The Time is Now: Model-Based Dosing to Optimize Drug Therapy

Abstract

Historical perspective The underpinnings for model-based dosing to support clinical decisions were laid in the late 1960s [1,2]. A seminal paper in 1977 further laid down the principles and methods required to implement individualized dosing into routine patient care [3]. Although these concepts have been utilized with significant impact in advancing model-informed drug development over the last 40 years, little progress has been made in advancing clinical therapeutics on an individual patient level. However, the tide is changing and many of the intellectual and technological barriers are no longer impeding the progress toward a more data-driven and model-informed individualized dosing paradigm for routine clinical care. The challenge for model-based dosing lies in the idea that drug development programs are often incentivized to devise dosing recommendations in the product label primarily for ease of prescribing. This extends to the dosing guidelines for special populations where the label specifies dosing based on certain cut-points for prognostic factors such as age, weight, kidney function or disease status. Historically, the primary reason for such simplified label recommendations was to facilitate approval for the average patient. This, however, is no longer the case as advances in quantitative clinical sciences (e.g., pharmacometrics) and technology enable an individualized approach to drug therapy. For much therapeutics this signifies an important paradigm shift from a predefined dose to a more tailored and personalized dose aimed to increase efficacy and reduce toxicity. Focus should now turn to multidisciplinary, interprofessional education for future trainees (both professionals and graduates) with modern tools designed to support clinical decision-making for individualized therapy. The utility of model-based dosing & example of busulfan Patient, disease and drug characteristics define the need and utility of model-based dosing for drugs [4]. Factors for which model-based dosing can be particularly impactful include complex patient populations such as pediatrics, drugs with a narrow therapeutic index and drugs with significant association with morbidity and mortality [5–8]. Examples of model-based dosing to address clinically relevant challenges currently exist in different therapeutic areas. However their large-scale implementation into routine clinical practice has yet to be achieved. The overarching goal of model-based dosing is to effectively treat diseases without acute toxicity and to prevent long-term side effects of drug therapy. For example, in pediatrics it is well-recognized that the pharmacokinetics (PK) and pharmacodynamics of drugs in infants can differ widely between children and adults [9]. Within the first year of life, age-related developmental changes in physiologic and metabolic processes can lead to significantly altered drug disposition [10]. Additionally, the relationship between dose, plasma concentration and pharmacodynamics effect may be highly variable across different age groups and disease states. An example of how model-based dosing can be applied to patient care is the use of busulfan, an alkylating agent, commonly used in the setting of pediatric autologous and allogeneic hematopoietic cell transplantation (HCT). Therapeutic drug monitoring (TDM) is routinely performed in children receiving busulfan as a part of high-dose chemotherapy prior to HCT to optimize systemic exposure. Several strategies for monitoring drug levels exist,