Computing optimal drug dosing with OptiDose: implementation in NONMEM.

Determining a drug dosing recommendation with a PKPD model can be a laborious and complex task. Recently, an optimal dosing algorithm (OptiDose) was developed to compute the optimal doses for any pharmacometrics/PKPD model for a given dosing scenario. In the present work, we reformulate the underlying optimal control problem and elaborate how to solve it with standard commands in the software NONMEM. To demonstrate the potential of the OptiDose implementation in NONMEM, four relevant but substantially different optimal dosing tasks are solved. In addition, the impact of different dosing scenarios as well as the choice of the therapeutic goal on the computed optimal doses are discussed.

Modeling of levothyroxine in newborns and infants with congenital hypothyroidism: challenges and opportunities of a rare disease multi-center study.

Modeling of retrospectively collected multi-center data of a rare disease in pediatrics is challenging because laboratory data can stem from several decades measured with different assays. Here we present a retrospective pharmacometrics (PMX) based data analysis of the rare disease congenital hypothyroidism (CH) in newborns and infants. Our overall aim is to develop a model that can be applied to optimize dosing in this pediatric patient population since suboptimal treatment of CH during the first 2 years of life is associated with a reduced intelligence quotient between 10 and 14 years. The first goal is to describe a retrospectively collected dataset consisting of 61 newborns and infants with CH up to 2 years of age. Overall, 505 measurements of free thyroxine (FT4) and 510 measurements of thyrotropin or thyroid-stimulating hormone were available from patients receiving substitution treatment with levothyroxine (LT4). The second goal is to introduce a scale/location-scale normalization method to merge available FT4 measurements since 34 different postnatal age- and assay-specific laboratory reference ranges were applied. This method takes into account the change of the distribution of FT4 values over time, i.e. a transformation from right-skewed towards normality during LT4 treatment. The third goal is to develop a practical and useful PMX model for LT4 treatment to characterize FT4 measurements, which is applicable within a clinical setting. In summary, a time-dependent normalization method and a practical PMX model are presented. Since there is no on-going or planned development of new pharmacological approaches for CH, PMX based modeling and simulation can be leveraged to personalize dosing with the goal to enhance longer-term neurological outcome in children with the rare disease CH.

Clinically practical pharmacometrics computer model to evaluate and personalize pharmacotherapy in pediatric rare diseases: application to Graves' disease.

Objectives: Graves' disease (GD) with onset in childhood or adolescence is a rare disease (ORPHA:525731). Current pharmacotherapeutic approaches use antithyroid drugs, such as carbimazole, as monotherapy or in combination with thyroxine hormone substitutes, such as levothyroxine, as block-and-replace therapy to normalize thyroid function and improve patients' quality of life. However, in the context of fluctuating disease activity, especially during puberty, a considerable proportion of pediatric patients with GD is suffering from thyroid hormone concentrations outside the therapeutic reference ranges. Our main goal was to develop a clinically practical pharmacometrics computer model that characterizes and predicts individual disease activity in children with various severity of GD under pharmacotherapy. Methods: Retrospectively collected clinical data from children and adolescents with GD under up to two years of treatment at four different pediatric hospitals in Switzerland were analyzed. Development of the pharmacometrics computer model is based on the non-linear mixed effects approach accounting for inter-individual variability and incorporating individual patient characteristics. Disease severity groups were defined based on free thyroxine (FT4) measurements at diagnosis. Results: Data from 44 children with GD (75% female, median age 11 years, 62% receiving monotherapy) were analyzed. FT4 measurements were collected in 13, 15, and 16 pediatric patients with mild, moderate, or severe GD, with a median FT4 at diagnosis of 59.9 pmol/l (IQR 48.4, 76.8), and a total of 494 FT4 measurements during a median follow-up of 1.89 years (IQR 1.69, 1.97). We observed no notable difference between severity groups in terms of patient characteristics, daily carbimazole starting doses, and patient years. The final pharmacometrics computer model was developed based on FT4 measurements and on carbimazole or on carbimazole and levothyroxine doses involving two clinically relevant covariate effects: age at diagnosis and disease severity. Discussion: We present a tailored pharmacometrics computer model that is able to describe individual FT4 dynamics under both, carbimazole monotherapy and carbimazole/levothyroxine block-and-replace therapy accounting for inter-individual disease progression and treatment response in children and adolescents with GD. Such clinically practical and predictive computer model has the potential to facilitate and enhance personalized pharmacotherapy in pediatric GD, reducing over- and underdosing and avoiding negative short- and long-term consequences. Prospective randomized validation trials are warranted to further validate and fine-tune computer-supported personalized dosing in pediatric GD and other rare pediatric diseases.

OptiDose: Computing the Individualized Optimal Drug Dosing Regimen Using Optimal Control.

Providing the optimal dosing strategy of a drug for an individual patient is an important task in pharmaceutical sciences and daily clinical application. We developed and validated an optimal dosing algorithm (OptiDose) that computes the optimal individualized dosing regimen for pharmacokinetic-pharmacodynamic models in substantially different scenarios with various routes of administration by solving an optimal control problem. The aim is to compute a control that brings the underlying system as closely as possible to a desired reference function by minimizing a cost functional. In pharmacokinetic-pharmacodynamic modeling, the controls are the administered doses and the reference function can be the disease progression. Drug administration at certain time points provides a finite number of discrete controls, the drug doses, determining the drug concentration and its effect on the disease progression. Consequently, rewriting the cost functional gives a finite-dimensional optimal control problem depending only on the doses. Adjoint techniques allow to compute the gradient of the cost functional efficiently. This admits to solve the optimal control problem with robust algorithms such as quasi-Newton methods from finite-dimensional optimization. OptiDose is applied to three relevant but substantially different pharmacokinetic-pharmacodynamic examples.