Julia Korell

Nintedanib reduces the rate of decline in forced vital capacity (FVC) in adult patients with idiopathic pulmonary fibrosis (IPF), chronic progressive‐fibrosing interstitial lung diseases (ILDs) and systemic sclerosis‐associated ILD (SSc‐ILD). A pediatric Phase 3 trial (InPedILD) has been conducted in children 6–17 years, and partial extrapolation from adults to pediatrics was performed to support dose selection and benefit–risk assessment in pediatric patients with progressive‐fibrosing ILDs. Previously developed population pharmacokinetic (popPK) and efficacy exposure‐response (ER) meta‐models across all non‐oncologic pulmonary indications of nintedanib in adults were used as a basis for partial extrapolation to pediatric patients. Data from InPedILD and its open‐label extension trial (InPedILD‐ON) were incorporated and a Bayesian approach was utilized to extrapolate PK and FVC‐based efficacy endpoints. PK of nintedanib was adequately described using a similar structure as the adult popPK model. The weight‐based dosing scheme applied in InPedILD resulted in exposures similar to those in adult patients receiving the approved dose of nintedanib 150 mg twice daily. The ER models for FVC %predicted and FVC Z ‐score were similar to those developed in adults. Compared to adults, pediatric patients showed a slower estimated rate of decline for both endpoints. The estimated EC50 and Emax values in children and adolescents were comparable to those in adults. Partial extrapolation from adult to pediatric patients showed that the pre‐defined pediatric dosing regimen resulted in similar nintedanib exposures compared to the efficacious exposures in adults. ER models suggested a similar beneficial treatment effect of nintedanib on FVC in children and adults.

The tyrosine kinase inhibitor, nintedanib, reduces the rate of decline in forced vital capacity (FVC) in a comparable manner in patients with idiopathic pulmonary fibrosis (IPF), other forms of progressive pulmonary fibrosis (PPF), and systemic sclerosis‐associated ILD (SSc‐ILD). The recommended dose of nintedanib in all indications is 150 mg twice daily (BID). Data from Phase II and III trials in IPF, PPF, and SSc‐ILD were incorporated into a meta‐model to holistically investigate the relationship between nintedanib exposure and efficacy. Using data from 2642 patients with IPF, PPF, or SSc‐ILD treated with nintedanib doses ranging from 50 to 150 mg BID, disease progression models with a maximum drug effect on the annual rate of change in absolute FVC (i.e., mL), FVC %predicted, and FVC Z‐score were developed. The estimated plasma concentration producing 50% of the maximum drug effect (EC ₅₀ ) ranged from 6.21 to 10.4 nM (with respect to nintedanib trough concentration) across the explored FVC‐based endpoints. While the disease progression for absolute FVC (mL), FVC %predicted, and FVC Z‐score was different between IPF and PPF patients compared to SSc‐ILD patients, the relative treatment effect of nintedanib, described by a disease‐modifying E _max effect, was comparable across indications. The majority of patients achieve exposure levels at or exceeding the EC ₅₀ with the approved starting dose of 150 mg BID.

The shiny R package has enabled pharmacometrics (PMX) scientists to create and share interactive R‐based tools, or “shiny apps”. Initially, shiny apps are developed ad hoc (i.e. project specific) to provide simulations, and their complexity have evolved to be more general‐purpose and “platform‐like” in recent years. Despite their complexity and increased amount of features, an unexplored aspect is the design considerations for user interface and user experience (UI/UX) to optimize end‐user interactivity and enjoyment.

Background: The drug candidate BI 730357 is a Biopharmaceutics Classification System (BCS) Class II compound showing atypical absorption after oral administration in fasted and fed healthy individuals, for which conventional traditional deconvolution methods could not explain formulation dependencies. Methods: A physiologically based pharmacokinetic (PBPK) model of BI 730357 was developed using the Open Systems Pharmacology (OSP) PBPK software tool PK-Sim^®, which could describe the pharmacokinetics in fasted and fed subjects after single and multiple doses. A Weibull function was used to describe the in vivo formulation kinetics, whereas colonic absorption was adopted as the main driver to describe the late phases of observed pharmacokinetics after oral administration. The food effect was applied using the implemented feature PK-Sim^®. Results: The model accurately predicted an observed itraconazole drug–drug interaction (DDI) in fasted subjects and was used to explore the effects of the strong CYP3A4 inducer rifampicin on the pharmacokinetics of BI 730357 after administration in fed subjects. Conclusions: The combined results suggest that the BI 730357 PBPK model with semi-mechanistic absorption can prospectively explore the effects of CYP3A4 inhibitors and inducers on the pharmacokinetics after administration in fed or fasted subjects within the given dose range.

BI 730357 is investigated as an oral treatment of plaque psoriasis. We analyzed the impact of three dosage regimens on the Psoriasis Area and Severity Index (PASI) response with modeling based on phase I and II data from 109 healthy subjects and 274 patients with moderate‐to‐severe plaque psoriasis. The pharmacokinetics (PK) was characterized by a two‐compartment model with dual absorption paths and a first‐order elimination. Higher baseline C‐reactive protein was associated with lower clearance and patients generally had lower clearance compared with healthy subjects. A bounded integer PK/pharmacodynamic model characterized the effect on the observed PASI. The maximum drug effect was largest for patients with no prior biologic use, smaller for patients with prior use of non‐interleukin‐17 inhibitors, and smallest for patients with prior interleukin‐17 inhibitor use. The models allowed robust simulation of large patient populations, predicting a plateau in PASI outcomes for BI 730357 exposure above 2000 nmol/L.

We describe a parametric time‐to‐event model for idiopathic pulmonary fibrosis (IPF) exacerbations and identify predictors of exacerbation risk using data obtained for the tyrosine‐kinase inhibitor nintedanib in two phase III studies (INPULSIS‐1/2). Parametric survival analysis was performed on time to first exacerbation (censoring on day 372), with univariate analysis to select statistically significant covariates (P = 0.05). Multivariate covariate models were developed using stepwise covariate modeling with forward inclusion (P = 0.05) and backward elimination (P = 0.01). Sixty‐three first exacerbation events were reported across 1,061 subjects in the INPULSIS studies. Baseline and decline of forced vital capacity (FVC)/percent‐predicted FVC (%pFVC), supplemental oxygen use, baseline CO diffusing capacity and age were statistically significant in the univariate analysis. The final covariate model included decline in FVC to week 52, baseline %pFVC, supplemental oxygen use, and age. The developed model may be used to identify patients at high risk of IPF exacerbations and accelerate development of novel treatments.

Schizophrenia is a common disease which is commonly managed using antipsychotic medications (APS). Inadequate response and lack of adherence often prevent optimal therapeutic effectiveness. Monitoring APS concentrations can be useful to help improve outcomes for the patient.

Schizophrenia is a common disease managed by a range of interventions, with the primary treatment being antipsychotic medications (APS). Inadequate response, lack of adherence, and/or adverse events often prevent optimal therapeutic effects or therapeutic efficiency. Monitoring APS plasma concentrations can be used together with a full clinical evaluation to help improve patient care or offer better treatment options for the patient. To enable interpretation of individual risperidone and paliperidone plasma concentrations, we developed “reference ranges,” which consider the expected variability in plasma concentrations between subjects across the population, rather than representing a “therapeutic range” that relates to efficacy and/or safety outcomes. The reference ranges were derived from population pharmacokinetic models, which varied based upon administration route, dose, and time after dose. Good agreement between the proposed reference ranges and external data was obtained through graphical and numerical evaluations, indicating they could be reliably used in clinical practice.