A paediatric dose adaptation of 2.0 mg/kg twice daily with a maximum of 100 mg twice daily for body weight >50 kg is predicted to ensure steady-state plasma concentrations in the same range as in adult patients receiving 100 mg twice daily (highest recommended dose). Data suggest no need to change brivaracetam dosing when used concomitantly with carbamazepine, phenobarbital or valproate.

Methods and strategies for assessing uncontrolled drug-drug interactions in population pharmacokinetic analyses: results from the International Society of Pharmacometrics (ISOP) Working Group.

The purpose of this work was to present a consolidated set of guidelines for the analysis of uncontrolled concomitant medications (ConMed) as a covariate and potential perpetrator in population pharmacokinetic (PopPK) analyses. This white paper is the result of an industry-academia-regulatory collaboration. It is the recommendation of the working group that greater focus be given to the analysis of uncontrolled ConMeds as part of a PopPK analysis of Phase 2/3 data to ensure that the resulting outcome in the PopPK analysis can be viewed as reliable. Other recommendations include: (1) collection of start and stop date and clock time, as well as dose and frequency, in Case Report Forms regarding ConMed administration schedule; (2) prespecification of goals and the methods of analysis, (3) consideration of alternate models, other than the binary covariate model, that might more fully characterize the interaction between perpetrator and victim drug, (4) analysts should consider whether the sample size, not the percent of subjects taking a ConMed, is sufficient to detect a ConMed effect if one is present and to consider the correlation with other covariates when the analysis is conducted, (5) grouping of ConMeds should be based on mechanism (e.g., PGP-inhibitor) and not drug class (e.g., beta-blocker), and (6) when reporting the results in a publication, all details related to the ConMed analysis should be presented allowing the reader to understand the methods and be able to appropriately interpret the results.

Covariate modeling in pharmacometrics: General points for consideration.

Modeling the relationships between covariates and pharmacometric model parameters is a central feature of pharmacometric analyses. The information obtained from covariate modeling may be used for dose selection, dose individualization, or the planning of clinical studies in different population subgroups. The pharmacometric literature has amassed a diverse, complex, and evolving collection of methodologies and interpretive guidance related to covariate modeling. With the number and complexity of technologies increasing, a need for an overview of the state of the art has emerged. In this article the International Society of Pharmacometrics (ISoP) Standards and Best Practices Committee presents perspectives on best practices for planning, executing, reporting, and interpreting covariate analyses to guide pharmacometrics decision making in academic, industry, and regulatory settings.

Characterization of exposure-response relationships of ipatasertib in patients with metastatic castration-resistant prostate cancer in the IPATential150 study.

PURPOSE: The exposure-response relationships for efficacy and safety of ipatasertib, a selective AKT kinase inhibitor, were characterized using data collected from 1101 patients with metastatic castration-resistant prostate cancer in the IPATential150 study (NCT03072238). METHODS: External validation of a previously developed population pharmacokinetic model was performed using the observed pharmacokinetic data from the IPATential150 study. Exposure metrics of ipatasertib for subjects who received ipatasertib 400 mg once-daily orally in this study were generated as model-predicted area under the concentration-time curve at steady state (AUCSS). The exposure-response relationship with radiographic progression-free survival (rPFS) was evaluated using Cox regression and relationships with safety endpoints were assessed using logistic regression. RESULTS: A statistically significant correlation between ipatasertib AUCSS and improved survival was found in patients with PTEN-loss tumors (hazard ratio [HR]: 0.92 per 1000 ng h/mL AUCSS, 95% confidence interval [CI] 0.87-0.98, p = 0.011). In contrast, an improvement in rPFS was seen in subjects receiving ipatasertib treatment (HR: 0.84, 95% CI 0.71-0.99, p = 0.038) but this effect was not associated with ipatasertib AUCSS in the intention-to-treat population. Incidences of some adverse events (AEs) had statistically significant association with ipatasertib AUCSS (serious AEs, AEs leading to discontinuation, and Grade ≥ 2 hyperglycemia), while others were associated with only ipatasertib treatment (AEs leading to dose reduction, Grade ≥ 3 diarrhea, and Grade ≥ 2 rash). CONCLUSIONS: The exposure-efficacy results indicated that patients receiving ipatasertib may continue benefiting from this treatment at the administered dose, despite some variability in exposures, while the exposure-safety results suggested increased risks of AEs with ipatasertib treatment and/or increased ipatasertib exposures.

