Drug Interaction Between Favipiravir and Warfarin: A Case Series.

Introduction: Initiating favipiravir in COVID-19 patients with long-term warfarin use can lead to increased INR. However, data on the onset and duration of the increasing INR are limited. Method: We reviewed patient charts to include COVID-19 adult patients who received favipiravir for at least 5 days and used warfarin at the same dose for at least 12 weeks. Data on demographics, comorbidities, other medical characteristics, international normalized ratio (INR), and signs of bleeding were collected. Result: Eight patients, with a mean age of 70.88 ± 8.49 years old, received the standard dose of favipiravir. The mean maximum INR (4.30 ± 1.26) was statistically different from the baseline INR (P = .00029) and the change was observed within 4.38 ± 1.99 days after initiating favipiravir. Warfarin was then discontinued without favipiravir discontinuation in most patients, allowing the INR to gradually decrease within 2 to 3 days. Conclusion: Concurrent use of favipiravir and warfarin led to INR prolongation within approximately 4 days. The effect of such interaction can be acute as the prolongation occurred within 1 day in 1 of the patients.

Communication between healthcare professionals and patients with hearing loss: A systematic review and meta-analysis.

PURPOSE: We aimed to systematically review and meta-analyze published evidence on modes of communication between healthcare professionals and patients with hearing loss. METHODS: MEDLINE/PubMed, Scopus, CINAHL, ScienceDirect, and Thai Journals Online Complete databases were searched. A meta-analysis was performed using a random-effects model. Data on the prevalence and types of communication between healthcare professionals and patients with any extent of hearing loss were extracted. RESULTS: Twenty studies were included. Using a hearing aid (pooled prevalence, 57.4%; 95% CI, 11.4%-103.4%, N = 3, I2 = 99.33) and gestures (pooled prevalence = 54.8%, 95%CI: 17.4% to 92.1%, N = 7, I2 = 99.68) were the most commonly reported modes of communication. Few healthcare professionals could use sign language, and limited access to qualified interpreters was common. CONCLUSION: Communication barriers exist. Qualified sign language interpreters and assistive technology should be used to improve communication.

Genetic alterations in myeloid sarcoma among acute myeloid leukemia patients: insights from 37 cohort studies and a meta-analysis.

Introduction: Variations in mutation rates among acute myeloid leukemia (AML) patients with myeloid sarcoma (MS) underscore the need for a thorough examination. This meta-analysis was conducted to fill the information gap concerning mutation frequencies in AML patients presenting with MS. Materials and methods: This study included retrospective and prospective cohorts. It examined genetic alterations in AML patients with and without MS across all age groups. The search strategy employed terms such as "acute myeloid leukemia," "extramedullary," "granulocytic sarcoma," "myeloid sarcoma," and "leukemic cutis" in the EMBASE, MEDLINE, and Scopus databases. Excluded from the study were reviews, case reports, and case series with fewer than 10 cases. Statistical analyses were performed with Review Manager 5.4 software. Results: The primary analysis incorporated data from 37 cohorts involving 5646 diagnosed AML patients and revealed a 17.42% incidence of MS. The most prevalent mutation among AML patients with MS was FLT3-ITD, with a pooled prevalence of 17.50% (95% CI 12.60% to 22.50%; I2 82.48%). The dominant fusion gene was RUNX1::RUNX1T1, displaying a pooled prevalence of 28.10% (95% CI 15.10% to 41.20%; I2 96.39%). In comparison, no significant intergroup differences were observed for NPM1, FLT3-ITD, KIT, and IDH2 mutations. Interestingly, the CEBPA mutation exhibited protective effects for MS patients, with an odds ratio of 0.51 (95% CI 0.32 to 0.81; I2 0%). Conversely, the NRAS mutation was associated with an increased risk of MS development, with an odds ratio of 5.07 (95% CI 1.87 to 13.73; I2 0%). Conclusion: This meta-analysis sheds light on the prevalence of genetic mutations in AML patients with MS, providing insights into the unique characteristics of the mutations and their frequencies. These discoveries are crucial in informing therapeutic and prognostic decisions for individuals with myeloid sarcoma.

