How to Handle Delayed or Missed Doses: A Population Pharmacokinetic Perspective

Delayed or missed doses are unavoidable in clinical practice and remain as a challenge that threatens a patient's health and quality-of-life, especially in the pharmacotherapy of chronic disease treatment. Unfortunately, information or guidance concerning the management of delayed or missed doses is scarce, precluding clinicians or clinical pharmacologists from instructing patients in a precision dosing manner. It is therefore urgent to develop remedial strategies to inform patients of alternative dosing regimens in compensation for the loss of efficacy due to delayed or missed doses and minimize unintended clinical consequences. Studies aiming to establish remedial regimens have been conducted since the 1980s for oral contraceptives and antihypertensive agents, using the controlled substitution of placebos for active medications. However, it appeared to be unethical in many areas of pharmacotherapy due to deliberately discontinuing or restarting the medication. Alternatively, pharmacometric modeling and simulation offers an opportunity to investigate the effect of various non-adherence scenarios on pharmacokinetic profiles and establish the optimum remedial dosing regimen in a time-effective and systematical way. This review provides a general overview of procedures and strategies on how to develop remedial dosing regimens based on pharmacometric approaches through the scrutiny of case examples in the literature.