Population Pharmacokinetics of Ipatasertib and Its Metabolite in Cancer Patients.

Ipatasertib is a selective AKT kinase inhibitor currently in development for the treatment of several solid tumors, including breast and prostate cancers. This study was undertaken to characterize pharmacokinetic profiles of ipatasertib and its metabolite M1 (G-037720) and to understand the sources of variability. Population pharmacokinetic models of ipatasertib and M1 were developed separately using data from 342 individuals with cancer from 5 phase 1 and 2 studies. The final population pharmacokinetic models for ipatasertib and M1 were 3-compartmental, with first-order elimination and sequential zero- and first-order absorption. Ipatasertib bioavailability and M1 formation increased after multiple dosing, resulting in an increase in exposure beyond that expected from accumulation alone. Covariate effects of ipatasertib include decreased oral clearance with increasing age and with coadministration of abiraterone, as well as decreased bioavailability with increasing weight. For ages 37 and 80 years, steady-state area under the curve (AUCss ) was predicted to be 81% and 109%, respectively, of the typical population value (64 years). For body weight of 49 and 111 kg, AUCss was predicted to be 132% and 78%, respectively, of the typical population value (75 kg). The small magnitude of change in ipatasertib exposure is not likely to be clinically relevant. For M1, the peripheral distribution volume and intercompartmental clearance increased with increasing weight. Coadministration of abiraterone was estimated to increase M1 exposure by 61% at steady state. Mild and moderate renal impairment, mild hepatic impairment, and race were not identified as significant covariates in the final models for ipatasertib and M1.

Basic PK/PD principles of drug effects in circular/proliferative systems for disease modelling.

Disease progression modelling can provide information about the time course and outcome of pharmacological intervention on the disease. The basic PK/PD principles of proliferative and circular systems within the context of modelling disease progression and the effect of treatment thereupon are illustrated with the goal to better understand/predict eventual clinical outcome. Circular/proliferative systems can be very complex. To facilitate the understanding of how a dosing regimen can be defined in such systems we have shown the derivation of a system parameter named the Reproduction Minimum Inhibitory Concentration (RMIC) which represents the critical concentration at which the system switches from growth to extinction. The RMIC depends on two parameters (RMIC = (R(0) - 1) x IC(50)): the basic reproductive ratio (R(0)) a fundamental parameter of the circular/proliferative system that represents the number of offspring produced by one replicating species during its lifespan, and the IC(50), the potency of the drug to inhibit the proliferation of the system. The RMIC is constant for a given system and a given drug and represents the lowest concentration that needs to be achieved for eradication of the system. When exposure is higher than the RMIC, success can be expected in the long term. Time varying inhibition of replicating species proliferation is a natural consequence of the time varying inhibitor drug concentrations and when combined with the dynamics of the circular/proliferative system makes it difficult to predict the eventual outcome. Time varying inhibition of proliferative/circular systems can be handled by calculating the equivalent effective constant concentration (ECC), the constant plasma concentration that would give rise to the average inhibition at steady state. When ECC is higher than the RMIC, eradication of the system can be expected. In addition, it is shown that scenarios that have the same steady state ECC whatever the dose, dosage schedule or PK parameters have also the same average R (0) in the presence of the inhibitor (i.e. R (0-INH)) and therefore lead to the same outcome. This allows predicting equivalent active doses and dosing schedules in circular and proliferative systems when the IC(50) and pharmacokinetic characteristics of the drugs are known. The results from the simulations performed demonstrate that, for a given system (defined by its RMIC), treatment success depends mainly on the pharmacokinetic characteristics of the drug and the dosing schedule.