After morning, phew! A knowledge, attitudes, and practices survey related to emergency oral contraception in Thai pharmacists.

INTRODUCTION: Pharmacists' knowledge and attitude toward Emergency Oral Contraception (EOC) can affect users' access to EOCs, especially where EOCs are provided by pharmacists without the need for prescriptions. We conducted a Knowledge, Attitudes, and Practice (KAP) survey on Thai pharmacists to better understand KAP related to EOCs and the correlation among KAP components. METHODS: An in-depth interview, GoogleTrend search, and Pantip.com search were conducted. The findings, together with data from a previously published systematic review and meta-analysis, were used to develop KAP survey questions which were distributed online. Spearman's rank correlation coefficient and linear mixed model were used to investigate the correlation and association among KAP components. RESULTS: The in-depth interview with pharmacists showed that sex and unwanted pregnancy are very sensitive topics in Thailand. Sex and EOC education should be provided by parents and healthcare professionals at a young age. This agreed with opinions from Thai internet users that sex literacy was generally low and sex education was not provided adequately. From the total of 421 survey responses, Thai pharmacists had average knowledge, poor attitude, and average practice related to EOCs (median score = 51.02%, 21.81%, and 60.0%, respectively). The correlations between KAP in pharmacists were weak (ρ = 0.107-0.525, p < 0.02). Pharmacists who rated themselves as having higher scores in knowledge and attitude also rated themselves higher in the practice score. However, the total scores describing the knowledge of or attitude toward EOCs were not associated with EOC practice scores. CONCLUSIONS: In Thai pharmacists, self-rating KAP scores overestimated total KAP scores. The correlation among KAP components was weak. EOC knowledge and attitudes should be promoted, although this may not improve EOC practice in Thai pharmacists.

A systematic review and meta-analysis of the prevalence and association between levonorgestrel and ectopic pregnancy.

BACKGROUND: The use of levonorgestrel emergency oral contraceptives (EOCs) is one of the factors that may be associated with ectopic pregnancy. We aimed to investigate the incidence of ectopic pregnancy in EOC users and the association between EOCs and ectopic pregnancy. RESEARCH DESIGN AND METHODS: We searched for articles that provided the incidence of and the association between levonorgestrel EOCs and ectopic pregnancy in women of reproductive ages in CINAHL Complete, Medline, OpenDissertations, Scopus, Science Direct, and Thai Journal Online. The risk of bias was assessed by Risk Of Bias In Non-randomized Studies or Risk of Bias 2. A meta-analysis was conducted using the random-effects model. RESULTS: We retrieved 1839 nonredundant articles from the systematic search. The meta-analysis showed that the prevalence of ectopic pregnancy was not statistically different from zero (pooled prevalence estimate = 0.029%; 95%CI: -0.006, 0.065; N = 9; I2 = 0) and rare. In addition, levonorgestrel EOCs increased the risk of ectopic pregnancy (OR = 6.17; 95%CI: 3.78, 10.08; N = 5; I2 = 43%). CONCLUSIONS: Women with extrauterine or ectopic pregnancy had higher odds of using levonorgestrel emergency oral contraceptives than those with intrauterine pregnancy. However, the prevalence of ectopic pregnancy is rare.

Efficacy and safety of bromelain: A systematic review and meta-analysis.

Background: Pineapple has an important role in ethnopharmacology and its enzyme, bromelain, has been extensively investigated for its medicinal properties. Aim: This systematic review and meta-analysis aimed to assess clinical evidence concerning the efficacy and safety of bromelain. Methods: A systematic search was conducted from conception to August 2022 using CINAHL Complete, MEDLINE, ScienceDirect, Scopus, and Thai Journal Online (TJO). The risk of bias was assessed using Risk of Bias 2 or ROBIN-I. A random-effect model with inverse variance weighting and DerSimonian and Laird method was used for meta-analysis. The heterogeneity was evaluated by I2 statistics. Results: We included 54 articles for qualitative summary and 39 articles for meta-analysis. The systematic review found that bromelain presented in serum with retained proteolytic activity after oral absorption. Bromelain may be effective against sinusitis but was not effective for cardiovascular diseases. Pain reduction from oral bromelain was slightly but significantly better than controls (mean difference in pain score = -0.27; 95% CI: -0.45, -0.08; n = 9; I2 = 29%). Adverse events included flatulence, nausea, and headache. Topical bromelain significantly reduced the time to complete debridement (mean difference in time = -6.89 days; 95% CI: -7.94, -5.83; n = 4; I2 = 2%). Adverse events may be irrelevant and include burning sensation, pain, fever, and sepsis. Conclusions: Moderate-quality studies demonstrated the potential of oral bromelain in pain control and topical bromelain in wound care. Major health risks were not reported during the treatment with bromelain.

