Rivaroxaban has been widely used to prevent and treat various thromboembolic diseases for more than a decade. However, whether a lower dose of rivaroxaban is required for Asians is still debatable. This review aimed to explore the potential ethnic difference in pharmacokinetic/pharmacodynamic (PK/PD) characteristics between Asians and Caucasians. A systematic search was conducted and twenty-four studies were identified, of which 10 were conducted on Asian adults, 11 on predominantly Caucasian adults, and 3 on Caucasian pediatrics. The apparent clearance (CL/F) of rivaroxaban in Caucasian adults with non-valvular atrial fibrillation (6.45–7.64 L/h) was about 31–43% higher than that in Asians (4.46–5.98 L/h) taking 10~20 mg rivaroxaban every 24 h. Moreover, there was no obvious difference in CL/F among Japanese, Chinese, Thai, and Irani people. Regarding PK/PD relationship, prothrombin time was linked to rivaroxaban concentration in a linear or near-linear manner, and Factor Xa activity was linked with the E_max model. The exposure–response relationship was comparable between Asians and Caucasians. Renal function has a significant influence on CL/F, and no covariate was recognized for exposure–response relationship. In conclusion, a lower dose of rivaroxaban might be required for Asians, and further studies are warranted to verify this ethnic difference to facilitate optimal dosing regimens.

Olanzapine is widely used for treating schizophrenia and bipolar I disorder. Due to its high pharmacokinetic variability, several population pharmacokinetic studies have been performed to identify factors contributing to the variability and thus facilitate individualized dosing. This review aims to provide a comprehensive overview of published population pharmacokinetic studies and explore potential covariates. We systematically searched PubMed, Web of Science, and EMBASE databases from their inception to 31 December 2022. Information on the study design, characteristics, and final parameter estimates was summarized and compared. Monte Carlo simulations provided visual predictive distributions to compare eligible studies. Forest plots were constructed to explore the effects of covariates on olanzapine pharmacokinetics. A total of 10 population pharmacokinetic and three population pharmacokinetic/pharmacodynamic studies involving infants, children, adolescents, and adults were finally included. The median apparent clearance was 0.253 L/h/kg in adults, 27-43% lower than that of infants and children. Men and smokers increased the apparent clearance of olanzapine by 32% and 34%, respectively. The concentration required to achieve half of the maximum effect for the Positive and Negative Syndrome Scale total score was 24.80 ng/mL, comparable with 22.32 ng/mL for dopamine D₂ receptor occupancy. A higher dosage may be required for men or heavy smokers than for women or non-smokers to reach the same exposure. Moreover, further population studies are essential to be conducted to clarify the dose-exposure-response relationship of olanzapine. CRD42022368637.

Quetiapine exhibits notable pharmacokinetic and pharmacodynamic (PK/PD) variability, the origins of which are poorly understood. This systematic review summarizes published population PK/PD studies and identifies significant covariates accounting for this variability to inform precision dosing. We systematically searched the PubMed, Web of Science, and Embase databases and compared study characteristics, model parameters, and covariate effects. Visual predictive distributions were used to compare different models. Forest plots and Monte Carlo simulations were used to assess the influence of covariates. Six population PK and three population PK/PD studies were included. The median apparent clearance in adults was 87.7 L/h. Strong and moderate CYP3A4 inducers increased the apparent clearance approximately fourfold, while strong CYP3A4 inhibitors reduced it by 93%. The half-maximum effect concentrations were 82.8 ng/mL for the Brief Psychiatric Rating Scale and 583 ng/mL for dopamine D₂ receptor occupancy. Both treatment duration and quetiapine exposure were associated with weight gain. Concurrent administration of potent or moderate CYP3A4 inducers and inhibitors need to be avoided in quetiapine-treated patients. When co-medication is required, it is recommended to adjust the dosage based on therapeutic drug monitoring. Additional research is warranted to delineate the dose-exposure-response relationships of quetiapine and norquetiapine in pediatrics, geriatrics, hepatically-impaired patients, and women using contraceptives or are pregnant or menopausal. CRD42023446654.

Rivaroxaban is an oral anticoagulant widely used for stroke prevention in patients with non-valvular atrial fibrillation (NVAF). During long-term anticoagulant therapy, delayed or missed doses are ...

Micafungin (MFG) is a widely used echinocandin antifungal agent for treating invasive candidiasis, particularly in critically ill patients. However, its pharmacokinetics can be highly variable in this population. This systematic review aims to summarize population pharmacokinetic models and provide recommendations for its use in intensive care unit (ICU) patients. Monte Carlo simulations were implemented to compare pharmacokinetic parameters and probability of target attainment (PTA) against various Candida species. A total of 16 studies were included, of which 6 studies were conducted in adult ICU patients. The key covariates were body size, liver function, and sepsis-related organ failure assessment score (SOFA) score. The median MFG clearance in adult ICU patients was 30–51% higher than in adult non-ICU patients. For infections with C. albican with MIC below 0.016 mg/L, micafungin dosages of 100 and 150 mg/d were recommended for adult non-ICU and ICU patients, respectively. For C. tropicalis and C. glabrata, 200 and 250 mg/d were recommended, respectively. However, for C. krusei and C. parapsilosis, none of the tested dosage regimens achieved assumed PTA criteria within MIC ranges of 0.125–0.25 mg/L and 0.125–2 mg/L, respectively. Therefore, MFG dosage regimens in ICU and non-ICU patients should be tailored based on the Candida spp. and their respective MIC values.