Changing Body Weight-Based Dosing to a Flat Dose for Avelumab in Metastatic Merkel Cell and Advanced Urothelial Carcinoma.

Avelumab, an anti-programmed death-ligand 1 monoclonal antibody approved for the treatment of metastatic Merkel cell carcinoma and platinum-treated urothelial carcinoma, was initially approved with a 10 mg/kg weight-based dose. We report pharmacokinetic (PK)/pharmacodynamic analyses for avelumab comparing weight-based dosing and a flat 800 mg dose, developed using data from 1,827 patients enrolled in 3 clinical trials (NCT01772004, NCT01943461, and NCT02155647). PK metrics were simulated for weight-based and flat-dosing regimens and summarized by quartiles of weight. Derived exposure metrics were used in simulations of exposure-safety (various tumors) and exposure-efficacy (objective responses; Merkel cell or urothelial carcinoma). Flat dosing was predicted to provide similar exposure to weight-based dosing, with slightly lower variability. Exposure-safety and exposure-efficacy simulations suggested similar benefit:risk profiles for the two dosing regimens. These pharmacometric analyses provided the basis for the US Food and Drug Administration approval of a flat dose of avelumab 800 mg every 2 weeks in approved indications.

Time-Varying Clearance and Impact of Disease State on the Pharmacokinetics of Avelumab in Merkel Cell Carcinoma and Urothelial Carcinoma.

Avelumab, a human anti-programmed death ligand 1 immunoglobulin G1 antibody, has shown efficacy and manageable safety in multiple tumors. A two-compartment population pharmacokinetic model for avelumab incorporating intrinsic and extrinsic covariates and time-varying clearance (CL) was identified based on data from 1,827 patients across three clinical studies. Of 14 tumor types, a decrease in CL over time was more notable in metastatic Merkel cell carcinoma and squamous cell carcinoma of the head and neck, which had maximum decreases of 32.1% and 24.7%, respectively. The magnitude of reduction in CL was higher in responders than in nonresponders. Significant covariate effects of baseline weight, baseline albumin, and sex were identified on both CL and central distribution volume. Significant covariate effects of black/African American race, C-reactive protein, and immunogenicity were found on CL. None of the covariate or time-dependent effects were clinically important or warranted dose adjustment.

A receptor theory-based semimechanistic PD model for the CCR5 noncompetitive antagonist maraviroc.

AIM: To develop a novel combined viral dynamics/operational model of (ant-)agonism that describes the pharmacodynamic effects of maraviroc, a noncompetitive CCR5 inhibitor, on viral load. METHODS: A common theoretical framework based on receptor theory and the operational model of (ant-)agonism has been developed to describe the binding of maraviroc to the CCR5 receptor and the subsequent decrease in viral load. The anchor point of the operational model in the differential equations of the viral dynamic model is the infection rate constant; this is assumed to be dependent on the number of free activated receptors on each target cell. RESULTS: The new model provides one explanation for the apparent discrepancy between the in vivo binding of maraviroc to the CCR5 receptor (K(D) = 0.089 ng ml(-1)) and the estimated in vivo inhibition (IC(50) = 8 ng ml(-1)) of the infection rate. The estimated K(E) value of the operational model indicates that only 1.2% of free activated receptors are utilized to elicit 50% of the maximum infection rate. CONCLUSIONS: The developed model suggests that the target cells, when activated, express more receptors (spare receptors) than needed. In the presence of maraviroc these spare receptors first require blocking before any decrease in the infection rate, and consequently in the viral load at equilibrium, can be detected. The model allows the simultaneous simulation of the binding of maraviroc to the CCR5 receptor and the change in viral load after both short- and long-term treatment.

Extrapolation of a Brivaracetam Exposure-Response Model from Adults to Children with Focal Seizures.