Phytochemicals and Antioxidant Activities of Red Oak, Red Coral and Butterhead.

Lactuca sativa L. is an economically important vegetable that contains numerous phytochemicals. This study aimed to determine the phytochemicals in three lettuce cultivars (red oak, red coral, and butterhead) and assess their total phenolics, total flavonoids and antioxidant activities. The dried leaves of each lettuce cultivar were macerated with hexane, ethyl acetate (EtOAc), and 95% ethanol (EtOH). Total phenolics, total flavonoids, and antioxidant activities from the three solvent extracts were measured. The phytochemical screening showed that the leaves from the three lettuce cultivars contained flavonoids, hydrolyzable tannins, coumarins, steroids, and phenolic compounds. While the EtOAc fraction of the red coral lettuce showed the highest total phenolic content (9.747 ± 0.021 mg gallic acid equivalent/g) and the hexane fraction of the butterhead lettuce contained the highest flavonoids (7.065 ± 0.005 mg quercetin equivalent/g). In the DPPH (2,2-diphenyl-1-picryl-hydrazyl-hydrate) assay, the EtOAc fraction of the red coral lettuce had the highest antioxidant capacity with an IC50 of 0.277 ± 0.006 mg/mL, whereas, in the ABTS (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)) assay, the 95% EtOH of the red coral lettuce had the highest antioxidant capacity with an IC50 of 0.300 ± 0.002 mg/mL. All three lettuce cultivars contained high levels of phenolic content and flavonoids, which are the source of antioxidant activities. These lettuce cultivars, especially the red coral lettuce, are a potential source of natural antioxidants. Further research on the application of natural antioxidants is required to investigate the therapeutic or the neutraceutical implication of the lettuce cultivars.

The development of an in-situ biopolymer-based floating gel for the oral delivery of metformin hydrochloride.

Diabetes remains a global public health threat because of its increasing prevalence and mortality, especially in people under the age of 25. Metformin hydrochloride (HCl), as recommended by American Diabetes Association in 2022, is the first-line therapy for type 2 diabetes in adults. Metformin has low oral bioavailability due to poor permeability. Therefore, by developing metformin HCl oral in situ gel, sustained delivery of metformin can be achieved, thus enhancing the absorption of the drug. Sodium alginate and pectin were used for formulating the system. Different adjuvant polymers, including HPMC K4M, HPMC K100 LV, PEG 4000, and SCMC were used as released-pattern-modifying agents. All formulations could afloat in 0.1 N HCl at the pH of 1.2 within a minute and stay afloat for over 8 h. The optimized formulation could be made from either sodium alginate (2%) and HPMC K4M (0.5%) or pectin (2%) and HPMC K4M (2%). The optimized formulations gradually released metformin HCl with a cumulative release of 80% within 8 h. We successfully developed floating in situ gels that can release metformin HCl sustainedly.

A multidisciplinary approach to verify and de-label of drug allergic histories in a university hospital in Thailand: a retrospective descriptive study.

