Methods: A search of publications for population pharmacokinetic analyses of clozapine either in healthy volunteers or patients from inception to April 2019 was conducted in PubMed and SCOPUS databases. Reviews, methodology articles, in vitro and animal studies, and noncompartmental analysis were excluded.
Results: Twelve studies were included in this review. Clozapine pharmacokinetics was described as one-compartment with first-order absorption and elimination in most of the studies. Significant interindividual variations of clozapine pharmacokinetic parameters were found in most of the included studies. Age, sex, smoking status, and cytochrome P450 1A2 were found to be the most common identified covariates affecting these parameters. External validation was only performed in one study to determine the predictive performance of the models.
Conclusions: Large pharmacokinetic variability remains despite the inclusion of several covariates. This can be improved by including other potential factors such as genetic polymorphisms, metabolic factors, and significant drug-drug interactions in a well-designed population pharmacokinetic model in the future, taking into account the incorporation of larger sample size and more stringent sampling strategy. External validation should also be performed to the previously published models to compare their predictive performances.
METHODS: A total of three databases were searched on September 15, 2020: PubMed, Web of Science, and Science Direct. The searches were conducted using a pre-specified search strategy to record studies reported the reproductive number of coronavirus from its inception in December 2019. It includes keywords of coronavirus and its reproductive number, which were combined using the Boolean operators (AND, OR). Based on the included studies, we estimated a summary reproductive number by using the meta-analysis. We used narrative synthesis to explain the results of the studies where the reproductive number was reported, however, were not possible to include in the meta-analysis because of the lack of data (mostly due to confidence interval was not reported).
RESULTS: Total of 42 studies included in this review whereas 29 of them were included in the meta-analysis. The estimated summary reproductive number was 2.87 (95% CI, 2.39-3.44). We found evidence of very high heterogeneity (99.5%) of the reproductive number reported in the included studies. Our sub-group analysis was found the significant variations of reproductive number across the country for which it was estimated, method and model that were used to estimate the reproductive number, number of case that was considered to estimate the reproductive number, and the type of reproductive number that was estimated. The highest reproductive number was reported for the Diamond Princess Cruise Ship in Japan (14.8). In the country-level, the higher reproductive number was reported for France (R, 6.32, 95% CI, 5.72-6.99) following Germany (R, 6.07, 95% CI, 5.51-6.69) and Spain (R, 3.56, 95% CI, 1.62-7.82). The higher reproductive number was reported if it was estimated by using the Markov Chain Monte Carlo method (MCMC) method and the Epidemic curve model. We also reported significant heterogeneity of the type of reproductive number- a high-value reported if it was the time-dependent reproductive number.
CONCLUSION: The estimated summary reproductive number indicates an exponential increase of coronavirus infection in the coming days. Comprehensive policies and programs are important to reduce new infections as well as the associated adverse consequences including death.
METHODS: A pooled population-pharmacokinetic model was built in NONMEM based on data from 14 different studies in different patient populations. Steady-state exposure was simulated and compared across patient subgroups for two US Food and Drug Administration/European Medicines Agency-approved drug labels and optimised doses were derived.
RESULTS: The final model uses postmenstrual age, weight and serum creatinine as covariates. A 35-year-old, 70-kg patient with a serum creatinine level of 0.83 mg dL-1 (73.4 µmol L-1) has a V1, V2, CL and Q2 of 42.9 L, 41.7 L, 4.10 L h-1 and 3.22 L h-1. Clearance matures with age, reaching 50% of the maximal value (5.31 L h-1 70 kg-1) at 46.4 weeks postmenstrual age then declines with age to 50% at 61.6 years. Current dosing guidelines failed to achieve satisfactory steady-state exposure across patient subgroups. After optimisation, increased doses for the Food and Drug Administration label achieve consistent target attainment with minimal (± 20%) risk of under- and over-dosing across patient subgroups.
CONCLUSIONS: A population model was developed that is useful for further development of age and kidney function-stratified dosing regimens of vancomycin and for individualisation of treatment through therapeutic drug monitoring and Bayesian forecasting.