Background Linezolid is often used for the infections caused by drug-resistant Gram-positive bacteria. Recent studies suggested that large between-subject variability (BSV) and within-subject variability could alter drug pharmacokinetics (PK) during linezolid therapy due to pathophysiological changes. Objective The review synthesized information on linezolid population PK studies and summarized the significant covariates that influence the PKs of linezolid. Methods A literature search was performed from PubMed, Web of Science, and Embase from their inception to 30 September 2021. Published studies were included if they contained data analyzing linezolid PK parameters in humans using a population approach with a nonlinear mixed-effects model. Results Twenty-five studies were included in adults and five studies in pediatric patients. One- and two-compartment models were the commonly used structural models for linezolid. Body size [weight, lean body weight, and body surface area], creatinine clearance (CLcr), and age significantly influenced linezolid PK. The median clearance (CL) values (range) in infants [0.128 L/h/kg (0.121-0.135)] and children [0.107 L/h/kg (0.088-0.151)] were higher than in adults [0.098 L/h/kg (0.044-0.237)]. For patients with severe renal impairment (CLcr ≤ 30 mL/min), the CL was 37.2% (15.2-55.3%) lower than in patients with normal renal function. Conclusion Linezolid’s optimal dosage could be adjusted based on the patient’s body size, renal function, and age. More studies are needed to explore the exact mechanism of elimination of linezolid and evaluate PK characteristics in pediatric patients.

Aim This is the first review to summarize the population pharmacokinetic studies of oxcarbazepine and explored the significant covariates that may have an impact on the dosage regimen and clinical use of oxcarbazepine. Methods PubMed and Embase databases were searched before 31 October 2020, and references of all selected studies were further screened to identify the pertinent population pharmacokinetic studies of oxcarbazepine. Relevant information about the identified population pharmacokinetic studies was summarised, and the quality of the reports was evaluated. Moreover, studies among infant, children, and adult patients were compared. Results Twelve studies were included: seven studies enrolled paediatric patients only; two enrolled both paediatric and adult patients; and two enrolled adult patients only. The apparent clearance per weight for children (median: 0.0505 L/h/kg, range: 0.016-0.084) and infants (0.078 L/h/kg) were higher than that for adults (median: 0.036 L/h/kg, range: 0.029-0.06). Furthermore, children had a larger variation on clearance compared to adults. Weight, co-administration with enzyme-inducing antiepileptic drugs, and renal function were found to significantly affect clearance of 10-hydroxycarbazepine. Conclusion The oxcarbazepine dose regimen was dependent on weight, co-administration with enzyme-inducing medications, and renal function. Further study is essential to explore the pharmacodynamics in epilepsy patients and pharmacokinetics of oxcarbazepine in infants.

Aim: Edoxaban is a non-vitamin K antagonist oral anticoagulant (NOAC) widely used for long-term stroke prevention in patients with non-valvular atrial fibrillation (NVAF). Adherence to NOACs is unsatisfactory and decreases over time. The aim of this study was to explore appropriated remedial dosing regimens for non-adherent edoxaban-treated NVAF patients through the Monte Carlo simulation. Methods: Six proposed regimens were compared with the recommendations in the European Heart Rhythm Association (EHRA) guide regarding the trough total deviation time considering both edoxaban plasma concentration and inactive factor Xa activity. Monte Carlo simulations were performed using RxODE based on the published population pharmacokinetics/pharmacodynamics model. Results: The proposed remedial strategies were different from EHRA recommendations and were related to delay duration. The missed dose can be taken immediately if the delay time is within 11 h. When the delay period is between 12 and 19 h, a half dose followed by a regular dosing schedule is recommended. When the delay time exceeds 19 h, a full dose followed by a half dose is preferred compared to that recommended in the EHRA guide. Our proposed strategies resulted in a shorter total deviation time than EHRA guide. Conclusion: PK/PD modelling and simulation are effective in developing and evaluating the remedial strategies of edoxaban, which could help maximize its therapeutic effect.

Background: Rivaroxaban is an oral anticoagulant used widely for stroke prevention in patients with non-valvular atrial fibrillation (NVAF). During long-term anticoagulant therapy, delayed or missed doses are common. However, a lack of practical instructions on remedial methods has created a barrier to maximise the benefit of the medications. This study aimed to explore appropriate remedial dosing regimens for non-adherent rivaroxaban-treated patients. Methods: Monte Carlo simulation based on a previously established rivaroxaban population pharmacokinetic/pharmacodynamic (PK/PD) model for patients with NVAF was employed to design remedial dosing regimens. The proposed regimens were compared with remedial strategies in the European Heart Rhythm Association (EHRA) guide by assessing deviation time in terms of drug concentration, factor Xa activity, and prothrombin time under various scenarios of non-adherence. Results: The proposed remedial dosing regimens were dependent on delay duration. The missed dose should be taken immediately when the delay does not exceed 6 h; a half dose is advisable when the delay is between 6-20 h. A missed dose should be skipped if less than 4 h remains before the next dose. Age or renal function does not significantly influence remedial dosing regimens. The proposed regimens resulted in shorter deviation time than that of the EHRA guide in most non-adherence scenarios. Conclusion: EHRA guide may not provide optimal remedial strategies for rivaroxaban-treated non-adherent patients based on simulation. PK/PD and simulation provide valid evidence on the remedial dosing regimen of rivaroxaban for patients with NVAF, which could help to minimise the risk of bleeding and thromboembolism.