BACKGROUND: Mislabeling of drug allergic histories causes avoidable negative impacts on patients and healthcare system. Although multidisciplinary adverse drug reaction (ADR) services to verify and de-label drug allergic histories have been operated in particular hospitals in Thailand, their performances have not been reported. This research aimed to examine the effectiveness of verification of drug allergic history and de-labeling (VD) services of the physician-led multidisciplinary ADR clinic. METHODS: This research was a retrospective descriptive study. Medical charts of patients with at least one drug allergic history who received VD services at the multidisciplinary clinic between January 2017 to December 2018, were reviewed. Data on the history of drug allergy, VD services, and results were analyzed and presented using descriptive statistics. RESULTS: Seventy patients' charts were reviewed, and 171 unconfirmed drug allergic histories were identified. 79.53% of the reported reactions involved skin and soft tissues. The most found adverse skin reactions were maculopapular rash, pruritic and erythematous rash, and angioedema. The remaining 20.47% were systemic reactions which included drug reaction with eosinophilia and systemic symptoms (DRESS), anaphylaxis, and nausea/vomiting was the most prevalent. Antituberculosis, beta-lactam antibiotics, and nonsteroidal anti-inflammatory drugs (NSAIDs) were the most reported suspected drugs. Drug allergic history reviewing by physicians or pharmacists could confirm and de-label for 3 and 20 reactions, respectively. Seven and one reactions were confirmed by enzyme-linked immunospot assay and patch test, respectively. The provocation tests with the suspected or alternative drug were conducted in 64 reactions. Twelve reactions were confirmed, and 45 reactions were de-labeled. Totally, 65/171 (38.01%) allergic histories were successfully de-labeled, 23/171 (13.45%) were confirmed, and 83/171 (48.53%) were inconclusive. CONCLUSIONS: More than half of drug allergic histories were successfully confirmed or de-labeled by the multidisciplinary ADR team. The collaborative activities of various healthcare professionals, consisting of physicians, nurse, and pharmacists as presented in the study were effective in VD services and should be implemented in other healthcare settings.

Population pharmacokinetics of doxorubicin: A systematic review.

Because of the high interindividual pharmacokinetic variability, several population pharmacokinetic (PopPK) models of doxorubicin (DOX) were developed to characterize factors influencing such variability. However, significant predictors for DOX pharmacokinetics identified using PopPK models varied across studies. Thus, this review aims to summarize PopPK models of DOX and its metabolites (if any) as well as significant covariates influencing DOX (and its metabolites) pharmacokinetic variability. A systematic search from PubMed, CINAHL Complete, Science Direct, and SCOPUS databases identified 503 studies. Of these, 16 studies met the inclusion criteria and were included in this review. DOX pharmacokinetics was described with two- or three-compartment models. Most studies found a significant increase in DOX clearance with an increase in body surface area from the median value of 1.8 m2 . Moreover, this review identified that while a 10-year increase in patient age resulted in a decrease in DOX clearance in adults and the elderly, younger children had lower DOX clearance compared to older children. Further, low DOX exposure was observed in pregnant women, and thus dosage adjustment is required. Concerning model applicability, predictive performance assessment of these published models should be performed before implementing such models in clinical practice.

Clinical Outcomes of Acute Myeloid Leukemia Patients Harboring the RUNX1 Mutation: Is It Still an Unfavorable Prognosis? A Cohort Study and Meta-Analysis.

Acute myeloid leukemia (AML) with mutated RUNX1 (RUNX1mut) is considered to have an unfavorable prognosis. However, recent studies have reported comparable survival outcomes with wild-type RUNX1 (RUNX1wt). To assess the clinical outcomes of AML with and without RUNX1mut, we performed a prospective cohort study and systematic review and meta-analysis. The study enrolled 135 patients (27 with RUNX1mut; 108 with RUNX1wt). There were no significant differences in the median OS and RFS of the RUNX1mut and RUNX1wt groups (9.1 vs. 12.2 months; p = 0.268 and 7.8 vs. 14.6 months; p = 0.481, respectively). A subgroup analysis of de novo AML patients with intermediate-risk cytogenetics showed similar outcomes. Our meta-analysis pooled data from 23 studies and our study. The complete remission rate was significantly lower in the RUNX1mut group (pooled odds ratio: 0.42). The OS, RFS, and event-free survival rates also favored the RUNX1wt group (pooled risk ratios: 1.36, 1.37, and 1.37, respectively). A subgroup analysis of de novo AML patients with intermediate-risk cytogenetics demonstrated nearly identical OS and RFS outcomes. This study confirms that patients with AML and RUNX1mut had poor prognoses. Nonetheless, in de novo AML with intermediate-risk cytogenetics, the survival outcomes of both groups were comparable.