INTRODUCTION: Prediction of brivaracetam effects in children was obtained by scaling an existing adult pharmacokinetic/pharmacodynamic (PK/PD) model for brivaracetam to children, using an existing population PK model for brivaracetam in children. The scaling was supported by estimating the change from adults to children in the concentration-effect relationship parameters for levetiracetam, a compound interacting with the same target protein (synaptic vesicle protein SV2A). METHODS: The existing adult PK/PD model for brivaracetam was applied to a combined adult-pediatric dataset of levetiracetam. This model was then used to predict the effective oral twice-daily dose of brivaracetam in children aged ≥4 to <16 years as adjunctive treatment for focal (partial onset) seizures. The existing model described daily seizure counts using a negative binomial distribution, taking previous-day seizure frequencies into account, and using a mixture model to separate 'placebo-like' and 'responder' subpopulations. The model was adapted to describe aggregated monthly seizure counts for adult patients in the levetiracetam studies: daily seizure counts were only available for children in the levetiracetam studies. RESULTS: The levetiracetam PK/PD model successfully described both the adult and pediatric data using the same drug effect parameters, and using a model structure similar to the existing adult brivaracetam PK/PD model. CONCLUSION: Simulation with the adult brivaracetam PK/PD model in combination with an existing pediatric brivaracetam population PK model allowed characterization of the dose-response curve, suggesting maximum response at brivaracetam 4 mg/kg/day dosing (capped at 200 mg/day, the maximum adult dose) in children aged ≥4 years.

Evaluation of brivaracetam efficacy as monotherapy in adult patients with focal seizures.

Brivaracetam is a selective, high-affinity ligand for synaptic vesicle protein 2A, recently approved as adjunctive therapy in the treatment of focal (partial-onset) seizures in patients 16 years of age and older with epilepsy. The goal of the present analysis was to determine if the dose-response of brivaracetam as monotherapy would fall within the range associated with brivaracetam efficacy as adjunctive therapy. An existing brivaracetam population pharmacokinetic model consisting of first-order absorption, single compartment distribution, and first-order elimination components was extended by estimating the clearance changes due to co-administration of 12 widely prescribed AEDs. Data for the population pharmacokinetic analysis originated from three Phase III add-on trials and two terminated Phase III monotherapy trials. An existing population model of daily seizure rate versus brivaracetam daily average concentration was applied to the data from the three add-on trials. Simulations allowed the assessment of the combined impact of covariate effects on both the pharmacokinetics and the pharmacodynamics of brivaracetam, and indicated that in the absence of other AEDs, only marginal changes in the overall dose-response relationship would be expected. This suggests that brivaracetam can be used as monotherapy without dose modifications.

Brivaracetam Population Pharmacokinetics and Exposure-Response Modeling in Adult Subjects With Partial-Onset Seizures.

Brivaracetam is a selective high-affinity ligand for synaptic vesicle protein 2A, recently approved as adjunctive therapy in the treatment of partial-onset (focal) seizures in patients 16 years of age and older with epilepsy. A population pharmacokinetic (PK) model and a population pharmacokinetic/pharmacodynamic (PKPD) model were developed describing brivaracetam plasma concentration and the relationship with daily seizure counts in adequate well-controlled efficacy trials. The effect of body weight on clearance and volume was implemented using allometric scaling, and a range of covariates were investigated for their influence on brivaracetam clearance. The PKPD model described daily seizure counts using a negative binomial distribution, taking previous day seizures into account, and using a mixture model to separate "placebo-like" and "response" subpopulations. The PK and PKPD models provided a good description of the data, documented using visual predictive checks. Coadministration with carbamazepine, phenytoin, and phenobarbital decreased brivaracetam exposure by 26%, 21%, and 19%, respectively, without significant effects on PD response. Covariate analysis indicated that levetiracetam coadministration reduced the fraction of subjects in the mixture model response population to 4% and identified baseline seizure frequency as a strong predictor for being assigned to the mixture model response population. Simulation allowed characterization of the dose-response curve, suggesting maximum response is obtained at brivaracetam 150-200 mg/day.

Evaluation of the effects of the weak CYP3A inhibitors atorvastatin and ethinyl estradiol/norgestimate on lomitapide pharmacokinetics in healthy subjects.