Predictors of sirolimus pharmacokinetic variability identified using a nonlinear mixed effects approach: a systematic review.

Several sirolimus (SRL) population pharmacokinetics (PopPK) were conducted to explain its pharmacokinetic variability, and the results varied across studies. Thus, we conducted a systematic review to summarize significant predictors influencing SRL pharmacokinetic variability. Moreover, discrepancies in model methodologies across studies were also reviewed and discussed. Four databases (PubMed, CINAHL Complete, Science Direct, and Scopus) were systematically searched. The PICO framework was used to identify eligible studies conducted in humans and employ a nonlinear-mixed effects strategy. Based on the inclusion and exclusion criteria, 20 studies were included. SRL pharmacokinetics were explained using 1- or 2-compartment models. Only one study assessed the model using an external approach, while the rest employed basic or advanced internal approaches. Significant covariates influencing SRL pharmacokinetics were bodyweight, age, CYP3A5 polymorphism, gender, BSA, height, cyclosporine dose or trough concentration, triglyceride, total cholesterol, hematocrit, albumin, aspartate aminotransferase, alanine aminotransferase, and total bilirubin. Of these, bodyweight, age, and CYP3A5 polymorphism were the three most identified significant predictors for SRL clearance. This review summarizes significant predictors to predict SRL clearance, which can subsequently be used to individualize SRL maintenance dose. However, the PopPK model selected for such prediction should be based on the resemblance of population characteristics between the target population and those used to conduct the model. Moreover, the predictability of the models in the target population should be assessed before implementation in clinical practice.

Safety of Vitamin K in mechanical heart valve patients with supratherapeutic INR: A systematic review and meta-analysis.

BACKGROUND: Patients who had mechanical heart valves and an international normalized ratio (INR) of >5.0 should be managed by temporary cessation of vitamin K antagonist. This study aimed to investigate the safety of low-dose vitamin K1 in patients with mechanical heart valves who have supratherapeutic INR. METHODS: CINAHL, Cochran Library, Clinical trial.gov, OpenGrey, PubMed, ScienceDirect, and Scopus were systematically searched from the inception up to October 2021 without language restriction. Studies comparing the safety of low-dose vitamin K1 treatment in patients with placebo or other anticoagulant reversal agents were included. We used a random-effect model for the meta-analysis. Publication bias was determined by a funnel plot with subsequent Begg's test and Egger's test. RESULTS: From 7529 retrieved studies, 3 randomized control trials were included in the meta-analysis. Pooled data demonstrated that low-dose vitamin K was not associated with thromboembolism rate (risk ratio [RR] = 0.94; 95% CI: 0.19-4.55) major bleeding rate (RR = 0.58; 95% CI: 0.07-4.82), and minor bleeding rate (RR = 0.60; 95% CI: 0.07-5.09). Subgroup and sensitivity analysis demonstrated the nonsignificant effect of low-dose vitamin K on the risk of thromboembolism. Publication bias was not apparent, according to Begg's test and Egger's test (P = .090 and 0.134, respectively). CONCLUSION: The current evidence does not support the role of low-dose vitamin K as a trigger of thromboembolism in supratherapeutic INR patients with mechanical heart valves. Nevertheless, more well-designed studies with larger sample sizes are required to justify this research question.

Nutritional Support with Omega-3 Fatty Acids in Burn Patients: A Systematic Review with Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: In burn patients, the profound effect of nutritional support on improved wound healing and a reduced rate of hospitalization and mortality has been documented. Fish oil as a primary source of omega-3 fatty acids in nutritional support may attenuate the inflammatory response and enhance immune function; however, unclear effects on the improvement of clinical outcomes in burn patients remain. METHODS: The systematic literature review was conducted by searching the electronic databases: Cochrane Library, PubMed, ScienceDirect, and Scopus to assess the randomized controlled trials of nutritional support with omega-3 fatty acids compared to control diets in patients that presented with burns from any causes. RESULTS: Seven trials were included in this meta-analysis. We found no significant differences in length of stay (LOS) (p = 0.59), mortality (p = 0.86), ventilation days (p = 0.16), gastrointestinal complications-e.g., constipation and diarrhea (p = 0.73)-or infectious complications-e.g., pneumonia and sepsis (p = 0.22)-between the omega-3-fatty-acid-receiving group and the control/other diets group. CONCLUSIONS: We did not find a benefit of omega-3 support in reducing the various complications, mortality and LOS in burn patients. Further studies are necessary to find the effect of nutritional support with omega-3 fatty acids over low-fat diets in this population.

A systematic review and meta-analysis of attitude and knowledge involving emergency oral contraceptive use in patients and healthcare providers.

BACKGROUND: Levonorgestrel and ulipristal acetate are common emergency oral contraceptives (EOCs). Lack of knowledge and negative attitude toward EOCs pose barriers to the EOCs access and utilization. AIM: This study aimed to summarize the studies on the knowledge and attitudes of healthcare providers and patients on the use of EOCs. METHOD: A systematic search was conducted from conception to April 2022 using the following databases: CINAHL Complete, MEDLINE, ScienceDirect, Scopus, and Thai Journal Online. Data were extracted independently and were meta-analyzed using DerSimonian and Laird method for the binary random-effects model. RESULTS: 121 articles with a total number of 92,484 participants were included. The awareness of levonorgestrel as an EOC was 66.7% while the awareness of ulipristal acetate as an EOC was 36.9%. EOCs users received EOC information mainly from the internet, media, and friends. We found that 32.2% of EOCs users and providers agreed that EOCs acted post-fertilization, and 39.8% of the prescribers know the correct time to take the pill postcoital. Negative attitudes toward EOC use were found in 25.4% of the participants. For example, 39.4% of the participants agreed that EOCs users had increased sexual activity. CONCLUSION: The awareness of EOCs was low and misunderstandings or negative attitudes towards the use or prescription of EOCs were still prevalent. Educating healthcare providers, using media as educational tools, and improving education and economics can be useful in improving EOC users' awareness, knowledge, and attitude towards EOCs.

Pharmacokinetic Outcomes of the Interactions of Antiretroviral Agents with Food and Supplements: A Systematic Review and Meta-Analysis.

Because pharmacokinetic changes in antiretroviral drugs (ARV), due to their concurrent administration with food or nutritional products, have become a clinical challenge, it is necessary to monitor the therapeutic efficacy of ARV in people living with the human immunodeficiency virus (PLWH). A systematic review and meta-analysis were conducted to clarify the pharmacokinetic outcomes of the interaction between supplements such as food, dietary supplements, and nutrients, and ARV. Twenty-four articles in both healthy subjects and PLWH were included in the qualitative analysis, of which five studies were included in the meta-analysis. Food−drug coadministration significantly increased the time to reach maximum concentration (tmax) (p < 0.00001) of ARV including abacavir, amprenavir, darunavir, emtricitabine, lamivudine, zidovudine, ritonavir, and tenofovir alafenamide. In addition, the increased maximum plasma concentration (Cmax) of ARV, such as darunavir, under fed conditions was observed. Area under the curve and terminal half-life were not significantly affected. Evaluating the pharmacokinetic aspects, it is vital to clinically investigate ARV and particular supplement interaction in PLWH. Educating patients about any potential interactions would be one of the effective recommendations during this HIV epidemic.

Factors influencing methotrexate and methotrexate polyglutamate in patients with rheumatoid arthritis: a systematic review of population pharmacokinetics.