Lomitapide is a microsomal triglyceride transfer protein inhibitor approved as an adjunctive treatment for adult patients with homozygous familial hypercholesterolemia. Lomitapide is extensively metabolized via cytochrome P450 3A (CYP3A) and is a weak CYP3A inhibitor. Two phase 1 open-label, randomized (1:1), 2-arm drug interaction studies in healthy subjects assessed the effects of atorvastatin and ethinyl estradiol (EE)/norgestimate, both weak CYP3A inhibitors, on lomitapide pharmacokinetics with staggered (separated by 12 hours) or simultaneous administration. All subjects received a single dose of lomitapide (20 mg) in the evening on day 1. Atorvastatin (80 mg once daily, n = 32) or EE/norgestimate (0.035/0.25 mg once daily, n = 32) dosing was initiated on days 11 or 8, respectively, with evening (arm 1) or morning (arm 2) dosing; at steady state (days 15 or 22), a single lomitapide dose was administered; CYP3A inhibitor dosing continued for 6 days. Blood samples for pharmacokinetic analysis were taken until 168 hours postdose. With atorvastatin, lomitapide exposure was increased by approximately 2-fold and 1.3-fold, respectively, with simultaneous and staggered administration, respectively. Simultaneous and staggered EE/norgestimate and lomitapide administration resulted in an approximately 1.3-fold increase in lomitapide exposure. Reductions in lomitapide dose may be required for some patients when administered concomitantly with a weak CYP3A inhibitor.

Population pharmacokinetic analysis of certolizumab pegol in patients with Crohn's disease.

Certolizumab pegol (CZP), an anti-tumor necrosis factor α agent, is an effective therapy for Crohn's disease (CD). A population pharmacokinetic (PK) analysis of subcutaneously administered CZP was performed using data from 2157 CD patients from 9 separate studies. The aim was to determine which covariates influence the disposition of CZP. The final CZP population PK model consisted of a baseline, first-order absorption, and 1-compartment disposition. CZP antibodies were treated as a structural model covariate and caused apparent clearance (CL/F) to increase from 0.685 to 2.74 L/day. Body surface area (BSA) influenced both CL/F and apparent volume of distribution (V/F) in a linear fashion; both parameters increased by more than 53% and 49%, respectively, across the range of BSA measurements in the data. Albumin influenced CZP CL/F in a nonlinear fashion; CL/F decreased from 1.05 to 0.613 L/day with increasing albumin concentrations in antibody-negative patients. C-reactive protein (CRP) had a borderline influence and CL/F increased by more than 20% across the range of CRP measurements in the data set. Race had a minor influence on V/F. The determined covariates' impact on CZP disposition may be of clinical utility in CZP therapy of CD patients when the PK/pharmacodynamic relationship becomes available.

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%).

A guide for reporting the results of population pharmacokinetic analyses: a Swedish perspective.

Population pharmacokinetic analyses are frequently part of regulatory submissions and are mainly used to provide information on special populations (effects of age, renal impairment, etc) and drug-drug interactions. A varying standard of population analysis reports has been received at the Medical Products Agency in Sweden, some very good and some unassessable. In the latter case, it may be that it is a report of an inadequate analysis or may be a report of a perfectly acceptable analysis, but too little detail has been provided in the report for the conclusions reached to be properly assessed. A sufficient level of detail must be present in these reports in order for them to be assessable and to allow the conclusions reached to be incorporated into the summary of product characteristics. The report should specify the goal(s) of the analysis, describe in detail the origin and nature of the data, clearly describe the model-building process, include a range of goodness of fit (GOF) plots to support decisions made during the model-building process, and demonstrate that the final model is a good description of the data. The use of color in GOF plots is encouraged so that key features are easily visible. Covariate effects in the final model should be clearly presented and their clinical relevance discussed. In the case of many covariates in the final model, it may be useful to perform some simulations to illustrate the effect of various covariate combinations for a series of different "typical" subjects.