Low dose methotrexate (MTX) is commonly used in the treatment of rheumatoid arthritis. The clinical effect is mediated by its metabolite, methotrexate polyglutamate (MTX-PGn). The drug exhibits high interindividual pharmacokinetic variability and the optimal MTX dose is different among individuals. Thus, several MTX population pharmacokinetic (PopPK) models were developed to characterize factors affecting MTX pharmacokinetic variability. This review summarizes significant predictors for MTX pharmacokinetics and identifies knowledge gaps to be further examined. A total of 359 articles were identified from a systematic search of four databases: PubMed, Science Direct, and CINAHL Complete. Of these eight studies were included. Most studies investigated influential factors on MTX pharmacokinetics, but information on MTX-PGn is limited, with only one study performing a parent-metabolite (MTX-PG3) model. MTX pharmacokinetics was described using a two-compartment model with first-order elimination in most studies, with the MTX clearance ranging from 6.94 to 12.39 L/h. Significant predictors influencing MTX clearance included weight, creatinine clearance, sex, OATP1B3 polymorphism, and MTX multiple dosing. While body mass index and red blood cell counts were significant predictors for MTX-PG3 clearance. Providing that MTX-PGn plays a crucial role in clinical effect, further studies should determine other factors affecting MTX-PGn as well as its relationship with clinical response.

Population Pharmacokinetics of Levetiracetam: A Systematic Review.

BACKGROUND: The use of levetiracetam (LEV) has been increasing, given its favorable pharmacokinetic profile. Numerous population pharmacokinetic studies for LEV have been conducted. However, there are some discrepancies regarding factors affecting its pharmacokinetic variability. Therefore, this systematic review aimed to summarize significant predictors for LEV pharmacokinetics as well as the need for dosage adjustments. METHODS: We performed a systematic search for population pharmacokinetic studies of LEV conducted using a nonlinear-mixed effect approach from PubMed, Scopus, CINAHL Complete, and Science Direct databases from their inception to March 2020. Information on study design, model methodologies, significant covariate-parameter relationships, and model evaluation was extracted. The quality of the reported studies was also assessed. RESULTS: A total of 16 studies were included in this review. Only two studies were conducted with a two-compartment model, while the rest were performed with a one-compartment structure. Bodyweight and creatinine clearance were the two most frequently identified covariates on LEV clearance (CLLEV). Additionally, postmenstrual age (PMA) or postnatal age (PNA) were significant predictors for CLLEV in neonates. Only three studies externally validated the models. Two studies conducted pharmacodynamic models for LEV with relatively small sample size. CONCLUSION: Significant predictors for LEV pharmacokinetics are highlighted in this review. For future research, a population pharmacokinetic-pharmacodynamic model using a larger sample size should be conducted. From a clinical perspective, the published models should be externally evaluated before clinical implementation.

Predictive Performance of Published Tacrolimus Population Pharmacokinetic Models in Thai Kidney Transplant Patients.

BACKGROUND AND OBJECTIVE: Tacrolimus is a narrow therapeutic index drug with high pharmacokinetic variability, and several tacrolimus population pharmacokinetic (PopPK) models were developed to guide individualized drug dosing. These models, however, may not perform well in other clinical settings. Therefore, we aimed to assess the predictive ability of published tacrolimus PopPK models using a dataset of Thai kidney transplant patients. METHODS: The external dataset was retrospectively collected from medical records of Bhumibol Adulyadej Hospital, Thailand. Published tacrolimus PopPK models were systematically searched from PubMed, Science Direct, CINAHL Complete, and Scopus databases. Models conducted using a nonlinear mixed-effects approach with covariate resemblance to our external dataset were selected. The external dataset consisted of Thai kidney transplant patients receiving oral immediate- or extended-release tacrolimus formulations twice or once daily, respectively. Accuracy and precision of predicted concentrations were evaluated using mean absolute prediction error (MAPE), root mean square error (RMSE), and goodness of fit plots. RESULTS: Only three models produced acceptable population predictions with the MAPE of < 50%. By using the Bayesian posthoc estimate of individual pharmacokinetic parameters, all models well performed with the MAPE and RMSE of < 30% and 40%, respectively, except two models; one could not successfully converge and the other substantially underpredicted tacrolimus concentrations. CONCLUSION: We evaluated ten tacrolimus PopPK models, and eight models resulted in satisfactorily individual predicted tacrolimus concentrations in Thai kidney transplant patients and may be used to aid tacrolimus dose adjustment along with a clinical judgment.